bluuebunny/crossref_metadata_2025 huggingface dataset:
Expression of the multidrug transporter genes ABCC1/MRP1, ABCC3/MRP3, and ABCC4/MRP4 are powerful predictors of clinical outcome in childhood neuroblastoma
Authors: Norris M. D. , Smith J. , Kwek A. , Flemming C. , Cohn S. L. , London W. B. , Buxton A. , Marshall G. M. , Haber M.
Published: March 2020

9524

Background: We have previously shown, both retrospectively and prospectively, that high-level expression of the multidrug transporter gene ABCC1/MRP1, is strongly predictive of poor outcome in the childhood cancer neuroblastoma (NEJM, 334:231–8, 1996; JCO, 24:1546–53, 2006), and that ABCC1/MRP1 can be regulated by the MYCN oncogene. The contribution of other ABCC family genes to clinical outcome in this disease has now been examined. Methods: Real-time quantitative PCR was used to determine ABCC gene expression in a large prospectively accrued cohort (n=209) of primary untreated neuroblastomas from patients enrolled on POG biology protocol 9047. Results: Older age, advanced stage, and MYCN amplification were all predictive of poor outcome in the cohort. Amongst the ABCC family, high levels of ABCC1 and ABCC4, but low levels of ABCC3, were strongly associated with reduced survival and event-free survival (P<0.005) in the overall study population, and also in subgroups of patients lacking MYCN amplification. Following adjustment for the effect of MYCN gene amplification and other prognostic indicators by multivariate analysis, expression of ABCC1 (HR=2.3; p=0.03), ABCC3 (HR=2.7; p=0.0141), ABCC4 (HR=3.4; p=0.002) retained significant prognostic value for outcome, whereas age and MYCN amplification lost all prognostic significance. By combining the expression of these three transporter genes, patients could be stratified into groups having excellent, intermediate or poor outcome (EFS=84%, 59%, 17%, respectively). Conclusions: These data, suggest that ABCC1, 3 and 4 are amongst the most powerful prognostic markers yet identified for childhood neuroblastoma and as such represent important targets for potential therapeutic intervention.

No significant financial relationships to disclose.
My child matters program: A UICC-sanofi-aventis partnership to improve pediatric cancer care in developing countries
Authors: Ribeiro R. C. , Eden T. , Hartford J. , Lemerle J. , Magrath I. , Sancho-Garnier H. , Steliarova-Foucher E. , Thaxter G. , Tabah-Fisch I. M. , Cavalli F.
Published: March 2020

9526

Background: Despite dramatic advances in curing childhood cancer in developed countries, most children with cancer live in low-income countries, where misdiagnosis, late diagnosis, lack of access to treatment and abandonment of treatment hinder progress. Methods: In 2004 the International Union against Cancer and sanofi-aventis initiated a campaign to improve childhood cancer care in developing countries through grants for local projects (up to 50,000 euros/year each), a survey of childhood cancer care (conducted by the public health consulting firm Sanisphere), and lobbying to increase political support. The projects focus on professional education, improved access to care, pain management, and psychosocial/educational support. Results: During 2006, 14 pilot projects in Bangladesh, Egypt, Honduras, Morocco, Philippines, Senegal, Tanzania, Ukraine, Venezuela, and Vietnam were selected on the basis of feasibility, expected benefit, sustainability, and potential to serve as models. Only eight countries had pediatric hematology/oncology units, ranging from 20 (Tanzania) to 350 (Egypt) beds. These units manage 100 (Senegal) to 1,000 (Bangladesh) children with cancer per year (a small fraction of actual cases in these countries). One-year outcome analysis showed that various short-term objectives were met, including improved patient care infrastructure, public and professional education, earlier detection, improved access to care, the introduction of psychosocial support, decreased abandonment and better follow up. On the basis of these results, 12 additional projects have been funded in Bolivia, Indonesia, Kenya, Mali, Peru and Romania. Conclusions: Relatively small investments, accompanied by external mentoring, can help build sustainable capacity for the diagnosis and care of children with cancer in selected institutions in developing countries.

