bluuebunny/crossref_metadata_2025_split huggingface dataset:
NCIC CTG MA.17: Intent to treat analysis (ITT) of randomized patients after a median follow-up of 54 months
Authors: Ingle J. , Tu D. , Shepherd L. , Palmer M. , Pater J. , Goss P. 
Published: March 2020

549 Background: MA.17 evaluated letrozole (LET) or placebo (PLAC) after 5 years of tamoxifen (Tam) and showed [median follow-up 30 months (mos)] significant improvement in disease-free survival (DFS) for LET [hazard ratio (HR) 0.57, p = 0.00008]. The trial was unblinded and PLAC patients (pts) were offered LET. An ITT analysis of all outcomes, before and after unblinding, based on the original randomization was performed. Methods: A stratified log-rank test was used to compare DFS, distant (D)DFS, overall survival (OS) and incidence of contra-lateral breast cancer (CBC). The Cox regression model used baseline stratification variables and two prespecified factors, menopausal status at the start of Tam and time on Tam. Subgroup analyses for DFS and OS were performed for the two prespecified subsets. All p-values were two-sided Results: 5187 pts were randomized at baseline and, at unblinding, 1655 of 2268 PLAC pts accepted LET. At median follow-up of 54 mos (range,16–86) 363 recurrences or CBC’s (144 LET and 219 PLAC) occurred; 118 LET and 176 PLAC pts had recurrent disease and 26 LET and 43 PLAC pts had CBC. 4 year DFS was 94.3% (LET) and 91.4% (PLAC) (HR 0.64; 95% CI, 0.52 - 0.79; p = 0.00002). Corresponding 4 year DDFS was 96.2% and 94.9% (HR 0.76; 0.58–0.99; p = 0.041). 4 year OS was 95.0% (LET) and 95.1% (PLAC) (HR 1.00; 0.78–1.28; p = 0.99). LET was equally effective in node +ve and -ve pts (i.e., similar HRs) in DFS. OS was not significantly different for LET and PLAC in any subgroup. The annual rate of CBC was 0.29% LET (0.18–0.40) and 0.47% PLAC (0.34–0.61); HR 0.61 (0.38–0.98) p = 0.037. 255 pts had died as of the data cut-off (128 LET and 127 PLAC). Conclusions: In this ITT analysis, pts originally randomized to LET within 3 months of stopping Tam did better than PLAC pts in DFS, DDFS and CBC, despite 73% of PLAC pts crossing to LET after unblinding. This highlights the strong beneficial effect of extended adjuvant therapy with LET. [Table: see text]
Pre-treatment and treatment related risk factors for severe late toxicity after chemo-RT for head and neck cancer: An RTOG analysis
Authors: Machtay M. , Moughan J. , Trotti A. , Garden A. S. , Weber R. S. , Cooper J. S. , Swann R. S. , Ang K. K. 
