bluuebunny/crossref_metadata_2025 huggingface dataset:
Study of cisplatin, etoposide, bleomycin, and escalating dose cyclophosphamide therapy for children with high-risk germ cell tumors: A Children's Oncology Group report
Authors: Malogolowkin M. H. , Krailo M. , Frazier L. A. , Olson T. A.
Published: August 2020

10035

Background: In the intergroup high-risk germ cell tumors (HR-GCT) study (CCG-8882/POG-9049) patients with extragonadal GCT treated with high-dose cisplatin, etoposide, and bleomycin (HD-PEB) had a 2 year-EFS of 84% versus 74% for those treated with standard PEB (PEB), suggesting that treatment intensification might be beneficial. The goal of this study was to establish the maximum tolerated dose (MTD) and toxicity profile of cyclophosphamide combined with PEB in untreated patients with HR-GCT. Methods: From July 2004 to August 2007, 19 eligible children and adolescents with stage III/IV extragonadal GCT received cisplatin 20 mg/m2/day × 5, etoposide 100 mg/m2/d × 5, bleomycin 15 mg/m2 on d1, and escalating doses of cyclophosphamide (1.2, 1.8 or 2.4 g/m2) on d1. DLT was defined as any grade 4 non-hematologic toxicity other than nausea and vomiting, fever and infection, and any non-hematologic grade 3 toxicity which had not reversed (< grade 2) within 28 days of treatment; or hematologic toxicity grade 3 or 4, which despite hematopoietic growth factor support, was not reversible within 28 days of treatment. Results: The toxicities reported were expected for this treatment regimen, protocol therapy was well tolerated and all 3 cyclophosphamide levels were feasible. Only 1 patient who had hyperglycemia was considered to have DLT by the institutional investigator. Fifteen of the 19 patients were removed from protocol therapy after 4 cycles of therapy; 11 were disease-free, 2 electively terminated protocol therapy, 1 patient was lost to follow-up, and 1 had progressive disease (PD). Four patients received 2 more cycles of C-PEB, of these 3 were disease-free and 1 had PD. The 2 year-EFS and OS were 71% (95% CI: 43–87%) and 88% (95% CI: 59–97%), respectively. Conclusions: The addition of cyclophosphamide to the standard PEB regimen is feasible and well tolerated at all dose levels used on this study. Due to the small sample size we cannot establish that the addition of cyclophosphamide to the standard PEB regimen is beneficial in increasing the EFS when compared to the standard PEB regimen. Further evaluation of this regimen is warranted.

No significant financial relationships to disclose.
Childhood osteosarcoma: Evaluation of 94 cases. A single institution study
Authors: Ayan I. , Kebudi R. , Ozger H. , Yaman Agaoglu F. , Gorgun O. , Bilgic B. , Eralp L. , Dizdar Y. , Darendeliler E.
Published: August 2020

10040

Background: Osteosarcoma is the most frequent bone tumor in children and adolescents. The aim of this study is to evaluate the demographic characteristics, therapy, and long term outcome of children with osteosarcoma in a single institution. Methods: Between January 1990 and December 2006, 94 children (53 male, 41 female) with a median age of 13 (5–16) years and a histopathologic diagnosis of osteosarcoma were treated with an institutional chemotherapy regimen comprising of 6 courses (3 pre-, 3 postoperatively) of epirubicin (90 mg/m2), cisplatin(100 mg/m2), and ifosfamide(2 g/m2 × 3 days) every 3 weeks. Results: The median follow-up time was 36 (2–219) months. 68 patients were alive at the time of analysis. 26 patients died; 20 of disease, 5 of toxicity, and 1 of second malignancy (acute myeloid leukemia). 90% of the patients had a limb salvage. 5 and 10 year OS for all patients were 64.7 % ( [95 % CI] 74.8–52.94 %) and 62.2 % (95 % CI 74.6–49.9 %), respectively. 5 and 10 year EFS for all patients was 51.8 % (95% CI 40.2–63.4 %). 5 and 10 year OS for nonmetastatic patients were 78.3 % (95% CI 66.9–89.7 %) and 75.1 %(95% CI 62.6–87.6), vs. 13.5 % 5 year OS for metastatic patients(95% CI 0–30.8 %) (p< 0.001). 5 and 10 year EFS for nonmetastatic patients was superior to those with metastatic disease [62.4 % (95% CI 49.9–79.9 %) vs. 6.9 % (95% CI 0–19.9 %)) (p<0.001). A total of 33 patients experienced relapse and/or progression at a median of 9 months (range 0–40 months). 10 year OS for 18 patients (11 metastatic at diagnosis) who progressed during preoperative chemotherapy was 13 % vs. 75 % for those who didnot have progressive disease (p< 0.001). The rate of histologically good response to preoperative chemotherapy was 64.5 %. Histologic response (<90 percent necrosis vs ≥90 percent) significantly correlated with 5 year EFS (31 % vs 67.6 %, p=0.023) but not with OS (57.7 % vs 76.5 %, p=0.13). Conclusions: The presence of metastases at diagnosis was the most significant characteristic influencing outcome. Our results demonstrate that the combination of epirubicin, cisplatin, and ifosfamide is an active and reasonably well-tolerated regimen for childhood osteosarcoma.