No significant financial relationships to disclose.
Aberrant indoleamine 2,3 dioxygenase (IDO) expression is present in pediatric patients with Hodgkin's lymphoma
Authors: Shahlaee A. H. , Al-Quran S. Z. , Hou W. , Schwartz C. , Munn D. H.
Published: March 2020

9531

Background: Indoleamine 2,3 dioxygenase (IDO) is a tryptophan-catabolizing enzyme capable of inducing local immunosuppression and systemic tolerance. IDO activity, as measured by serum levels of tryptophan (TRP) and kynurenine (KYN), has been shown to portend a worse prognosis in several different malignancies. Additionally, IDO expression in tumor draining lymph nodes predicts a worst outcome in patients with malignant melanoma making IDO a potential target for therapeutic intervention. To date, no studies have evaluated the expression pattern of IDO in the setting of pediatric Hodgkin Disease. Methods: 20 cases of pediatric Hodgkin Disease (2 stage I, 11 stage II, 2 stage III and 5 stage IV), treated on Children's Oncology Group trials were studied. Paraffin-embedded tumor tissues and matching pre- and post-chemotherapy sera were obtained via the Cooperative Human Tissue Network (CHTN). Immunohistochemical studies were performed on sections of paraffin-embedded tissues to evaluate aberrant IDO expression and secondary serum KYN/TRP changes were analyzed. Results: Tumor tissues from 17/20 patients (85%) were positive for IDO. Two cases showed no expression and one was not evaluable due to tissue necrosis. Morphologically several cell types were noted to express IDO including eosinophils, dendritic cells and large cells, some of which are bi-nucleated, possibly consistent with Reed-Sternberg cells and variants. The mean serum KYN/TRP ratio was elevated pre-chemotherapy in comparison to post therapy levels (P value=0.0043 by Wilcoxon sign rank test). Conclusions: This pilot data demonstrates that aberrant IDO expression is a common finding in pediatric Hodgkin Disease, and that the potential immunomodulatory role of IDO expression in the context of Hodgkin Disease needs to be further studied. These data warrant further prospective evaluation in a larger cohort of patients to determine the clinical applicability of this observation.

No significant financial relationships to disclose.
Rate of positive blood cultures after 3 days of empiric antibiotics in pediatric cancer
Authors: Kanathezhath B. , Feusner J.
Published: March 2020

9535

Background: Infections continue to be a major cause of morbidity and mortality in pediatric oncology patients (pts) with febrile neutropenia (FN). The proportion of such pts who have bacteremia documented after 72 hours (hrs) of broad-spectrum antibiotics, in the absence of local or systemic signs of infection, has not been previously reported. Methods: We conducted a retrospective analysis of all FN oncology pts admitted to our hospital during the period of August 1999 to October 2006. Blood cultures (BCs) from pts who were persistently febrile more than 3 days after initiation of empiric broad-spectrum antibiotics (ceftazidime and tobramycin) were analyzed. Medical records of pts with positive late blood cultures (LBCs) after 72 hrs were reviewed for onset of new signs and symptoms of infection. Hematopoietic stem cell transplant and HIV pts were excluded. Results: Ninety-seven episodes of persistent fever occurred in 71 FN pts. The total number of positive BCs in the first 72 hours was 24 (33.8%). Three (4.2%) of the persistently febrile pts had positive LBC. Of these 3 pts, one had preceding new signs and symptoms. Another had a probable contaminant (only 1 positive BC for coagulase-negative staphylococcus). Only one pt (1.4%) had positive LBC without any new local or systemic signs of infection. The observed frequency of positive LBC was 4.2% for pts and 0.8% (3/391) for total cultures obtained after 72 hours. There were no changes made in the antibiotic regimen of pts with positive LBC and none of them suffered from sepsis related mortality. Conclusions: This is the first report of late blood culture results in FN pediatric oncology pts. The practice of obtaining daily blood culture in such pts who are stable after 72 hrs of broad- spectrum antibiotics has a low yield (<5%), and even lower (<2%) if pts with new signs or symptoms at the LBC are excluded. This observation, if confirmed by larger studies from other centers, could lead to a more efficient, risk based strategy for following these pts.

