bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison of two induction chemotherapy regimens in combination with radiotherapy in patients with advanced nasopharyngeal carcinoma
Authors: Chua D. T. , Ma J. , Sham J. , Mai H. , Hong M. , Lu T. , Ming H.
Published: March 2020

5535

Background: Prospective randomized trials failed to show any survival benefits associated with the use of induction chemotherapy in nasopharyngeal carcinoma (NPC). Although cisplatin-based regimens were commonly used in these trials, the impact of cisplatin dose was not clear. Methods: Individual patient data of two published phase III trials using different cisplatin-based induction chemotherapy regimens were pooled together for analysis. A total of 365 patients with stage II-IV NPC received either cisplatin & epirubicin (EP, n = 144) or cisplatin, bleomycin & fluorouracil (PBF, n = 221) followed by radiotherapy between September 1989 and July 1994. The mean total cisplatin dose received by patients ranged from 162 mg/m2 in EP group to 232 mg/m2 in PBF group. Median follow-up time was 59 months. Results: The response rates at the end of induction chemotherapy were 86% in PBF group and 84% in EP group. No significant differences in tumor control and survival were observed between the two groups. Five-year overall survival rates were 63% in PBF group and 62.5% in EP group. Five-year loco-regional failure-free rates were 74% in PBF group and 65% in EP group, the difference being not significant after adjusting for stage grouping. Conclusions: No significant difference in treatment outcome was observed in patients using different cisplatin-based induction chemotherapy. The absence of survival benefits in chemotherapy arms was probably not related to the dose-intensity of cisplatin used, and escalating the total cisplatin dose alone in induction chemotherapy is not likely to improve survival.

No significant financial relationships to disclose.
Chemo-selection of patients (pts) for organ preservation in advanced laryngeal cancer: Failure of chemotherapy (CT) as the sole treatment for complete histologic responders (CHR) to neoadjuvant chemotherapy
Authors: Worden F. P. , Wolf G. , Eisbruch A. , Lee J. , Bradford C. , Chepeha D. , Teknos T. , Prince M. , Hogikyan N. , Tsien C. , Urba S.
Published: March 2020

5560

Background: We conducted a phase II organ preservation trial for stage III/IV laryngeal cancer pts in an attempt to identify pts, who were CHR after 1 cycle of induction CT, who might be curable with CT alone. Methods: Pts received 1 cycle of cisplatin 100 mg/m2 & 5-FU 1000 mg/m2/day x 5 days (P+5FU). CHR received 1 cycle of P+5FU, followed by weekly docetaxel (D) 35 mg/m2 x 3 wks, followed by 1 cycle of P+5FU, & no radiotherapy (RT). Pts with >50% (but < 100%) response (PR) received chemoradiation (CRT) with 70 Gy & P 100 mg/m2 days 1, 22, & 43. Pts with < 50% response underwent laryngectomy. Final planned tumor assessment with direct laryngoscopy with biopsy was done 8 wks after CRT or 3 wks after the last cycle of P+5FU (CT alone arm). CHR after CT alone received 2 cycles of P+5FU alternating with 2 cycles of D. CHR after CRT received 2 cycles of P+5FU, & pts with residual disease had planned salvage surgery. Results: 32 eligible pts were enrolled, 24 M; 8 F; median age 56, stage III/IV- 7/25. After 1 cycle CT, 4 pts (13%) had CHR & received CT alone; 24 (75%) had PR & received CRT; 3 had surgery; & 1 refused surgery. Of pts who had CT alone, 4/4 had regional failures; 3/4 underwent neck dissection & 1/4 had laryngectomy & neck dissection; all had adjuvant RT because of multiple nodes or extracapsular spread; 3/4 are alive without disease & 1/4 is dead of complications. 5/24 who received CRT failed; 2/24 had surgery & 3/24 were unresectable. Toxicity: Gr 3/4 granulocytopenia 19%, Gr 3/4 mucositis with CT alone 12.5%. Median follow-up is 16.5 months. 2 yr overall survival is 88.2% (95% CI = 75.3%, 100%). 1 yr disease-free survival (DFS) is 81.8% (CI=67.2%, 96.5%). 2 yr DFS is 76% (CI=58.4%, 93.5%). The proportion of pts alive & free of cancer with intact larynx at 1 yr is 69.1% (CI = 51.9%, 86.3%) & at 2 yrs is 63.8% (CI=45%, 82.5%). 1 pt developed distant metastases. Larynx preservation was achieved in 24 pts (75%). Conclusions: CT alone is not an effective strategy for advanced laryngeal cancer pts, even in CHR after 1 cycle of induction CT, due to high nodal failure rate. Planned integration of early regional control by surgery or lower-dose RT may be necessary to allow treatment approaches that spare selected pts high-dose RT.