Published: March 2020

5500 Background: Concurrent chemoradiotherapy (CCRT) for squamous cell carcinoma of the head and neck (SCCHN) improves tumor control, but its toxicity is formidable. This study evaluates factors that might predict for severe late toxicity following CCRT. Methods: Patients treated with CCRT were analyzed from three RTOG trials of locally advanced SCCHN: 91–11 arm #2 (XRT + high dose cisplatin for larynx cancer); 97–03 (phase II study of various doublets of chemotherapy with XRT); and 99–14 (phase II study of accelerated XRT + high dose cisplatin). Severe late toxicity was defined in this secondary analysis as late (>180 days from the start of XRT) Grade 3–4 pharyngeal/laryngeal toxicity (RTOG/EORTC late toxicity scoring system); requirement for a feeding tube ≥2 years after registration; or potential treatment-related death (e.g. pneumonia) within 3 years. Case-control analysis was performed to determine factors predictive of severe late toxicity, with a multivariate logistic regression model that included pre-treatment and treatment potential factors. Results: The total sample size of patients treated with CCRT from these three studies was 479; 226 were evaluable (119 patients had severe pre-treatment laryngopharynx dysfunction and 134 had persistent/recurrent cancer). There were 98 cases (patients with severe late toxicity) and 128 controls. In the multivariate model, significant predictors of severe late toxicity were older age (odds ratio 1.05 per year, p = 0.002); advanced T-stage (odds ratio 2.21; p = 0.014); larynx/hypopharynx tumor site (odds ratio 3.20; p = 0.011); and neck dissection (ND) after XRT (odds ratio 2.22; p = 0.029). Radiotherapy dose intensity and chemotherapy dose intensity were not predictive. Among 47 patients who underwent post-XRT ND, the crude rate of severe late toxicity was 55%, compared with 40% for the subgroup of 179 patients who did not undergo post-XRT ND (p = 0.05). Conclusions: Severe late toxicity following CCRT is common. Older age, advanced T-stage, and larynx/hypopharynx primary site were independent risk factors. Neck dissection after CCRT may be associated with an increased risk of these complications. This work was supported in part by the Commonwealth of Pennsylvania (Tobacco Settlement Grant). No significant financial relationships to disclose.
Letrozole suppresses plasma oestradiol (E2) levels more completely than anastrozole in postmenopausal women with breast cancer
Authors: Dixon J. M. , Renshaw L. , Young O. , Murray J. , Macaskill E. J. , McHugh M. , Folkerd E. , Cameron D. , Dowsett M. 
Published: March 2020

552 Background: Letrozole (L) is a more potent aromatase inhibitor in vitro than anastrozole (A). One study in 12 patients showed that in patients L provides more complete inhibition of whole body aromatase and suppression of estrone sulphate levels than A but L did not significantly suppress E2 levels more than A possibly because of the small size of the study and the difficulty of measuring E2 in postmenopausal women (Geisler et al, JCO, 20, 751, 2002). The current aim was to conduct a much larger study to determine whether 2.5mg L suppresses E2 significantly more than 1mg A and if so in what proportion of patients this is the case. Methods: 54 postmenopausal women with invasive estrogen receptor positive breast cancer were randomised as part of their adjuvant hormone therapy to receive either: 12 weeks of L followed by 12 weeks of A (L→A) or 12 weeks of A followed by 12 weeks of L (A→L). Blood for hormones were taken at the same time of the day before and after 12 weeks of each drug. E2 was measured by a highly sensitive radioimmunoassay (Dowsett et al, Cancer Res 1987;47:1957–61) with a formal detection limit of 3pmol/l. In this study we also quantified values by extrapolation below this limit. Results: 27 patients had L→A and 27 A→L. Baseline E2 levels varied from 3 to 91 pmol/l with a median of 26 pmol/l. Only 1of 54 (2%) patients had an E2 value ≥ 3pmol/l after L compared with 20 of 54 (37%) after A(p <0.000005). After extrapolation, mean E2 level after A was 2.91 (SEM 0.18) pmol/l with a median of 2.70 pmol/l and after L was 1.76 (SEM 0.10) pmol/l with a median of 1.70 pmol/l (p<0.0001). Mean residual estradiol was 9.2% of baseline with A and 5.6% with L. Conclusions: This study has demonstrated unequivocally that the more complete inhibition of aromatase achieved by 2.5mg of letrozole than 1mg of anastrozole results in a greater degree of suppression of E2, the most bioactive oestrogen. [Table: see text]
Cetuximab in combination with cisplatin or carboplatin and 5-fluorouracil (5-FU) in the first-line treatment of patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (R&M SCCHN) (EXTREME)
Authors: Vermorken J. B. , Mesia R. , Vega-Villegas M. E. , Remenar E. , Hitt R. , Kawecki A. , Rottey S. , Zabolotnyy D. , Erfan J. , Amellal N. 