No significant financial relationships to disclose.
Burkitt lymphoma in children: The Israel Society of Pediatric Hematology Oncology retrospective study
Authors: Weyl Ben Arush M. , Hersalis Eldar A. , Abrahami G. , Attias D. , Ben Barak A. , Dvir R. , Gabriel H. , Kapelushnik J. , Kaplinsky H. , Vilk-Revel S.
Published: August 2020

10051

Background: From 2000 to 2005, the Israel Society of Pediatric Hematology Oncology studied the results of the FAB-LMB 96 protocol in children with B cell lymphoma. Methods: Eighty eight patients (pts) were eligible, 63 boys, 25 girls, median age was 8.9 years. Fifty patients (57%) were classified as burkitt lymphoma, 5 (5.7%) as burkitt-like lymphoma, 22 (25%) as diffuse large B cell (DLBC), 9 (10.2%) as burkitt leukemia. Initial disease sites included the abdomen in 43%, head and neck in 45%, mediastinum in 7%. Stage I: 9.1%, Stage II in 28.4%, stage III in 45.5%, stage IV in 17%. Five pts had bone marrow involvement (BM) alone, 5 pts CNS alone and 4 both CNS and BM. Five children were treated according to group A, 69 pts group B and 14 pts group C. Results: At a median follow up of 3 years, Kaplan Meier for EFS and OS for all pts was respectively 88.6%, 90.9%, group A, 100%,100%, group B: 90%, 93%, group C 79%, 79%. In group A: there were neither events nor deaths in this group, 6 patients relapsed in group B, among them 4 patients had died, tumor lysis syndrome in 3 patients, death of toxicity in 1 patient. In group C, 3 patients had relapsed and died, no death of toxicity. EFS for LDH less then twice was 96.4%, EFS for LDH more than twice was 73.3% (p = 0.002). OS according to primary site: bone and ovary (100%), head and neck (95%), abdomen (92%) and mediastinum (50%) (p = 0.003). All of the mediastinal tumors were of DLBC origin, but when comparing the DLBC to other histologies, no significant difference in outcome were found.(DLBC: 81.8%, other B line: 90.9%). The OS for Arab ethnic origin is 79.2%, OS for Jewish is 95.3% (p = 0.02). Conclusions: In nonresected mature B cell lymphoma of childhood and adolescence with no BM or CNS involvement, a 93% cure rate was achieved. Patients with primary DLBC mediastinal mass had a significantly reduced overall survival, indicating the need for a different therapeutic approach.

No significant financial relationships to disclose.
Bone marrow infiltration in infants with disseminated neuroblastoma
Authors: De Bernardi B. , Sorrentino S. , Pasino M. , Gigliotti A. R. , Dau D. , Scuderi F. , Rosanda C.
Published: August 2020

10056

Background: The INSS definition of stage 4S neuroblastoma allows a bone marrow infiltration (BMI) no greater than 10%. More extensive involvement is to be consider stage 4. However, the degree of BMI may be difficult to establish, since tumor cells in the marrow commonly aggregate in clumps. So far, no studies have specifically investigated this issue. In this study we have reviewed the bone marrow slides of infants with disseminated neuroblastoma enrolled between January 1998 and July 2008 in the Italian Neuroblastoma Registry. Methods: BMI was arbitrarily considered <10% when it consisted of a maximum of 5 tumor cell aggregates/slide in association to normal cellularity. Marrow was aspirated from iliac crests and slides were stained with Wright-Giemsa method. A minimum of 2 slides for aspirate were examined at low magnification. The same 2 hematologists (CR, MP) examined the slides independently along the study period, blind for clinical data. A third hematologist (FS) joined to perform the reviewing process. Results: Of 142 infants enrolled, we retrieved and reviewed bone marrow slides of 73. Before results of bone marrow study, 31 patients were defined as stage 4, and 42 as stage 4S. Following bone marrow study, 2 patients previously defined as stage 4S who had ≥10% BMI were moved to stage 4. The results of the revision are summarized ( Table ). Conclusions: In this study, only 2/42 infants with stage 4S clinical features had BMI ≥ 10% and were eventually labeled as stage 4. Whether chemotherapy for stage 4 is of advantage for these patients remains to be seen. [Table: see text]

No significant financial relationships to disclose.
Incidence, detection, and management of cardiac metastasis in pediatric sarcoma patients
Authors: Hughes D. P. , Crutchley M. , Douglas W. I. , Munsell M. F. , Vaporciyan A. A. , Herzog C. , Tsai F. W. , Huh W.
Published: August 2020

10060

Background: Sarcoma metastasizing to the heart is a difficult and complicated clinical problem, yet local control is feasible and effective for select patients with cardiac metastasis. Diligence is required to detect these lesions while still amenable to treatment, and echocardiogram remains the best tool for detecting cardiac disease. Methods: We reviewed all echocardiograms (1330) performed on 307 pediatric sarcoma patients treated at UT M. D. Anderson Cancer Center between 1997 and 2008. Measures of cardiac function and pathology (including size of ventricles and atria, function of ventricles and valves, presence of metastasis, and presence of pericardial effusion) were assigned numerical values. Fisher's exact test and the Wilcoxon rank-sum test compared clinical characteristics of patients with and without cardiac metastases. Results: The prevalence of cardiac metastases was 1.6% (5/307) with 95% confidence interval 0.5% to 3.8%. The presence of cardiac metastasis positively correlated with pericardial effusion (p = 0.001) and tricuspid valve insufficiency (p = 0.014). The probability of a patient with pericardial effusion having a cardiac metastasis was 28.6% (95% CI: 3.7%-71%). Of the 5 patients with documented sarcoma metastasis to the heart, 3 had widespread refractory disease, were given no cardiac-specific therapy, and rapidly died from disease. One patient who had widespread disease controlled with chemotherapy and radiation had open resection of 2 cardiac metastases which resulted in site-specific disease control for 6 months before succumbing to progressive extra-cardiac disease. Another patient had isolated cardiac metastasis, treated with open resection of 2 metastases followed by adjuvant chemotherapy, and has been without recurrent cardiac metastases for 5 years and 9 months. Conclusions: Durable local control for sarcoma metastasizing to the heart is possible and effective for select patients. Pericardial effusion merits evaluation for potential associated cardiac metastasis. Echocardiogram monitoring of sarcoma patients remains important, and should include screening for possible cardiac metastasis.