No significant financial relationships to disclose.
The role of panendoscopy in the staging of high risk head & neck squamous cell carcinoma prior to therapy: Is it of value?
Authors: Bhandari T.
Published: March 2020

5569

Background: Panendoscopy (triple endoscopy) has historically been advocated to adequately stage patients w/ head & neck squamous cancer, especially in the setting of neoadjuvant therapy. This role is controversial by in view of comparable information provided by current imaging techniques Objective: The primary objective was to analyze the results of panendoscopy in a series of patients enrolled in a neoadjuvant chemo radiation protocol. Methods: We reviewed the panendoscopy results of 69 pts w/ stage III/IV head & neck squamous cell carcinoma (H&N ca) treated w/ neoadjuvant chemo radiation at a single institution from 1996–2005. All pts had detailed laryngoscopy/microlaryngoscopy w/ strategic biopsies, esophago-duodeno-scopy (selected biopsies for Barretts) & placement of percutaneous gastrostomy (PEG) & bronchoscopy washings for cytology. Pts were initially treated w/chemo radiation protocols (H&N 53,67); subsequent protocols utilized induction chemotherapy/chemo radiation (H&N 79,86). Results: Two of 69 pts had malignant cells in bronchial cytology in absence of any lung findings (both were NED at 5 yrs). A radiologically occult primary bronchial cancer was found in an additional pt excluding pt from the protocol. Two pts were diagnosed w/ Barrett’s esophagus; another pt also had a synchronous primary cancer of the cervical esophagus. Nine of 69 pts underwent panendoscopy for cervical metastases from an apparent unknown primary ca (at initial diagnosis). The primary cancer was demonstrated in 6 pts at staging panendoscopy and in another patient at follow up panendoscopy. Conclusion: Panendoscopy is essential in staging high risk H & N ca pts prior to initiation of therapy. A detailed laryngoscopy (micro-laryngoscopy) w/ strategic biopsies is required for adequate staging of all cancers of oropharynx & larynx. Esophago-gastro-duodenoscopy had a low but definable yield, but is also necessary for PEG placement to ensure adequate nutrition during neoadjuvant therapy. Bronchoscopy has a limited role in the absence of radiologic chest findings.

No significant financial relationships to disclose.
Celecoxib (Ce) + exemestane (Ex) versus placebo + Ex in post-menopausal (PM) metastatic breast cancer (MBC) patients (pts): A double-blind phase III GINECO study
Authors: Freyer G. , Debled M. , Geay J. F. , Bachelot T. , Blot E. , Cretin J. , Delozier T. , Mille D. , Ferrero J. M. , Romestaing P. , Pujade-Lauraine E.
Published: March 2020

565

Background: in vitro and in vivo studies suggest that COX-2 inhibitors have proper antitumor effect and could enhance the activity of aromatase inhibitors (AI). Methods: PM first-line MBC pts without previous adjuvant AI were randomized to receive per os until progression either A: Ce (400 mg bid) + Ex (25mg/d) or B: placebo (1 tablet bid) + Ex (25mg/d). PFS was the main end-point. The trial was prematurely stopped (Dec 2004) with 157/342 pts enrolled (A: 74, B: 83 pts) after occurrence of Ce cardio-vascular toxicity in other trials. Results: patient (median age, A:61, B:63 yrs) characteristics were well balanced between A and B (%) : ER and/or PR positive (93, 94), HER2 positive (4, 5), adjuvant chemotherapy (45, 53) or tamoxifen (57, 61), ECOG PS 0–1 (90, 90), visceral (63, 53) or bone involvement (35, 41). Tolerance: compared to placebo (B), pts treated with Ce (A) experienced less gr 2–3 CTCAE: pain (A:52, B:63%), arthralgias (19, 28), asthenia (20, 30), Gr 1–3 insomnia (32, 47), but more hypersentivity reactions (7,0) and oedema (8, 2). Gastro-intestinal toxicity was not increased in A. One episode of paroxystic arythmia occurred in the Ce arm, without complication in a patient with known cardiopathy. Overall response rate was significantly higher in A (35 vs 20%, p=.034). Median PFS in intent-to-treat analysis was similar in A (9.8 months) and B (9.8), but tend to be superior in A (A:12.2, B:9,8, p=.09) in pts who were included at least 3 months before early trial stopping. In addition, PFS was significantly longer in pts treated with Ce +Ex (A: 8.4 months, B: 4.7, p=.019) in the subgroup of pts who developed MBC under Tam or within 12 months after Tam stopping (A: 26, B: 29 pts). Conclusion: The combination of celecoxib and exemestane is promising and should be further explored in MBC with adequate cardiac monitoring.

No significant financial relationships to disclose.
Presence of bone marrow micrometastasis (BMM) in breast cancer patients predicts a poor-prognosis pattern of first distant metastasis: Results from the pooled analysis
Authors: Braun S. , Vogl F. D. , Pantel K.
Published: March 2020

567

Background: As a putative surrogate marker of ubiquitous distant metastasis, which is assessable both at initial diagnosis of breast cancer and during adjuvant therapy, BMM would be a valuable end-point marker for adjuvant clinical trials. Methods: Based on individual pt data of 4,686 breast cancer pts with a 10-year follow-up (median, 62 months), we analyzed distant disease-free survival (DDFS) of BMM+/BMM− pts, and looked specifically into sites of first metastatic relapse, expressed as bone metastasis-free (BFS), visceral metastasis-free (VFS), and multiple metastasis-free survival (MFS; i.e., simultaneous diagnosis of bone and visceral metastases). We performed Kaplan-Meier analysis and computed incidence rates (IR)/ incidence rate ratios (IRR) for the occurrence of metastasis at different sites. Results: BMM were detected in 1,432 (30.6%) of pts overall and significantly more often in pts with subsequent diagnosis of distant metastasis as compared to those who survived without metastases (48.5% vs. 26.0%, P<0.001). BMM+ pts had a significantly shorter DDFS than BMM- pts (IRR 2.36; 95%CI, 2.07–2.69; P<0.001). This was also true when we analyzed either bone (IRR 2.73; 95%CI, 2.27–3.29; P<0.001) or visceral metastases only (IRR, 2.48; 95%CI, 2.11–2.91; P<0.001). Among 952 pts with occurrence of distant metastasis, IR of such an event was 1.28-fold (95%CI, 1.12–1.46; P<0.001) higher in BMM+ pts than in BMM- pts. Among 462 BMM+ pts (but not among those 490 BMM- pts), IRs for MFS were significantly increased as compared to both VFS (IRR 1.72; 95%CI, 1.36–2.18; P<0.001) and BFS (IRR 1.85; 95%CI 1.21–2.06; P=0.001). IR for BFS of BMM+ patients (1.08; 95%CI 0.87–1.34) was not significantly increased over VFS. Conclusion: Our data provide conclusive evidence that presence of BMM predicts an early onset and a poor prognosis pattern of overt distant metastasis. With the similar likelihood of the occurrence of subsequent metastasis in bone and at visceral sites, BMM appears to be a marker of generalized tumor cell spread.