Published: March 2020

5537 Background: The epidermal growth factor receptor (EGFR) is expressed in nearly all SCCHN and carries a strong prognostic significance, providing the rationale for using EGFR-targeted agents, such as cetuximab, in this indication. This study assesses the efficacy and safety of cetuximab in combination with chemotherapy commonly used in the treatment of R&M SCCHN. Methods: Patients (pts) were enrolled into this phase III trial from December 2004 to December 2005 and randomized either to Group A: cetuximab (first dose 400 mg/m2 then 250 mg/m2 weekly) plus a maximum of 6 three-weekly cycles of cisplatin (100 mg/m2 IV on day 1) or carboplatin (AUC 5, day 1) and 5-FU (1000 mg/m2/day continuous infusion for the first 4 days of each cycle) or to Group B: cisplatin or carboplatin with 5-FU as before. Cetuximab was administered until progression or unacceptable toxicity. Primary endpoint is overall survival time; secondary endpoints are progression-free-survival, response rate, disease control rate, safety, and Quality of Life. It was planned to randomize a total number of 420 pts in order to detect a difference in improvement in overall survival of 2.5 months. Results: At the end of the recruitment,440 pts have been randomized, to date 320 pts are under treatment, 21 have withdrawn from the study and 99 have completed the study. The Data Safety Monitoring Board (DSMB) has performed an independent preplanned safety analysis from the first 140 pts, 138 pts of whom were treated. Patients were followed for a minimum of 6 weeks: M/F122/16, median age57 years [range, 38–79],median Karnofsky performance status (KPS) 80 [range, 70–100]. In this safety analysis, there were 14 deaths, none of which were treatment related. The most frequent drug related grade 3–4 toxicity was mainly represented by neutropenia, thrombocytopenia and anemia. Conclusions: The DSMB evaluated baseline and safety data, found no reason to stop the trial and recommended continuation of the study. [Table: see text]
Protection of chemo-radiation therapy induced oral mucositis (OM) in pre-clinical and clinical studies
Authors: Rehemtulla A. , Grove W. , Sunkara P. , Naidu M. , Ross B. D. 
Published: March 2020

5567 Background: D-methionine, was shown to selectively protect normal but not tumor cells from loss of mitochondrial integrity and viability in response to ionizing radiation. OM is a debilitating complication of radiotherapy (RT) and chemotherapy (CT). MRx-1024, a orally bio-available formulation of this agent was evaluated as a treatment for the protection of OM. Methods: A mouse model of radiation-induced lip erythema was used to evaluate the efficacy of MRx-1024. Pharmacokinetic profile of MRX-1024 in healthy human volunteers as well as evaluation of oral MRX-1024 was accomplished in patients (pts) with head and neck cancer receiving RT or RT+CT. Pts received 1.8–2.0 Gy of RT daily for 5 days each week, to a total of 60 Gy. Selected pts also received cisplatin, 50mg/m2 weekly. MRX-1024 suspension was given 1 hour before and again after each RT fraction. Pts were evaluated weekly using 4 accepted scales for assessing OM. Results: A significant protection of radiation-induced lip erythema was achieved in pre-clinical studies without compromising tumor control. Plasma concentrations of MRx-1024 achieved in normal volunteers after oral administration were similar to those required for efficacy in pre-clinical studies. No major adverse events were attributed to MRx-1024. The incidence of OM from 21 evaluable pts was compared with historical controls from the same institution. MRX-1024 was found to be a safe, easily administered and well-tolerated agent that completely ameliorated the incidence of Grade 4 (21% in historical controls) and reduced the incidence of Grade 3 by 80% over historical controls. In addition, preliminary analysis indicated that MRX-1024 did not compromise antitumor activity. Conclusions: These pre-clinical and clinical studies provide exciting proof of principle evidence for the use of MRx-1024 in the treatment of OM. Follow-up clinical studies are underway to further validate these results. [Table: see text]
Risk of cancer treatment-related osteoporosis and fractures among women with breast cancer receiving aromatase inhibitors
Authors: Mincey B. , Duh M. , Thomas S. , Moyneur E. , Marynchencko M. , Boyce S. , Perez E. 