No significant financial relationships to disclose.
Efficacy and safety of radioiodine in the treatment of disseminated differentiated thyroid cancer (DTC) in children
Authors: Handkiewicz-Junak D. , Roskosz J. , Kropinska A. , Kozielski J. , Krzywiecki A. , Krajewska J. , Krajewska J. , Puch Z. , Olczyk T. , Jarzab B.
Published: August 2020

10065

Background: Distant metastases, mainly to lung are diagnosed in about 20% of children with DTC. At present radioiodine is the treatment of choice in that case. However, it can results in massive lung fibrosis as was showed in historical groups of patients.The aim of this retrospective study was to evaluate results of radioiodine therapy in children and its long-term safety. Methods: From 235 children (median age 13.9) diagnosed either with papillary (82%) or follicular cancer (18%), 42 (17.9%) had lung, and 2 (9%) bone metastases (median time of observation 105 months). All were treated with radioiodine (accumulated activities 100 to 950 mCi). Treatment results were evaluated by means of scintigraphic, radiological, and biochemical examinations. 28 (67%) of the children were lately re-evaluated with high resolution CT, ultrasound, biochemistry, and spirometry. Results: In most children, 29/44 (66%), distant metastases were diagnosed in radioiodine scan while radiological examinations were normal. Complete scintigraphic and radiological remission was achieved in 38 (86%) children. In all children there was a decrease in thyroglobulin serum concentration after radioiodine therapy. However, it normalized at the last radioiodine treatment only in 13 (29%) cases. During follow-up Tg continued to decrease and at the last stimulated Tg evaluation it was < 10 ng/ml in 28 (64%) patients. In 5/28 (18%) of the children with lung metastases some small foci of focal lung fibrosis were diagnosed with CT. However, comparable percentage of focal fibrosis was observed in DTC children without lung metastases. Also the preliminary results didn't show an increased rate of abnormal spirometry results. Conclusions: Complete remission of distant metastases can be achieved in about 85% of children with DTC treated with radioiodine. This therapy is safe and does not cause any increased risk of lung fibrosis even in children treated with repeated courses of radioiodine.

No significant financial relationships to disclose.
Exploratory subset analysis according to prior endocrine treatment of two randomized phase II trials comparing gefitinib (G) with placebo (P) in combination with tamoxifen (T) or anastrozole (A) in hormone receptor-positive (HR+) metastatic breast cancer (MBC)
Authors: Cristofanilli M. , Schiff R. , Valero V. , Iacona R. , Yu J. , Speake G. , Smith I. , Osborne C. K.
Published: August 2020

1014

Background: Preclinical and clinical data suggest that increased EGFR and HER-2 activity contribute to acquired resistance to endocrine therapy. Strata of two clinical trials recently showed that the addition of G to T or A in HR+ MBC prolonged progression free-survival (PFS). Certain preclinical data also suggested that G should be combined with T or A from the start of endocrine therapy rather than waiting for resistance to develop. To examine this clinically a post hoc analysis compared the subsets of patients (pts) who had received prior endocrine therapy (may have already upregulated HER receptors) to those that were endocrine therapy naïve (not yet upregulated HER receptors). Methods: One trial evaluated G (250 mg/day orally) + A (1 mg/day orally) versus A+P ( NCT00077025 ) and one trial evaluated G (250 mg/day orally) + T (20 mg/day orally) versus T+P ( NCT00229697 ). Post hoc analysis of PFS was performed in two pt subgroups; previously treated with endocrine therapy (ET) and endocrine naïve (EN). The PFS HR and associated 95% CI and p-value for G relative to P were estimated using the Cox proportional hazards model along with interaction test for treatment by subset. Results: In the ET subgroup of the G+A versus A+P study, 31 PFS events were reobserved in 51 pts (hazard ratio [HR] 0.65 95% CI 0.32, 1.33; median PFS: G+A 11.2 mo, A+P 7.1 mo). In the EN subgroup, 23 PFS events were reobserved in 42 pts (HR 0.39, 95% CI 0.16, 0.97; median PFS: G+A 20.2 mo, A+P 8.4 mo). The interaction test p-value was 0.28. In the ET subgroup of the G+T versus T+P study, 95 PFS events were reobserved in 131 pts (HR 1.22, 95% CI 0.81, 1.86; median PFS: G+T 9.4 mo, T+P 10.9 mo). In the EN subgroup, 106 PFS events were reobserved in 158 patients (HR 0.78, 95% CI 0.52, 1.15; median PFS: G+T 12.1 mo, T+P 8.9 mo). The interaction test p-value was 0.13. Conclusions: The EN pt subgroups of both trials demonstrated prolonged PFS when G was combined with A or with T compared with A or T alone, respectively. A further prospective clinical trial of EGFR inhibition combined with endocrine therapy in EN pts with HR+ MBC is warranted on the basis of these findings.

[Table: see text]
A phase II study of trastuzumab-DM1 (T-DM1), a HER2 antibody-drug conjugate (ADC), in patients (pts) with HER2+ metastatic breast cancer (MBC): Final results
Authors: Vogel C. L. , Burris H. A. , Limentani S. , Borson R. , O'Shaughnessy J. , Vukelja S. , Agresta S. , Klencke B. , Birkner M. , Rugo H.
Published: August 2020