No significant financial relationships to disclose.
Autoimmune hypothyroidism protects against breast cancer development in the elderly
Authors: Sandhu M. , Zagorski B. , Sykora K. , Booth G. , Brezden-Masley C.
Published: March 2020

588

Background: An association between breast cancer and autoimmune hypothyroidism has been suggested. While a biological role for thyroid hormone in breast tumorigenesis has been demonstrated in vitro, epidemiological evidence is lacking. Methods: A retrospective, population-based cohort study was conducted to examine the risk of postmenopausal breast cancer (BRCA) in women with or without autoimmune hypothyroidism, identified on the basis of prescriptions for levothyroxine (LT4). Administrative health records were used to capture information on all women aged 66 and older living in Ontario, Canada at baseline (April 1, 1993 to March 31, 1996) and during a 10-year follow up. Propensity scores were used to create a matched cohort of LT4 and non-LT4 users. Cox proportional hazards modeling was used to evaluate the impact of LT4 use on the 5-year incidence of BRCA and benign breast disease, and on all-cause mortality rates among women diagnosed with breast cancer during follow-up. Results: LT4 users (N=89,093) and non-LT4 users (N=89,093) were well-matched with respect to baseline sociodemographics, estrogen use, comorbidity, and health care utilization, including the likelihood of receiving mammography or a breast biopsy. The 5-year incidence of BRCA was 0.86% in LT4 users compared to 0.97% in non-LT4 users (p=0.002). Adjustment for baseline characteristics did not alter these results (hazard ratio [HR] 0.86; 95% confidence interval [CI] 0.77–0.95; p= 0.004). Among women who developed BRCA, all cause mortality was significantly lower in LT4 users than in non-users (43.9% vs. 56.1%; adjusted HR 0.82; 95% CI 0.70–0.96; p= 0.01). The incidence of benign breast disease did not vary between groups. Conclusions: Elderly women with autoimmune hypothyroidism appeared to have a protective advantage in the incidence of BRCA and in mortality following a breast cancer diagnosis. These results suggest a biological role for thyroid hormone in the development of breast cancer, with a modulating effect of treated autoimmune hypothyroidism in promoting a less aggressive disease course. Further studies exploring the effect of thyroid hormone in breast cancer development are needed and may uncover novel therapeutic targets in the management of breast cancer in the future.

No significant financial relationships to disclose.
The impact of an exercise intervention on body composition, fat distribution, and weight in breast cancer survivors
Authors: Ligibel J. A. , Chen W. , Keshaviah A. , Adloff K. , Partridge A. , Salinardi T. , Winer E. P.
Published: March 2020

590

Background: Recent research has demonstrated that obesity increases a woman’s risk of breast cancer recurrence. Although the mechanism is not well understood, it is known that obese women have higher levels of insulin and other hormones related to energy balance. In this study, we sought to explore the impact of an exercise intervention on body composition, fat distribution, weight, and insulin levels in a population of breast cancer survivors. Methods: Inactive women with early stage breast cancer who had completed adjuvant chemotherapy and/or radiation were randomized to a 16-week exercise intervention or a normal care control group. The exercise intervention consisted of supervised strength training and unsupervised cardiovascular exercise, with a goal of 2 strength training sessions and 90 minutes of cardiovascular exercise each week. Measurement of weight, body composition, and circumference at the waist and hip, were collected at baseline and after 16 weeks in both groups. Fasting blood samples were also collected at these two time points for insulin and glucose levels, so that changes in these levels between the intervention and control groups could be compared. Results: Eighty-five women have been randomized; complete anthropometric data are presently available for 51. Women in the exercise group experienced a nonsignificant decrease in body weight, body fat, and circumference at the waist and hip, as compared to control patients. Participants completed a median of 84% of scheduled strength training sessions and 80% of recommended cardiovascular sessions. Strength increased by an average of 40% during the exercise intervention. Prior studies have demonstrated significant inter-assay variability in biomarker testing, thus insulin and glucose testing will be performed when all patients have completed the protocol. Conclusions: Compliance with the exercise intervention was good. Women in the exercise group experienced non-significant changes in anthropometric measures, and increased strength during the 16-week intervention. Final strength and anthropometric data from the entire cohort will be available for presentation. This project was supported by an ASCO Career Development Award and funding from the Lance Armstrong Foundation.