Published: March 2020

557 Background: Aromatase inhibitors (AIs) are a novel hormonal therapy for breast cancer. However, AIs can cause bone loss by blocking estrogen production. This study aims to assess the association between AIs and treatment-related bone loss in a large managed care population of women with breast cancer. Methods: Using medical and pharmacy claims data from over 5 million beneficiaries between 01/01/1998 and 01/31/2005, we identified 12,368 patients with ≥ 2 breast cancer claims in a 6-month period, who also had no bone metastasis and no prior osteoporosis or fracture claims. Patients who received anti-estrogen therapy were also excluded to remove the protective confounding effects. 1,354 patients receiving an AI (anastrozole, exemestane, letrozole) were compared to 11,014 controls who did not receive an AI with respect to their risk of bone loss. The observation start date for the AI and control groups was defined as the service date of the first AI claim and breast cancer claim, respectively. The bone loss endpoints analyzed were osteoporosis (including osteopenia) and clinical fractures. Results: The univariate analysis found that the prevalence of osteoporosis was 8.7% in the AI group vs. 7.1% in the control group, resulting in a statistically significant relative risk of 1.3 (95% CI=1.1–1.6, p=0.01). The prevalence of bone fracture was also statistically significantly elevated in the AI group compared to the controls (13.5% vs. 10.3%) with a relative risk of 1.4 (95% CI=1.2–1.6, p=0.001). Multivariate Cox proportional hazards regressions showed that after adjusting for age and comorbidities, the risk of bone loss remained statistically significantly higher in the AI group than the non-AI group, with 27% (95% CI=4%-55%, p=0.02) and 21% (95% CI=3%-43%, p=0.02) increase in the risk of osteoporosis and fractures, respectively. Conclusions: This retrospective longitudinal analysis of a large cohort of breast cancer patients corroborates previous findings from smaller clinical trials and demonstrates that AI therapies carry an increased risk of bone loss. Monitoring and treatment management strategies to alleviate bone loss risk are warranted in women receiving AI for breast cancer. [Table: see text]
Multimodality therapeutic approach in anaplastic thyroid cancer (ATC): Study of 56 patients
Authors: Koussis H. , Scola A. , Tonello S. , Busnardo B. , Donach M. , Pelizzo M. , Toniato A. , Mazzarotto E. , Mazzarotto E. , Karahontzitis P. , Monfardini S. 
Published: March 2020

5571 Background: To investigate the role of multimodality treatment in patients with ATC. Methods: From 1992 to 2005, 56 patients with a histologically or cytologically proven ATC were referred to the Thyroid Centre of Padua University General Hospital. There were 36 females and 20 males, median age 69 years (range 27–90). About one-third of patients had a history of prior nodular goitre. Aggressive local disease was present in 30 patients, distant metastases, mainly to the lung, were present in 32 at diagnosis or quickly developed during the observation period in all but one patient. Patients from our series can be subdivided into 3 groups: Group A: consisted of 19 patients in good general condition which were treated by radiotherapy (RT), total thyroidectomy (TT) and chemotherapy (CHT). All were treated with Cisplatin once a week and by RT 36 Gy in 18 fractions over 3 weeks, followed by TT and by further CHT with Adriamycin and Bleomycin. Additionally, five patients received weekly Docetaxel. Group B: consisted of 19 patients with distant metastasis at diagnosis, who received CHT (Platinum based combination). Group C: consisted of 18 elderly patients in poor general condition; 6 received local RT, while 12 did not receive any treatment. Results: Five complete responses were seen in patients from group A. Four patients had long-term survival (14, 15, 24 and 41 months) with a disease free survival interval of 6, 8, 11 and 32 months. From Group B one patient with a complete remission following antiblastic therapy was later treated by TT and metastasectomia and is still alive without disease after 74 months. Median survival rates for Groups A, B and C were 12, 5.7 and 4 months respectively. Conclusions: In some patients multimodality treatment is associated with increased survival. The best results were obtained in younger patients with less advanced disease. Early diagnosis is mandatory. Only a few patients responded to CHT confirming that anaplastic thyroid carcinoma is often resistant to anticancer drugs. Our experience with combination modalities suggests that aggressive and appropriate combinations of RT, TT and CHT may provide some benefit in patients with ATC. Preoperative RT and CHT may enhance surgical resectability of the primary tumor. No significant financial relationships to disclose.