1017

Background: T-DM1 is an ADC that combines the biological activity of trastuzumab (T) with targeted delivery of a potent antimicrotubule agent, DM1, to HER2-expressing cancer cells. In a phase I study, T-DM1 was administered IV q3w to pts with HER2+ MBC who had progressed on T + chemotherapy. T-DM1 was well-tolerated at the maximum tolerated dose (MTD) of 3.6 mg/kg, with no reports of cardiac toxicity. The confirmed objective response rate (ORR) for the 9 pts with measurable disease treated at the MTD was 44%. The phase II study described here further assesses tolerability and activity of T-DM1. Methods: This was a multi-institutional, open-label, single-arm phase II study, to enroll 100 pts. All eligible pts had progressed on HER2-directed therapy and had received chemotherapy in the metastatic setting. T-DM1 was administered at 3.6 mg/kg IV q3w. Primary objectives were assessment of ORR and of safety and tolerability. Results: As of the August 29, 2008, data-cut, 112 patients had enrolled, with baseline median age 54.5 (range 33–82); ECOG PS 2 or 3, 80%; 68.7% with > 3 sites of metastatic disease; median 3 (range 1–14) prior chemotherapy agents for metastatic disease, median 76.3 weeks prior T, and 55.4% with previous lapatinib. Due to limited F/U, the median number of T-DM1 cycles received was 5 (range 1–16), and 19 of the 107 efficacy evaluable patients had only one post-baseline tumor assessment. Fifty-six pts had discontinued study treatment. With a median follow-up of 4.4 mos, there were 42 (39.3%) ORs (CR or PR), 29 (27.1%) of which have been confirmed by follow-up (F/U) imaging. Among the subgroup of pts who had either >6 months F/U or had discontinued from the study at any time (n = 76) there were 33 ORs (43.4%), 29 (38.2%) of which were confirmed by F/U imaging. The most common grade 3–4 AE was thrombocytopenia (7.1%). Updated data will be presented at the meeting, including updated ORR, 6-month clinical benefit rate, ORR by independent review, progression-free survival, and duration of response. Conclusions: T-DM1 has single-agent activity in pts with previously treated, HER2+ MBC, and is well tolerated at the recommended phase II dose.

[Table: see text]
Randomized phase II study of weekly versus every-3-week ixabepilone plus bevacizumab (ixa/bev) versus paclitaxel plus bev (pac/bev) as first-line therapy for metastatic breast cancer (MBC)
Authors: Rugo H. S. , Campone M. , Amadori D. , Wardley A. , Villa E. , Conte P. F. , Mudenda B. , McHenry B. , Pivot X.
Published: August 2020

1029

Background: Pac/bev is superior to pac alone as first-line therapy for MBC. Ixa/bev has greater preclinical activity than pac/bev in human tumor models. The primary objective of this trial was to evaluate objective response rates (ORR) of ixa/bev given weekly or every 3 weeks relative to pac/bev as 1st line therapy for women with advanced breast cancer. Methods: Women with measurable disease and no prior chemotherapy for advanced breast cancer (locally advanced or MBC) were randomized in a 3:3:2 ratio to Arm A (ixa 16 mg/m2 IV on days 1, 8 & 15 q28 days/ bev 10 mg/kg IV q 2 wks), Arm B (ixa 40 mg/m2 IV q3 wks / bev 15 mg/kg IV q 3 wks) or Arm C (pac 90 mg/m2 IV, schedule/bev as in Arm A). Treatment was continued until disease progression or unacceptable toxicity. Results: Key efficacy and safety results from a pre-planned analysis of all randomized subjects after at least 24 weeks of follow-up are presented. Baseline characteristics were balanced between arms except for liver metastasis. Conclusions: The combination of ixa/bev weekly or q 3 wks demonstrated encouraging clinical activity and safety comparable to 1st line pac/bev in E2100. Final PFS will be provided when data is mature. These results support ongoing clinical trials of ixa given weekly or q 3wk in 1st line MBC, and in combination with bev.

[Table: see text]

[Table: see text]
Tolerability and efficacy of first-line bevacizumab (B) plus chemotherapy (CT) in elderly patients with advanced breast cancer (aBC): Subpopulation analysis of the MO19391 study
Authors: Biganzoli L. , Cortes-Funes H. , Thomssen C. , Pritchard K. I. , Pierga J. , Kupp A. , Borstnar S. , Smith I.
Published: August 2020

1032

Background: Limited data exist on the efficacy and safety of biological agents in elderly patients with aBC. This is essentially due to the lack of studies specifically targeting the older population and to strict inclusion criteria in clinical trials. B significantly improved the efficacy of 1st-line taxane therapy in two large, randomized phase III trials, E2100 and AVADO. Methods: In study MO19391, 1st-line B 10mg/kg q2w or 15mg/kg q3w + CT (primarily but not exclusively taxane monotherapy) was investigated in a broader, large aBC patient population, with the aim of understanding safety and efficacy in patients seen in routine clinical practice, including elderly patients. Results: A total of 2,027 patients were enrolled. Median age was 54 years (range 21–93); 359 patients (17.7%) were aged ≥65 years and 169 (8.3%) were ≥70 years. Baseline characteristics and safety and efficacy results according to age are shown below (Table). Conclusions: Treatment with B is feasible in elderly patients. Hypertension was the only grade 3 B-related side effect reported more frequently in the older than in the younger cohort. Efficacy was similar in the two subgroups. These results suggest that the combination of B with 1st-line CT shows a similar therapeutic index regardless of age. Data on compliance according to the different CT regimens, the impact of comorbidities on safety, and analyses in the subgroup of patients ≥70 years will be presented.