No significant financial relationships to disclose.
Use of statins and breast carcinoma: A case-control study
Authors: Dumasia L. , Lobocki C. , Couturier A. , Lebeis C. , Drelichman A.
Published: March 2020

592

Background: Statin drugs, which enzymatically inhibit HMG CoA reductase, are used in the treatment of hypercholesterolemia. In vitro, statins have been shown to induce apoptosis and inhibit growth in breast cancer cell lines. Although controversial, recent clinical data has indicated that statins may have a chemopreventive effect against breast cancer. Our objective was to determine whether the long-term intake of statins (at least four years) demonstrates a protective effect against breast cancer as a primary endpoint. Methods: We conducted a retrospective, case-control study of female patients from a community-based hospital and medical center located in southeastern Michigan. Cases included patients diagnosed with invasive breast carcinoma between 1995–2005, as identified through the tumor registry. Controls were family practice patients (age > 35 years) randomly selected from a database generated for this same time-period. Patients completed a mailed questionnaire with information pertaining to their use of statins and other medications, as well as other breast cancer risk factors. Subjects (N = 521) and controls (N = 521) were case matched by age, race, and body mass index (BMI). Results: The mean age of patients was 62.9 (range 35–101 yrs.) with an average BMI of 27.5. Reported usage of statins for four or more years prior to diagnosis was 5.5% in breast cancer subjects and 6.9% in case-matched controls. Compared to nonusers, women who had been on statin therapy for four or more years prior to diagnosis were not found to have a decreased risk of breast cancer (odds ratio 0.78: 95% CI 0.47 - 1.31). Similarly, there was no difference in risk for nonusers versus those taking statins for <1 yr., 1–4 yrs., or ≥ 4 yrs. However, nulliparity, positive family history, report of any benign breast biopsy, and ≥ 5-year use of oral contraceptives (before age 30) were significantly associated with the occurrence of breast cancer (p < 0.002, Chi-square test). Conclusion: Although statins have been shown to inhibit growth in breast cancer cell lines in vitro, its effect in vivo has remained inconclusive. Our study did not demonstrate a significant protective effect against breast carcinoma in women who had ever taken statins, or those who had taken the drug for a minimum of four years.

No significant financial relationships to disclose.
Measuring quality of care in the treatment of colorectal cancer: The Moffitt Network Initiative on Practice Quality (MNIPQ)
Authors: Jacobsen P. B. , Shibata D. , Siegel E. , Lee J. , Druta M. , Marshburn J. , Levine R. , Gondi A. , Defelice J. , Malafa M.
Published: March 2020

6001

Background: As the first step in a larger effort to improve quality of care among its member institutions, the MNIPQ sought to develop and implement methods to assess quality of care in the treatment of colorectal cancer. The current report focuses on our initial experience conducting quality assessments at 4 of 20 member institutions. Methods: Medical chart reviews were conducted of all patients diagnosed with colon or rectal cancer in 2004 and seen by a medical oncologist at the Moffitt Cancer Center or at any of three affiliate institutions. Abstractors, who were trained and periodically monitored, conducted the reviews using a web-based abstraction tool. Abstraction focused on assessing adherence to quality indicators consistent with evidence-, consensus-, and regulatory-based guidelines. Variability in adherence across sites was evaluated by conducting Fisher’s exact tests. The 186 patients whose charts were reviewed were predominantly female (57%) and diagnosed with colon cancer (74%). Results: Adherence was consistently (p values>.05) high across all four study sites for: presence of a pathology report confirming malignancy (91–100%); evidence of staging based on established criteria (88–94%); documentation of discussion or referral for chemotherapy in cases of lymph node (colon and rectal cancer) or rectal wall (rectal cancer) involvement (89–100%); and presence of chemotherapy flow sheets (92–100%). Adherence was consistently (p values>.05) lower across sites for: performance of complete colon evaluation within 12 months of surgery (24–47%) and performance of CEA test before (48–74%) or in the 6 months after (56–82%) surgery or chemotherapy. Adherence varied significantly (p < .001) across sites only for documentation of consent for patients treated with chemotherapy (41–100%). Discussion: Findings identified several areas where efforts should be made to improve the quality of colorectal cancer care at one or more member institutions. In addition, the methods developed have laid the groundwork for future efforts to measure and improve quality of care for other cancers and among a larger number of member institutions.

No significant financial relationships to disclose.
The relative influence of clinical information, financial incentives, and other factors on physician’s choice of chemotherapy
Authors: Johnson S. J. , Bilenker J. H. , Epstein A. J.
Published: March 2020

6002

Background: Understanding the effect of financial incentives for specialty pharmaceuticals on physician choice has been a priority for policy makers. This research seeks to identify the extent to which published clinical information and financial incentives affect a physician’s choice of chemotherapy along with other factors. Methods: SEER-Medicare and Medispan pricing data were formed into a panel of 4,503 patients who were diagnosed with metastatic breast cancer and treated with chemotherapy from 1991 to 2002. A conditional logit discrete choice model was employed to analyze the effects of product attributes, including financial margin, volume of randomized controlled trial citations, FDA labeled indications, years since launch, generic status, and other covariates, on odds of choice of chemotherapy. A chemotherapy-level fixed effects specification was used to analyze choices of drug in patients’ first and subsequent drug administrations. Results: The natural log of clinical information was positive and significant (β = 1.270; p < 0.001); a one unit increase in log of citations increased odds of choice by 27 percent, all else constant. Physicians avoided generics (β = 0.703; p < 0.01), preferred on- to off-label drugs (β = 0.468; p < 0.01), and preferred older drugs to newer ones. Financial incentives for the first chemotherapy administration were positive and significant influences on choice of drug (β = 1.001; p < 0.001). A $100 increase in reimbursement per day increased the odds of choosing a drug by 10 percent. Preference for financial incentives, more clinical information, and on-label drugs declined in subsequent administrations. Conclusions: This research provides evidence that financial incentives have a positive but modest effect on the average physician’s choice of chemotherapy when treating metastatic breast cancer. New clinical information about a drug also had a positive effect on choice.