Value of positron emission tomography (PET) scan in treatment decision making for nodal metastases in head and neck squamous cell cancer
Authors: Mehrotra B. , Roy R. , Radhakrishnan N. , Gabalski E. , Myssiorek D. , Rush S. , Ebling D. , Pollack J. , Dubner S. , Heller K. 
Published: March 2020

5577 Background: Management of neck disease in patients with Head and Neck Squamous cell cancer (HNC) who are initially treated with combined radiation and chemotherapy (CRT) remains controversial. Standard treatment options include neck dissection (ND) or close observation. More recently PET scans have been used to stage and monitor response to therapy in patients with HNC. We performed a retrospective analysis of patients diagnosed with HNC stages N2b or higher, treated with combined CRT, and who were monitored for disease response by PET scans. Our observations on the utility of PET scans in monitoring response to therapy and in determining the role of elective NDs in this setting are reported. Methods: A retrospective review of medical records of all patients diagnosed at our institution with HNC Stages TxN2b, N2c or N3 between the years 2002 and 2005 was undertaken. IRB approval was obtained for this study.To be eligible for this analysis, patients must have had baseline and follow up PET scans at the end of CRT and prior to ND. Data regarding age, gender, primary tumor site, stage, baseline and follow up PET scan results, operative pathology of ND when performed, and local control were recorded. Results: Fifteen patients were identified. Median age was 55 years (range 37–76). Male: Female ratio was 13:2. Primary site of tumor was Pharynx (Base of tongue: n = 3, tonsil: n = 11); Lip and oral cavity: n = 1. Stages: IVa : n = 12; IVb: n = 3. N stage: N2b: n = 12; N2c: n = 1; N3: n = 2. Post CRT, all patients were followed with serial clinical examinations, PET ± CT scans. 13 of 15 patients had negative PET activity in the neck at the completion of CRT and remain disease free in the neck at a median follow up of one year. Post treatment PET scans were positive at the primary site in 2 of 15 patients; and positive in the neck in 2 of 15 patients. These 4 patients underwent ND after completing CRT. Operative pathology was positive for nodal disease in 2 of 4 patients who had persistent mild or significant activity on PET scan either at the primary site or in the neck. Conclusions: Post CRT PET negativity in the neck and at the site of primary tumor is associated with continued disease free status in the neck and these patients may be managed conservatively without requiring a neck dissection. No significant financial relationships to disclose.
Toxicity of older and younger patients (pts) treated (Rx) with intensive adjuvant chemotherapy (Cx) for node-positive (N+) breast cancer (BC): The CALGB experience
Authors: Muss H. , Berry D. , Cirrincione C. , Budman D. , Henderson I. , Citron M. , Norton L. , Winer E. , Hudis C. 