No significant financial relationships to disclose.
Plasma heparanase as a significant marker of treatment response in pediatric malignancies: Pilot study
Authors: Ben Arush M. W. , Shafat I. , Ben Barak A. , Postovsky S. , Elhasid R. , Vlodavsky I. , Ilan N.
Published: March 2020

9540

Introduction: The aim of this pilot study was to determine heparanase plasma levels (HP) at diagnosis and at restaging in children diagnosed with cancer, and to investigate whether this parameter provides prognostic information for remission after induction therapy and response to treatment. Patients and Methods: Heparanase plasma levels of 45 consecutive pediatric patients (pts) with various types of cancer were assayed at diagnosis and at restaging. Mean age: 10.3 years (y) (0.5y-21y), 20 females, 25 males. Levels of heparanase were determined using a commercially available ELISA anti-human heparanase immunoassay kit. According to diagnosis, bone marrow aspiration, CAT scan, MRI, technetium bone scan, PET-CT fusion were performed to assess response to treatment after the first month of induction for leukemia patients, 2 to 3 courses of chemotherapy for other malignancies. Results: Changes in HP levels were found to correlate with response to treatment for most of the children. At diagnosis, average HP level was 1,539 pg/mL (range, 55 pg/mL-6,567 pg/mL) and decreased at restaging to 943 pg/mL (range, 0 pg/mL -3,682 pg/mL) (p=0.0133). At diagnosis, the average HP of the 37 patients in CR or VGPR was 1,692 pg/mL and at restaging decreased to 928 pg/mL (p=0.0071). At diagnosis, the average HP level for the 5 pts with TP or PR was 1,873 pg/mL and increased to 2,633 pg/mL at restaging (p=0.4223). Due to the small number of patients we did not observe any correlation with diagnosis or any other clinical prognostic factor. Conclusions: Changes in plasma heparanase levels correlated with response to treatment for all of the children diagnosed with cancer. This provides a rationale for exploring clinical interest in plasma heparanase measurements of a larger group of children with malignancies, and using the test for clinical trials of antiangiogenic therapies.

No significant financial relationships to disclose.
Phase II study of the combination of cisplatin + temozolomide in malignant glial tumours in children and adolescents at diagnosis or in relapse (cistem2/nct00147160)
Authors: Grill J. , Lowis S. , Frappaz D. , Michalski A. , Picton S. , Jouvet A. , Robson K. , Jaspan T. , Couanet D. , Le Deley M.
Published: March 2020

9543

Background: Temozolomide has been shown moderately effective in pediatric high-grade glioma (HGG). By decreasing the activity of MGMT, principal mechanism of resistance to temozolomide, cisplatin may increase the activity of this alkylating agent. Methods: Patients aged 4 to 21y with HGG outside the brainstem were treated at diagnosis or at relapse every 28 days with a combination of cisplatin 80 mg/m2 intravenously on day-1 and temozolomide 200 mg/m2 orally on days 2–6, according to the pediatric phase I recommendations. Patients treated at diagnosis had to proceed to involved field radiotherapy after the chemotherapy window. According to initial response, patients were offered additional courses, up to seven. We considered that this combination would be of interest if the response rate was superior or equal to 20%, using a two-stage Simon design in 3 cohorts: evaluable non measurable (infiltrative) at diagnosis (cohort A1); measurable disease (nodular) at diagnosis (A2); recurrent disease (B). The primary endpoint was complete or partial response after two courses, confirmed by central review. Up to 29 evaluable pts were to be entered in each cohort. If fewer than 4/29 responses were observed, it would be concluded that the combination is ineffective. Results: 56 pts were entered from 10/2003 through 07/2006 in 25 centers. One was excluded after central pathology review and 3 due to insufficient radiology work-out. 42 had grade III and 13 grade IV gliomas, including 21 tumors with oligodendroglial features. No response was observed in the first 11 pts in cohort A1 and in the first 12 pts in cohort B. Two partial and 4 minor responses were confirmed in 29 pts of cohort A2 leading to a 7% response rate (95% CI, 1–23%). Median time to progression was 1.7, 7.1 and 6.9 months in cohorts A1, A2 and B, respectively. Toxicity was manageable except in pts with large infiltrative lesions who did not tolerate hydration. Conclusion: CISTEM combination has insufficient efficacy in pediatric compared to adult HGG despite efficient down-regulation of MGMT activity. To overcome resistance to temozolomide in children and adolescents, one may need to target other known resistance mechanisms such as mismatch-repair deficiency.