[Table: see text]
Patients involved in clinical research are more concerned about intrinsic and traditional research (“publish or perish”) conflicts of interests (COI) than potential financial conflicts: Results of interviews with advanced cancer patients enrolling in phase I trials
Authors: Daugherty C. K. , Hlubocky F. J. , Gray S. , Ratain M. J.
Published: March 2020

6008

Background: Concerns exist about the potential for financial COI to bias the design, conduct, analysis, and reporting of clinical trials. However, information is lacking about the perceptions of these COI among actual research subjects—both in general and relative to more intrinsic and traditional research COI. Methods: Using a standardized survey, cancer patients (pts) were asked closed-ended and semi-qualitative questions regarding their concerns about extrinsic, e.g., financial, and intrinsic, e.g. career advancement, COI. Results: To date, 120 pts either enrolled, or being evaluated for participation, in phase I trials have been approached for an interview with 96 completing the interview (80% response rate). Median age of respondents is 61 y (33–82); 55% male; 83% Ca, 10% AA, 2% AsA or HA; 38% college educated. 91%, 100%, and 94% thought that the involved investigators (MDs), drug companies, and hospitals benefited from a clinical trial respectively. The benefits cited for MDs was improvement in knowledge/ability to treat pts. The benefits cited for the hospital and drug company were described as prestige and financial. 38% would be concerned if an MD involved in a clinical trial receives financial benefit from the research, e.g., being a paid consultant or owning stock in company involved in a trial, and 43% thought that they should be informed of these potential benefits. 64% thought they should be concerned if an MD receives career advancement benefits from trial participation, and 69% thought they should be informed of this benefit. 45% thought that investigators might feel institutional pressure to enroll pts. Qualitative data revealed that pts’ lack of concern about financial COI related to their assumption that MDs already receive financial benefits-believing this to be acceptable-with some even encouraging it. Conclusions: Cancer pts were more concerned about intrinsic and traditional research COI than potential financial COI. As well, many assume that MDs receive financial benefits from research. These results may be helpful when considering COI management policies.

No significant financial relationships to disclose.
Factors influencing accrual to ACOSOG Z0011, a randomized phase III trial of axillary dissection vs. observation for sentinel node positive breast cancer
Authors: Leitch A. M. , McCall L. , Beitsch P. , Whitworth P. , Reintgen D. , Blumencranz P. , Saha S. , Bauer T. , Hunt K. K. , Giuliano A.
Published: March 2020

601

Background: The American College of Surgeons Oncology Group opened a phase III randomized trial to assess the value of axillary node dissection (ALND) after positive sentinel node biopsy (SNB). After 5.5 years, the trial closed due to poor accrual with only 891 patients of the planned 1900 accrued. The purpose of the current analysis is to assess factors impacting accrual to Z0011. Methods: Women having SNB for T1 or T2 breast cancer were eligible for participation in the Z0010 trial to assess the significance of micrometastases identified by immunohistochemistry. If the SN was positive for metastasis by H&E, the patient was eligible for randomization on Z0011 trial. Intraoperative (IOR) and postoperative randomization were allowed. Patients having SNB outside of the Z0010 trial were eligible. Results: 1003 patients from the Z0010 trial were eligible for randomization on Z0011. Of these, only 37% were entered in Z0011. Z0010 participants accounted for 42% of patients in Z0011. 16% of patients not randomized refused ALND. 69% of those not randomized had ALND. 67% of these had no additional positive nodes. Only 14% had ≥ 4 positive nodes. Enrollment of eligible Z0010 patients varied by type of institution: 25% at academic sites, 42% at teaching affiliated and 53% at community (p < 0.0001). By geographic region, sites in the South entered 42% of eligible patients compared with 24–36% in other geographic regions (p=0.0027). Only 32% of patients were consented for IOR based on frozen section of the SN. Sites in the South and West were less likely to use IOR (25% and 28%) compared to Northeast and Midwest (45% and 46%) (p < 0.0001). 110 sites participated in Z0011, yet 48% of patients were enrolled by 10% of sites. Conclusions: Failure of this important trial to accrue as planned is likely related to the clinical bias of physicians and patients to standard ALND. Yet, 2/3 of patients had no additional positive nodes and extensive nodal disease was infrequent. While it was thought that IOR might improve accrual to Z0011, the most successful sites were less likely to use this approach. Community surgeons were most successful in randomizing patients.