Published: March 2020

559 Background: Recent data show older pts derive the same relapse-free and survival benefits as younger pts when treated with newer more intense adjuvant ADJ Cx regimens (Jama 293:1073, 2005). We now compare toxicity of older and younger pts treated in 3 CALGB ADJ trials that used recently developed, intensive Cx regimens including anthracyclines and paclitaxel (T). Methods: Toxicity data were available for 6174 of 6642 pts (93%) enrolled in 3 CALGB/CTSU randomized clinical trials for N+ BC [8541: comparison of CAF in 3 dose schedules; 9344: AC ± T; 9741: ATC dose-dense vs q3 weeks]. Grade (G) 3–5 (NCI criteria) toxicities were compared by age at enrollment (<50, 51–64, 65+). Results: 7% (458) pts were 65+, 3% were 70+, 38% were 51–64 and 55% were <50 years. Incidence of major toxicities and Cx-attributed causes of death are tabulated below. Discontinuation of Cx for toxicity was reported in 6% of 65+, 4% of 51–64 and 3% of <50 pts. 22 of 6642 pts (0.33%) died of causes attributed to Cx; 7/486 (1.4%) of 65+, 8/2480 (0.32%) of 51–64 and 7/3676 (0.19%) <50. In multivariate analysis older pts were significantly more likely to have WBC < 1000/cmm, any G4 hematologic toxicity, or to have discontinued Cx. There were no significant differences in G3–5 non-hematologic toxicity and no deaths due to neutropenia and sepsis.The incidence of AML/MDS due to Cx significantly increased with increasing age. Conclusions: Older pts who met the strict eligibility criteria for these trials had a higher incidence of Cx-related AML/MDS but not non-hematologic toxicity. It is uncertain if cardiac deaths attributed to Cx are definitely due to treatment. Except for AML/MDS, 5-year non-BC mortality, including Cx-attributed death, is similar in elders to age-adjusted rates in the normal population. Elders treated with intense but more effective ADJ regimens should be cautioned concerning the increased risks of AML/MDS. Physicians should help elders weigh the risks and benefits of ADJ treatment. [Table: see text] [Table: see text]
Endocrine and clinical responses to steroid sulfatase inhibition: Results from the first phase I trial in women with breast cancer
Authors: Stanway S. , Purohit A. , Woo L. W. , Wilson R. H. , Stanczyk F. Z. , Dobbs N. , Delavault P. , Potter B. V. , Reed M. J. , Coombes R. C. 
Published: March 2020

580 Background: Steroid sulfatase (STS) inhibitors, such as STX64, were developed to block the sulfatase pathway of estrogen formation in postmenopausal (PM) women with ER+ breast cancer. They act by blocking the formation of estrone from estrone sulfate but also inhibit the synthesis of androstenediol (Adiol), a steroid with potent estrogenic properties, which is derived from dehydroepiandrosterone sulfate (DHEAS). Methods: Fourteen PM women with ER+ metastatic breast cancer were recruited for this Phase I trial. All patients had received at least two previous lines of endocrine therapy and all but one had received prior chemotherapy. STX64 was administered orally as an initial test dose (5mg, n=9; 20mg, n=5) followed one week later by 3 two weekly cycles with dosing for 5 days followed by 9 days off treatment for 12–145 days. Blood samples were collected for the assessment of STS activity in peripheral blood lymphocytes and steroid concentrations. For some patients core biopsies of tumor samples were obtained before and during therapy. Results: Almost complete inhibition of peripheral STS (median 98%) and tumor (median 99%) activity was achieved on dosing with STX64. This was associated with significant decreases in the concentrations of estradiol, androstenediol (up to 90%) and unexpectedly, androstenedione (up to 86%). Monitoring the ratios of DHEAS:DHEA (a marker of STS inhibition) in patients receiving extended dosing revealed an inverse relationship between this ratio and serum Adiol concentrations. Three patients with prior adjuvant tamoxifen and aromatase inhibitor therapy showed stable disease for >6 months with a favorable safety profile. Full results will be presented at the meeting. Conclusions: STX64 is a potent, well tolerated STS inhibitor. The unexpected finding that androstenedione levels decreased indicates that peripheral formation, rather than secretion from the adrenal cortex, in the major source of this steroid which is the main substrate for the aromatase. The disease stabilization seen for 4 patients, all of whom had previously progressed on aromatase inhibitor therapy, suggests that STS inhibitors should have considerable therapeutic potential for the treatment of breast cancer. [Table: see text]