[Table: see text]

[Table: see text]
Long-term treatment with intravenous bisphosphonates in metastatic breast cancer (MBC)
Authors: Onishi T. , Singh V. , Rosenzweig M. , Sereika S. , Brufsky A. M.
Published: August 2020

1035

Background: Intravenous bisphosphonates (IV BPs) are safe and effective in reducing skeletal related events in MBC. The effects of IV BPs after 24 months of therapy are unknown. The incidence of osteonecrosis of the jaw (ONJ) and renal insufficiency (RI) among women with MBC receiving >= 24 months of IV BPs is also poorly defined. We studied the long term effect of IV BPs in a cohort of women with MBC. Methods: We maintain an ongoing prospective database of >600 women with MBC diagnosed and treated at our institution from January 1999. A long-term cohort (LTC) of 159 women with metastatic breast cancer to bone treated for >= 24 months with pamidronate (n = 9), zoledronic acid (n = 110), or both (n = 40) was identified. A control cohort (CC) of 62 women with MBC to bone treated with IV BPs for 12–23 months was also identified. RI was defined as an increase in serum creatinine (scr) of > 0.5 mg/dl or an absolute level of scr >1.5mg/dl; ONJ was diagnosed by dental consultation. Results: Median follow-up of the LTC was 39 months (range 24–99) months. Median overall survival in this cohort was 43 months (range 24–114). The vast majority of women in the LTC (140/159, 88.1%) continued to receive IV BPs at standard dose every 3–4 weeks. The incidence of ONJ in the LTC was 6/159 (3.8%), after a mean 42.2 treatment cycles, with a median time to ONJ of 44 months. Three of six patients with ONJ (50%) underwent surgical resection, and 3/6 (50%) were managed conservatively, and 3/6 (50%) resumed IV BPs after a mean 12 month hold. The incidence of RI (all pts had baseline scr < 1.4 mg/dl) in the LTC was 19/159 (11.9%), occurring after a mean 43.4 treatment cycles, with a median time to RI of 43 months. Eleven of 19 patients (57.9%) recovered to baseline scr and 7/19 (36.7%) patients showed partial recovery. Seventeen of 19 patients (89.4%) were able to resume therapy after temporary discontinuation, decreasing the dose, or increasing the interval of the IV BP. Incidence of ONJ in the CC was 1/62 (1.6%) and RI in the CC was 6/62 (9.7%). Conclusions: Long term (>=24 month) IV BP use in MBC is well tolerated and safe, with relatively low incidence of ONJ and RI. Most patients were able to resume IV BP therapy after a therapy hold without further complication.

No significant financial relationships to disclose.
Risk and cost of anthracycline-induced cardiotoxicity among breast cancer patients in the United States
Authors: Choi J. C. , Chang J. D. , Seal B. , Tangirala M. , Mullins C. D.
Published: August 2020

1037

Background: Onset of anthracycline-induced cardiotoxicity is well documented. However, information regarding the time of onset varies depending on literature. The purpose of this study was to compare the risk of cardiotoxicity among three cohort groups: anthracycline-containing-chemotherapy (ACC), no-anthracycline-containing-chemotherapy (NACC), and no-chemotherapy (control) groups. Methods: A retrospective cohort study was designed using commercial managed care claims database. Adult subjects (≥18) diagnosed with breast cancer, between January 1, 2002 to December 31, 2005, (index-period) were followed for 24 months. Subjects with a previous cardiotoxic events (CE), breast cancer diagnosis, or anthracycline-use 12-months prior to index date were excluded. Index date was the first chemotherapy claim date for ACC and NACC and non-chemotherapy medication claim date for controls. Cohorts were matched by index date and year of birth. CE was defined based on ICD-9-CM and Healthcare Common Procedure Coding System codes. Risk of CE was evaluated using a logistic model with and without adjusting for confounders. Results: 21,106 subjects were classified as ACC (n = 3,428), NACC (n = 7,125), and controls (n = 10,553). NACC cohort was significantly (p < 0.01) older (mean age: 62 years ±12.5) compared to ACC (53±9.7) or control cohorts (59±12.5). ACC cohort had a higher (p < 0.01) average degree of comorbidity, (1.8±0.8) compared to NACC (1.6±0.9) or control (1.3±0.8) as measured by Charlson comorbidity-index. Higher rates of CE were found within the ACC group compared to NACC and controls as early as month 3 post index-date and remained consistent over 24 months. At month 12 post index-date, 14% (n = 485) of ACC and 5% (n = 381) of NACC had CE compared to 3% (n = 310) of controls. After adjusting for all baseline differences, the odds ratio of CE compared to controls was 3.98 (95% CI: 3.27–4.85), and 1.31 (95% CI: 1.11–1.54) for ACC and NACC cohorts, respectively. The total mean costs were $59,287, $20,528, and $11,600, among ACC, NACC, and control cohorts respectively. Conclusions: Compared to NACC and controls, ACC cohorts had significantly higher risk of cardiotoxic events and seen as early as month 3 post treatment initiation.

[Table: see text]
Lapatinib plus letrozole compared with letrozole alone as first-line therapy in hormone receptor positive HER2+ metastatic breast cancer (MBC): A quality-of-life (QOL) analysis
Authors: Sherif B. N. , Sherrill B. , Amonkar M. , Wu Y. , Maltzman J. , O'Rourke L. , Johnston S.
Published: August 2020

1039

Background: A phase III randomized double-blind multicenter trial compared lapatinib plus letrozole (L+Let) with letrozole plus placebo (Let), as first-line therapy for hormone receptor positive (HR+) MBC. Median PFS, the primary endpoint of the study, in patients who were HER2+ was significantly prolonged for L+Let compared with Let (8.2 vs 3 months, Hazard Ratio (95% CI)=0.71(0.53,0.96), p=0.019). This analysis focuses on the impact of treatments on QOL in the HER2+ subgroup. Methods: QOL outcomes included the Functional Assessment of Cancer Therapy-Breast (FACT-B) total, FACT-general (FACT-G), and trial outcome index (TOI) scores assessed at screening, every 12 weeks and at withdrawal. Higher scores indicate better QOL. Changes from baseline were analyzed using analysis of covariance. In a responder analysis, patients achieving minimally important differences in QOL scores (QOL responders) were compared with Fisher's exact test. Results: Among 1,286 patients, 219 were identified as HER2+ (L+Let n=111; Let n=108). Baseline QOL scores were comparable in the two arms. In this population, mean changes in subscale and total QOL scores were generally stable over time in both treatment arms for patients who stayed on study. For example, on the FACT-B, the average change from baseline in both groups was positive at all scheduled visits through Week 48 and the maximum difference between arms was 2.6 points (CI: -5.8, 11). There were no significant differences between the two treatment arms in percentage of QOL responders (Table). Conclusions: The addition of lapatinib to letrozole significantly increases PFS while maintaining QOL when compared with letrozole alone thus confirming the clinical benefit of the combination therapy in the HR+, HER2+ MBC patient population. This combination provides an effective option in this patient population by maintaining QOL and delaying the need for chemotherapy and its accompanying side effects.