[Table: see text]
Preferences for and expectations about experimental therapy among participants in randomized trials
Authors: Joffe S. , Stumacher M. , Clark J. W. , Weeks J. C.
Published: March 2020

6013

Background: Equipoise is often viewed as the ethical precondition for randomized controlled trials (RCTs). Equipoise is usually defined as a state of uncertainty or disagreement among expert clinicians, but some ethicists argue instead that individual participants should be indifferent between the study arms. The degree to which cancer RCT participants have preferences for either arm is not known. Methods: Adults who had enrolled in a 2-arm RCT at a Dana-Farber/Harvard Cancer Center institution within 21 days were eligible. A mailed questionnaire asked about treatment assignment, treatment preference, and expectations about the relative efficacy and toxicity of the 2 arms. The primary analysis was a goodness-of-fit chi-square test of the null hypothesis that equal proportions of respondents would prefer the standard vs. investigational arm. Results: 82 of 126 RCT participants (65%) responded. 31 (38%) were assigned to the standard arm, 26 (32%) were assigned to the experimental arm, and 25 (30%) were enrolled in blinded trials. Respondents tended to prefer assignment to the experimental rather than the standard arm (p = 0.006), and expected the investigational arm to be more effective than the standard arm (p = 0.0004). Respondents did not consistently expect that either arm would be more toxic ( Table ). Conclusions: Cancer RCT participants tend to prefer the experimental arm. Thus either the design of cancer RCTs must be altered to accommodate participant preference, or individual-participant equipoise must be abandoned.

[Table: see text]

No significant financial relationships to disclose.
Do post-approval phase III trials for accelerated approved cancer drugs violate equipoise?
Authors: Lurie A. J. , Djulbegovic B. , Nebeker J. R. , Angelotta C. , Gordon L. I. , Raisch D. W. , Yarnold P. R. , Carson K. R. , McKoy J. M. , Bennett C. L.
Published: March 2020

6026

Background: Since 1992, the Food and Drug Administration (FDA) has allowed accelerated approval of novel cancer drugs based on improvements in surrogate outcomes, provided that subsequent phase III trials, in compliance with subpart H, show evidence of clinical benefits. However, drugs that receive accelerated approval must already show promise, making it difficult to recruit for randomized studies in which patients might get other drugs which are likely to be inferior. We evaluated whether drugs granted accelerated approval were just as likely to be superior as inferior to standard therapy during phase III clinical trials, a necessary condition known as equipoise, which is used as the ethical basis for recruitment. Methods: Descriptions of marketing approval decisions and subpart H commitments for all drugs that received accelerated approval for oncology indications between 1992 and 2005 were obtained from the FDA website, transcripts of the Oncologic Drug Advisory Committee of the FDA, and PubMed searches. Results: Accelerated approval has been granted for 25 drugs and 29 indications. These approvals have been based on phase II clinical trials (23 indications) or phase III trials (6 indications). 14 approvals were for novel cancer therapeutic drugs. Post-approval phase III clinical trials, outlined in subpart H commitments, have been reported for 9 indications associated with common cancers of the colon, lung, or breast, and 1 indication associated with multiple myeloma, a less common cancer, for which 9 studies identified improved clinical outcomes with the accelerated approved drug. Of 15 drugs that received accelerated approval prior to 2003 for cancers that affect small numbers of patients, 13 are years behind planned recruitment milestones for post-approval phase III trials. Conclusion: While the equipoise theory would predict that 50% of the completed phase III trials would support the novel therapy, empirical data have identified that 90% of the studies required by subpart H commitments support the novel therapy. Therefore, it is likely to hinder recruitment to ongoing phase III trials evaluating other accelerated approved cancer drugs.

No significant financial relationships to disclose.
Racial differences in treatment for breast cancer among black and white women in Atlanta
Authors: Lund M. J. , Brawley O. W. , Eley J. W. , Ward K. C. , Young J. L. , Liff J. M.
Published: March 2020

603

Background: Among women with breast cancer, Black women experience a disproportionate excess in mortality, a reflection of their marked poorer survival, which persists even within stage and age groups. Adherence to first course treatment guidelines for breast cancer may not be uniform across racial/ethnic groups and could be a major contributing factor to racial disparities in outcome. In this population-based study, we assessed racial differences in initial treatment of primary invasive breast cancer. Methods: All data were obtained from the Surveillance, Epidemiology, and End Results (SEER) program. The study population included all invasive breast cancers diagnosed during 2000–2001 among Black (n=877) and White (n=2437) female residents of the five Atlanta SEER counties, an area whose population is 36% Black and where several large teaching hospitals are located. Outcome factors included delay in first course treatment, type of treatment, performance of cancer directed surgery, type of surgery, and receipt of chemotherapy, radiotherapy, or hormonal therapy. Racial differences in treatment were analyzed according to their basis for treatment; stage or age at diagnosis and tumor factors. Analyses utilized frequency distributions, χ2 tests of independence, and Cochran-Mantel-Haenszel statistics in and across strata. Results: Black women were more likely to experience delays in treatment, regardless of stage at diagnosis, and 4–5 fold more likely to experience delays greater than 60 days (p<0.001). For local-regional disease, more Black women did not receive cancer directed surgery (14.2% vs. 2.9% of white women, p<0.001), but did receive breast conserving surgery (BCS) equivalently. However, only 61% of Black vs. 72% of White women received radiation with BCS (p<0.001). Black women eligible for hormonal therapy were less likely to receive it (p<0.001). Conclusions: Our findings suggest treatment standards are not adequately or equivalently implemented among Black and White women, even in a metropolitan area where teaching hospitals provide a substantial portion of breast cancer care. Treatment differences can adversely affect outcome and reasons for the differences need to be addressed.