[Table: see text]

[Table: see text]
Correlations of estrogen receptor (ER) related genomic transcription and ER gene expression with increasing AJCC stage of ER-positive breast cancer
Authors: Andreopoulou E. , Hatzis C. , Booser D. , Valero V. , Wallace M. J. , Sotiriou C. , Hortobagyi G. , Pusztai L. , Symmans W.
Published: August 2020

1044

Background: Advanced stages of ER-positive breast cancer may have decreased tumor dependence on estrogen, possibly due to biological selection and/or progression. The sensitivity to endocrine therapy (SET) index measures transcriptional activity of the ER genomic pathway (165 ER-related genes). We investigated whether expression of genes for receptors ER (ESR1), progesterone receptor (PGR), or HER-2 (ERBB2), the SET index, or a housekeeper gene (GAPDH) vary by stage of ER-positive breast cancer. Methods: We evaluated gene expression profiles (Affymetrix U133 microarrays, Affymetrix, Santa Clara, CA) from 956 patients’ clinical samples of ER-positive breast cancer, including 290 new samples profiled at MDACC and 666 samples from published datasets. Microarray data were uniformly normalized, log-transformed, and expression levels for single genes and the SET index were compared to pathologic AJCC stage (315 patients were stage I, 362 stage IIA, 151 stage IIB, 29 stage III, 27 stage IV at initial presentation, and 72 stage IV previously treated and/or at relapse) using a median ordered regression analysis (p < 0.05 was significant). Results: SET index significantly decreased with advancing pathologic stage (p < 0.001), and PGR expression levels showed a similar, but lesser, effect (p = 0.014). However, expression levels of ESR1 and ERBB2 did not vary by stage. Overall, GAPDH gene expression increased with stage (p < 0.001), but that effect was only observed in stages III and IV. Expression of these genes was not significantly different between stage IV disease at initial presentation or at relapse. Conclusions: Expression levels of ESR1 and ERBB2 receptor genes did not vary, but ER-related genomic transcription (SET index and, to a lesser extent, PGR) declined significantly with increasing pathologic stage. This suggests that ER-positive breast cancer tends to have less transcriptional dependence on estrogen with increasing pathologic stage. The observed increase in expression of GAPDH in stages III and IV might reflect higher metabolic activity in advanced ER-positive breast cancer and deserves further study.

[Table: see text]
HER-2-PET imaging with 89Zr-trastuzumab in metastatic breast cancer patients
Authors: Oude Munnink T. , Dijkers E. , Lub-de Hooge M. , Kosterink J. , Brouwers A. , de Jong J. , van Dongen G. , de Vries E.
Published: August 2020

1045

Background: Non-invasive diagnostic tools can optimize and evaluate HER2 directed therapy in HER2 positive breast cancer patients. HER2 imaging with 111In-trastuzumab SPECT showed promising results (Perik et al, J Clin Oncol. 2006). To further optimize HER2 imaging, we developed 89Zr-trastuzumab for high resolution, quantitative and sensitive PET imaging. A feasibility study was performed to determine optimal conditions (tracer dose and scans) for visualization HER2 positive lesions. Methods: Trastuzumab was labeled with 89Zr according to Verel et al. (J Nucl Med. 2003). HER-2 positive metastatic breast cancer patients received 37 MBq 89Zr-trastuzumab at 3 protein doses of trastuzumab: 1) 10 mg, or 2) 50 mg trastuzumab, or 3) 10 mg trastuzumab when on trastuzumab treatment. Patients underwent 2 or 3 PET-scans during 1–7 days post tracer injection. Images were analyzed visually and the relative tissue or tumor uptake was calculated as the ratio tissue/tumor to whole body uptake. Results: Fourteen patients were included. Optimal time point to assess 89Zr-trastuzumab tumor uptake was 4–5 days post injection. The tracer dose of 10 mg was sufficient for patients on trastuzumab treatment, while best imaging results in trastuzumab naive patients were obtained with the 50 mg dose as 10 mg resulted in rapid tracer clearance. In trastuzumab naive patients, 89Zr-trastuzumab clearance was not only dose-dependent but also clearly influenced by tumor burden, indicating a need for individualization of therapy. 89Zr-trastuzumab PET-imaging detected not only known tumor lesions in the liver, lung, bone and brain but also unknown brain and bone lesions were detected. The mean relative tumor uptake(± SD) in liver, bone and brain lesions was respectively 13.0±5.2, 4.2±1.5 and 3.5±4.2, while mean relative tissue uptake in normal liver, spleen, kidneys and brain was respectively 6.1±2.3, 2.7±0.8, 3.8±1.0 and 0.19±0.11. Conclusions: HER2-PET imaging with 89Zr-trastuzumab shows excellent tumor tracer uptake and can be used to detect HER2 positive breast cancer metastases and to quantify 89Zr-trastuzumab uptake, non-invasively. Patients on trastuzumab can be imaged with 37 MBq 89Zr-trastuzumab at a protein dose of 10 mg trastuzumab while trastuzumab naive patients require 50 mg.