No significant financial relationships to disclose.
Chemotherapy ordering in a computerized physician order entry (CPOE) environment: A longitudinal analysis of defects from oncologist to patient
Authors: Mertens W. C. , Cassells L. J. , Brown D. E. , Koertge V. , Cabana L. , Parisi R. , Naglieri-Prescod D. , Higby D. J.
Published: March 2020

6040

Background: While published data suggest low chemotherapy error rates, the rate of chemotherapy ordering process defects and who detects them remains uncertain. Methods: Outpatient treatment plans/orders were prospectively evaluated by pharmacy prior to preparation, then by nursing prior to administration. Data collected included the nature of defects, how detected, utility of regimen-specific care sets (facilitating antineoplastic dose calculation and adjunct agent selection), and patient impact. Results: Pharmacy recognized problems with 36% of orders (comprising 1,082 cycles/4,600 drugs), with 34% incomplete (absent orders 17%; missing cycle number 12.5%; other items 4%). Pharmacy identified incorrect orders in 6% (dose calculation 2%; cycle number 1.5%; other items 2.5%). Incomplete orders were more likely to have incorrect items (11.6% v. 3.5% if complete, p < .001). Care set use (76% of cycles) was associated with fewer overall problems and incomplete orders (both p < .001), with reduced absent orders and missing antiemetics, but not antineoplastics. Care set orders exhibited a trend for fewer incorrect items (p=.06). Nursing recognized problems with 14.6% of orders, again most commonly incomplete orders (10%; absent orders 7%; missing antiemetic or antineoplastic drug 4.6%); fewer missing items resulted from care set use (p < .001). Nursing detected fewer orders with problems and missing items but more instances of missing antineoplastic and antiemetic agents (all p < .001) despite prior pharmacy review. Nursing identified incorrect orders in 5% (wrong dosage 3.4%; wrong drug 2.5%) and classified 4% of cycles as having an error (“near miss” 3.3%; more serious error reaching the patient 0.6%). Conclusions: Defects in chemotherapy orders are common despite the relatively low error rate. The predominant defects–incomplete orders–are associated with incorrect items. Both care sets and pharmacy review reduce but do not eliminate incomplete orders; the effect on incorrect orders is smaller. Even with CPOE, sequential pharmacy and nursing review remain critical to reducing order defects; additional software enhancements are needed to further reduce defects.

No significant financial relationships to disclose.
Economic evaluation of adjuvant chemotherapy in Stage III (SIII) colon cancer: Capecitabine versus 5FU/LV
Authors: Virik K. , Skedgel C. , Younis T.
Published: March 2020

6046

Background: Adjuvant chemotherapy for SIII colon cancer is an accepted standard of care. Oral Capecitabine (C) has been shown to be at least equivalent and possibly superior to 5FU/LV (F) with a superior relapse free survival (RFS). This new option is associated with a higher drug cost. An economic analysis was undertaken to compare these two alternatives. Methods: A cost minimisation analysis was performed in Canadian $ ($) using C and F given as per the X-ACT (X) trial. The direct costs including chemotherapy drug acquisition, supportive medications, laboratory investigation and health resources utilisation were examined based in Nova Scotia. Indirect costs included travel and opportunity cost based on the average provincial wage and participation rates. Complete drug delivery was assumed. A direct payer perspective was used. A cost-effectiveness (CE) model was also constructed to estimate the required lower risk of cancer recurrence for C to be cost effective compared to F at a commonly used CE threshold. The Markov model developed used a hypothetical cohort of 1,000 patients with SIII colon cancer and projected costs and outcomes over 5 years (discounted 3% and in $2,005). All recurrences were modeled to death. Recurrence rates, median survival with recurrent disease, costs and utility scores were derived from the literature. Estimates of background mortality without recurrence were obtained from Canadian Life Tables. Sensitivity analysis (SA) was performed using a range of recurrence risk hazard ratios (HR) including that reported in the X trial. Results: Compared to F, C is associated with higher direct costs, principally reflecting the higher drug cost (difference: $5,589/patient) but less resources utilisation cost (difference: - $1,804/patient). The total indirect costs favour C (difference: - $2,464/patient). For C to be potentially CE compared to 5FU/LV, a ≥ 9% lower relative recurrence risk (HR = 0.91) with C would be required. At the reported RFS HR 0.86, the CE of C relative to F is $15,844 per disease free survival years gained and $22,097 per quality adjusted life years gained. Conclusions: C has more direct costs but has indirect cost savings. It has the potential to be cost effective as seen in the SA and is a CE alternative to F at the HR for RFS reported in the X trial.

No significant financial relationships to disclose.
An analysis of deficiencies identified during investigational new drug (IND) application reviews by the Division of Drug Oncology Products (DDOP) of the US FDA
Authors: Mann B. S. , Kane R. , Brave M. , Ryan Q. , Hazarika M. , Rock E. , Senderowicz A. , Dagher R. , Johnson J. , Justice R. , Pazdur R.
Published: March 2020

6052

Background: Regulations require IND application review by the FDA prior to initiation of the clinical study. Deficiencies identified in the study protocol require communication between the FDA reviewers and the Sponsor for resolution. If the deficiencies are not adequately resolved, clinical hold and subsequent delay in the start of the clinical study results. To identify and analyze the commonly encountered IND application deficiencies, data from recent reviews were collected. Methods: Eight clinical reviewers analyzed the deficiencies that had been identified in 268 IND applications reviewed in the DDOP FDA from January 2003 to June 2005. All of the study protocol deficiencies leading to a clinical hold, or requiring resolution prior to study initiation were categorized as deficiencies pertaining to: patient eligibility; starting drug dose; study conduct (toxicity management, dose adjustment, stopping criteria); statistical or endpoints; non-clinical; and other issues. Results: 268 IND applications reviewed over a 30-month period by eight medical officers were analyzed. One hundred and twelve (42%) of the applications had no deficiencies; however, 156 (58%) had one (31%) or multiple (69%) deficiencies. Deficiencies pertained to study conduct/scheme (65%), dose (48%), patient eligibility (46%), others (31%), statistics or endpoints (15%), and non-clinical (4%) issues. In 141 (90%) of the deficient applications the deficiencies were adequately addressed by FDA reviewer-Sponsor communication and the trials could start as scheduled. Fifteen (10%) deficient trials were placed on clinical hold. Fourteen (93%) of these trials had multiple deficiencies that pertained to patient eligibility in 12 (80%), starting drug dose in 12 (80%), study conduct in 11 (73%), other in 7 (47%), and non-clinical and statistical issues in 2 (13%) each. Conclusions: Deficiencies were identified in 58% of the reviewed IND applications: 90% of these were resolved by FDA-Sponsor communication. Only 10% of deficient studies were placed on clinical hold; all except one had multiple deficiencies. The most common deficiencies leading to clinical hold pertained to eligibility of study population and proposed starting drug dose.

No significant financial relationships to disclose.
Examining the cost and cost-effectiveness of adding bevacizumab to carboplatin and paclitaxel in advanced non-small cell lung cancer
Authors: Grusenmeyer P. A. , Gralla R. J.
Published: March 2020

6057

Background: Two-drug platinum-containing regimens are considered the standard of care in advanced non-small cell lung cancer. A recent randomized trial (ECOG 4599) compared carboplatin + paclitaxel (PC) with PC + bevacizumab (PCB). PCB was found to result in a modest improvement in survival (12.5 months vs 10.2 months with PC, p = .007). This finding was exceptional in showing a survival benefit with the addition of a molecularly targeted agent to chemotherapy in a largely unselected population, and doing so in this most common cause of malignant death in the US. Additionally, new therapies can have a major impact on health care costs. Using the known survival data and costs, we analyzed the cost-effectiveness of the addition of bevacizumab to this chemotherapy regimen. Methods: Medicare reimbursement (cost) of the two regimens was developed using the CMS Drug Payment Table and Physician Fee Schedule for January, 2005. Incremental cost effectiveness was calculated. Results: Carboplatin and paclitaxel regimen costs $14,073 for 6 cycles (the number of cycles planned in the clinical trial.) The addition of bevacizumab increases cost by $66,270 to $80,343. Given an increase of 2.3 months in median overall survival over chemotherapy alone, the addition of bevacizumab to chemotherapy costs $345,762 per year of life gained. Conclusions: Adding bevacizumab to chemotherapy is not cost effective even at the $100,000 per Year of Life Gained (YLG) threshold. To be cost effective at the $100,000/YLG level, bevacizumab reimbursement would have to be reduced to $14.70/10 mg. ($1,764/cycle) or 26% of 2005 Medicare reimbursement of $57.08/10 mg. ($6,849/cycle). Prior analyses have examined the impact of chemotherapy on survival and cost-effectiveness. Several factors beneficially influence survival in NSCLC, as shown in meta-analyses, including: chemotherapy vs supportive care, two-agents vs one, and the choice of which platinum agent to use. While all of these may increase costs, some are cost-effective, while others are not. The addition of bevacizumab is the most costly and least cost-effective of any of these interventions.

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Cost-effectiveness of MRI compared to mammography for breast cancer screening in a high risk population
Authors: Moore S. G. , Tumeh J. , Flowers C. R.
Published: March 2020

6060

Background: Breast magnetic resonance imaging (MRI) is a sensitive method of breast imaging virtually uninfluenced by breast density. Because of the improved sensitivity, breast MRI is increasingly being used for detection of breast cancer among high risk young women. However, the specificity of breast MRI is variable and costs are high. The purpose of this study was to determine if breast MRI is a cost-effective approach for the detection of breast cancer among young women at high risk. Methods: A Markov model was created to compare annual breast cancer screening over 25 years with either breast MRI or mammography among young women at high risk. Data from published studies provided probabilities for the model including sensitivity and specificity of each screening strategy. Costs were based on Medicare reimbursement rates for hospital and physician services while medication costs were obtained from the Federal Supply Scale. Utilities from the literature were applied to each health outcome in the model including a disutility for the temporary health state following breast biopsy for a false positive test result. The analysis was performed from the payer perspective with results reported in 2005 U.S. dollars. Univariate and probabilistic sensitivity analyses addressed uncertainty in all model parameters. Results: Breast MRI provided 23.287 quality-adjusted life-years (QALYs) at a cost of $30,317 while mammography provided 23.141 QALYs at a cost of $7,895 over 25 years of screening. The cost-effectiveness ratios for the two strategies were $1302 and $341, respectively. The incremental cost-effectiveness ratio of breast MRI compared to mammography was $131,376/QALY. In univariate analysis, breast MRI screening became <$50,000/QALY when the cost of the MRI was <$405. In the probabilistic sensitivity analysis, MRI screening produced a net benefit of +0.146 QALYs (95% central range: -0.825 QALYs to +1.378 QALYs). However, breast MRI screening was superior in <1%, <$50,000/QALY in 27%, >$50,000/QALY in 32%, and inferior in 41% of 10,000 probabilistic Monte Carlo simulations. Conclusions: Breast MRI provides a net benefit when compared to mammographic screening for high risk women, however, this approach does not appear to be cost-effective at this time.

No significant financial relationships to disclose.