No significant financial relationships to disclose.
Estrogen receptor expression and docetaxel efficacy in patients with metastatic breast cancer: A pooled analysis of four randomized trials
Authors: Mazouni C. , André F. , Broglio K. , Pusztai L. , Hortobagyi G. N.
Published: August 2020

1046

Background:Differences in the efficacy of various chemotherapies in patients with estrogen receptor (ER) positive metastatic breast cancer are not well understood. In the present study, we assessed the efficacy of docetaxel in patients with metastatic breast cancer according to ER expression.Methods: The efficacy of docetaxel on response rates and progression-free survival were analyzed according to ER expression in four randomized trials that included a total of 1,631 patients. Odds-ratio for tumor response was estimated with logistic regression and hazard ratio for progression-free survival was estimated with Cox proportional hazards models. Results: ER expression was assessable in 1,037 patients included in these trials (64%). ER was expressed in 601 tumors (58%). Overall, docetaxel was associated with an increased response rate (odds ratio: 2.66, 95% CI: 1.83 to 3.87) and decreased hazard of disease progression (hazard ratio: 0.85, 95% CI: 0.73 to 0.97) compared to non-docetaxel containing therapy. Docetaxel was associated with similar improvement in response rate both in patients with ER-positive (odds ratio: 2.90, 95% CI: 1.72 to 4.87) and ER-negative disease (odds ratio: 2.55, 95% CI: 1.44 to 4.51). Among all ER-positive patients, tumor response rate was 31.1% among patients who did not receive docetaxel and 46.8% among patients who did receive docetaxel. Decreased hazard of disease progression due to docetaxel was also similar in ER-positive (HR: 0.82, 95% CI: 0.67–1.00) and ER-negative cancers (HR: 0.86, 95% CI: 0.70–1.07), but these results were heterogeneous among trials. The effect of docetaxel was not different in ER-positive and ER-negative disease, both in terms of response rates and progression-free survival (interaction test, p = 0.77 and p = 0.93). Conclusions: Docetaxel increases response rates and decreases the risk of disease-progression in a statistically similar extent both in patients with ER-positive and ER-negative metastatic breast cancer.

No significant financial relationships to disclose.
Anthracycline-rechallenge using pegylated liposomal doxorubicin (PLD) in previously treated patients with metastatic breast cancer (MBC): A meta-analysis using pooled individual data from four prospective trials
Authors: Al-Batran S. , Scholz M. , Jäger E.
Published: August 2020

1047

Background: Few data are available on the efficacy of anthracycline rechallenge using PLD. Methods: Pooled individual data from 4 prospective trials (Keller, J Clin Oncol. 2004; O'Brien, Ann Oncol. 2004; Al-Batran, Br J Cancer. 2006; and Al-Batran, Oncology. 2006) were utilized to evaluate the activity of PLD in pts with MBC previously treated with conventional anthracyclines. Primary endpoint was clinical benefit rate (CBR), defined as objective response or stable disease, both lasting ≥ 6 months. CBR was assessed in the entire group (primary hypothesis CBR ≥ 30%) and in pre-defined subgroups of pts depending on the most important features of their prior anthracycline-based therapy. Results: The studies comprised a total 935 pts, of whom 274 pts had received PLD after prior exposure to conventional anthracyclines. At the time of PLD therapy, these (274) pts were heavily pre-treated for MBC (median lines of previous chemotherapy 4, range 1 to 9, and 93.4% of pts received PLD after ≥ 2 previous chemotherapies for MBC). Prior anthracycline treatment was adjuvant, anti-metastatic, or both in 14%, 46%, or 40% of pts, respectively. The overall CBR from PLD was 32.2% (95% CI, 26.7%-37.8%), with no difference between pts who were considered anthracycline resistant (based on the study records) and those who were not (31.9% vs. 31.6%, respectively; p = 1). There was also no difference in CBR from PLD between pts who received prior anthracyclines adjuvant only (33.3%), anti-metastatic only (34.4%) or both (29.4%; p = 0.71). There was a trend towards a higher CBR in pts who received PLD at > 12 months vs ≤ 12 months since the end of their prior conventional anthracycline treatment (34.2% vs. 26.3%, respectively; p = 0.21). Higher CBR (up to 47%) and longer survival times were observed in pts without taxane pretreatment or with a low number of previous chemotherapies, most likely reflecting a less advanced disease in these pts. Conclusions: This meta-analysis demonstrates a clinical benefit from PLD in MBC pts previously treated with multiple chemotherapies, including anthracyclines. Interestingly, the CBR was independent of resistance to, setting of, or time since previous conventional anthracycline therapy.

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A SARC global collaborative phase II trial of R1507, a recombinant human monoclonal antibody to the insulin-like growth factor-1 receptor (IGF1R) in patients with recurrent or refractory sarcomas
Authors: Patel S. , Pappo A. , Crowley J. , Reinke D. , Eid J. , Ritland S. , Chawla S. , Staddon A. , Maki R. , Vassal G. , Helman L.
Published: August 2020

10503

Background: The IGF1 system has been implicated in sarcoma development and inhibition of IGF1R function has been shown to induce clinical responses in select sarcomas. Methods: Objectives included response rate (RR) and progression-free survival (PFS) to R1507 in patients with recurrent or refractory Ewing's (ES, 2 cohorts- primary refractory vs. others) osteo (OS), synovial (SS), rhabdomyosarcoma (RMS), and other sarcomas. Eligibility included recurrent/refractory measurable disease, age ≥ 12 yrs, life expectancy ≥ 6 weeks, Karnofsky PS ≥ 70, adequate renal, hepatic and bone marrow function. R1507 was administered i.v. at 9 mg/kg over one hour weekly. Response was assessed by WHO criteria every 6 wks X 4 and every 12 wks thereafter. A two-stage design (Green and Dahlberg) was used. The endpoint for the primary refractory ES cohort was PFS at week 18 (planned n=65). RR was the primary endpoint for the remaining cohorts (planned n=240). Results: From 12/07–12/08, 203 eligible patients from 29 centers across the US, Europe and Australia were enrolled. Age ranged from 12–85 yrs (median=27 yrs) and 126 were male. Verified histologic subtypes were ES (n=71), OS (n=43), RMS (n=28), SS (n=25), and others (n=25). 15 severe adverse events were reported in 9 patients, the most common being fatigue (n=2), thrombocytopenia (n=2), dehydration (n=2), and hyperglycemia (n=2). Clinically significant activity has been observed in ES, RMS and OS with several dramatic responses seen in ES and RMS. Independent radiologic review is currently ongoing and updated data will be presented. Conclusions: The rapid accrual amongst many centers in diverse geographical locations demonstrates the feasibility of collaborative research in sarcomas. R1507 is well tolerated and a promising new agent for the treatment of various sarcomas. SARC and Roche are collaborating in additional clinical trials to better define the role of R1507 in the treatment of selected sarcomas.

[Table: see text]
Long-term results of a randomized phase II study of trabectedin by two different dose and schedule regimens in patients with advanced liposarcoma or leiomyosarcoma after failure of prior anthracyclines and ifosfamide
Authors: Demetri G. D. , Schuetze S. , Blay J. , Chawla S. , von Mehren M. , Casali P. , Morris D. , Bayever E. , Alfaro V. , LeCesne A.
Published: August 2020

10509

Background: This prospective, international randomized study evaluated two trabectedin dosing regimens [1.5 mg/m2 24-hour i.v. infusion once every 3 weeks (q3wk 24-h) vs. 0.58 mg/m2 3-hour i.v. infusion every week for 3 weeks of a 4-week cycle (qwk 3-h)] in adult patients (pts) with unresectable and/or metastatic liposarcoma or leiomyosarcoma following failure of at least prior anthracycline and ifosfamide chemotherapy. Methods: Pts were treated and continuously followed in this trial, and we now present final OS data with long-term follow-up (median = 41 mo). With 234 deaths, the study would have >80% power to detect a minimum 45% improvement in median overall survival (OS) (2-sided 5% significance level). Results: The primary efficacy endpoint (time to progression, TTP) was superior for the q3wk 24-h arm, as previously reported [Morgan, et al. J Clin Oncol: 25(18S June 20 Suppl.) 10060 (2007)]. At cutoff, 235 deaths had occurred (13% censored). This final OS analysis confirms the previously reported trend towards improved survival with trabectedin q3wk 24-h despite crossover of 32% of pts from qwk 3-h to the q3wk 24-h dosing regimen. Pts treated with q3wk 24-h had a 16% reduction in the relative risk of death (HR=0.843; p=0.1931). Median (95%CI) OS were 13.9 mo (12.5–18.6; q3wk 24-h) and 11.8 mo (9.9–14.9; qwk 3-h) (log-rank p=0.1920). OS rates at 12 mo were 60% (q3wk 24-h) and 50% (qwk 3-h). Sensitivity analyses censoring at crossover further highlighted this favorable trend in survival with trabectedin q3wk 24-h. With longer follow-up, updated median TTP (investigator assessment, 223 progression events) was 4.2 vs. 2.5 mo [HR: 0.658; p=0.0032], favoring the q3wk 24-h arm. With 59 additional cycles (for a total of 1,532 cycles) and longer exposure, trabectedin safety profile was consistent with that previously reported. Conclusions: Final survival data reinforce the internal consistency of all efficacy-related endpoints showing improved outcomes associated with the trabectedin q3wk 24-h regimen with an acceptable safety profile in this population of patients with advanced, previously-treated leiomyosarcomas and liposarcomas.

[Table: see text]
A phase II clinical trial of neoadjuvant trabectedin in patients with nonmetastatic advanced myxoid/round cell liposarcoma (MRCL)
Authors: Gronchi A. , Le Cesne A. , Bui N. B. , Palmerini E. , Demetri G. , Hohenberger P. , Hohl R. J. , Pilotti S. , Perez I. , Lardelli P.
Published: August 2020

10525

Background: Trabectedin (ET-743, Yondelis), a marine-derived alkaloid has demonstrated significant activity in the treatment of soft tissue sarcomas (STS) in phase III trials, and has recently received EMEA approval in this indication. A subtype that accounts for 10% of STS, MRCL, displays the fusion FUS-CHOP in 95% of all cases. Preliminary results of neoadjuvant trabectedin (T) in advanced MRCL show reduction in the radiological density of the tumor, clinical improvement, and a pathological complete response (pCR) in the resected tumor mass. A phase II study to further determine the response to T in the MRCL population is presented. Methods: In this multicenter Phase II trial, patients (pts) with locally advanced (stage III) or locally recurrent MRCL were treated for 3 - 6 cycles with T (1.5 mg/m2 q3wk) in the neoadjuvant setting. Main endpoints were: pCR rate, objective response rate by RECIST, and correlation of molecular parameters from tissue samples with clinical outcomes. Results: Twenty-five pts with locally advanced MRCL have been recruited, of whom 20 are evaluable. All had the translocation (t12q13, 16p11) which causes the chimeric FUS-CHOP. Median age was 53 (23–75) and male:female ratio was 1. Thirteen pts completed therapy and underwent curative surgery. Pathological assessment was performed in 10 pts: 2 achieved pCR, 1 as per central pathology review and 1 by local pathology assessment. In addition, 1 pt had a very good pathological response. Ten patients remain to be histologically evaluated. Response rate by RECIST from pts who completed therapy was: 6 partial responses (46%) and 7 disease stabilizations. Remarkably, pathological response does not entirely correlate with response by RECIST since the pts with pCR still had radiological disease but no malignant component was found in the excised tumor mass (only connective and reactive tissue). Two serious adverse reactions of severe rhabdomyolysis, and asthenia, nausea and transaminase elevation were reported. Most common toxicities were liver enzyme elevation, neutropenia and thrombocytopenia. Conclusions: These preliminary results in terms of objective and complete pathologic responses, strongly suggest that T may have a role in the neoadjuvant setting in pts with MRCL.

[Table: see text]