[Table: see text]
A phase I study of cetuximab and irinotecan in pediatric patients (pts) with refractory solid tumors
Authors: Trippett T. M. , Kuttesch J. , Herzog C. , Boklan J. , Bagatell R. , Hunger S. , Arceci R. , Lu H. , Langer C. , Gore L.
Published: March 2020

9547

Background: Irinotecan has shown antitumor activity in a number of pediatric tumors. In adults with colorectal cancer, combining irinotecan with cetuximab enhances clinical activity as compared to treatment with irinotecan alone. We implemented this first-in- pediatrics phase I study to determine the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) of cetuximab and irinotecan in pediatric patients. Methods: 35 heavily pre-treated pts with refractory solid tumors were enrolled: brainstem glioma/astrocytoma (16), hepatoblastoma (4), neuroblastoma (2), other (13). Weekly cetuximab was escalated in 3 sequential dose levels: 75, 150 or 250mg/m2; Irinotecan was given at 16 or 20 mg/m2/day over 1 hour [daily × 5] for two weeks, every 21 days. Correlative EGFR expression (immunohistochemistry and FISH) and/or mutations, pharmacokinetics (PK) of and immune response to cetuximab were performed. Results: Pts were treated in two age cohorts (ages 1–12 yrs = Group A, and 13–18 yrs = Group B). PK analyses show linearity, with similar t1/2, clearance, and volume of distribution between groups. Irinotecan-related DLT in 2/6 pts in Group A/dose 2 necessitated dose de-escalation. Three pts experienced Grade 3 hypersensitivity infusion reaction and were discontinued. A pt with an EGFR-negative high-grade glioma (dose level 1) achieved a >70% reduction in tumor size and remains on study for 16+ months (24 cycles). A pt with ependymoma experienced a partial response (PR) and continues on cycle 12+. 9 pts received ≥4 cycles of therapy. 16 pts had a best response of stable disease or PR (mean 17 wks, range 5–66+ wks) for a clinical benefit rate of 45%. Conclusions: The combination of cetuximab and irinotecan is well-tolerated over multiple repeat cycles without cumulative toxicity in children with refractory CNS and non-CNS solid tumors. Promising preliminary anti-cancer activity was observed in a variety of pediatric solid tumors. Detailed biologic correlative and PK data will be presented.

[Table: see text]

No significant financial relationships to disclose.
Osteosarcoma in children aged less than five years at diagnosis: Experience of the Cooperative Osteosarcoma Study Group
Authors: Kager L. , Zoubek A. , Kevric M. , Dominkus M. , Lang S. , Exner U. G. , Mass R. , Jürgens H. , Bielack S.
Published: March 2020

9554

Background: The incidence of osteosarcoma considerably varies with age and preschool children are reported to be extremely rarely affected. This study was conducted to investigate presentation, treatment, and outcome in very young children with osteosarcoma. Patients and Methods: The authors retrospectively analyzed the collected data of 2,706 consecutive patients with newly diagnosed high-grade osteosacroma of bone registered in the COSS studies between 1976 and 2005; and identified 28 patients (1%) aged less than five years at diagnosis. Demographic, diagnostic, tumor, and treatment related variables; response and survival data of these 28 patients were analyzed. Results: Of the 28 (male, N = 16; female, N = 12) identified toddlers (two years, N = 4; three years, N = 10; four years, N = 14), 27 presented with a high-grade central osteosarcoma of an extremity (femur, N = 12; humerus, N = 10; tibia, N = 5) and one with a secondary osteosarcoma of the orbit. The size of the primary extremity tumor was large in 74% of patients. Primary metastases were detected in 4/28 children. All 28 patients received multiagent chemotherapy, and 13 of the 21 analyzed tumors responded well to neoadjuvant chemotherapy (>90% necrosis). Limb sparing surgery was feasible in 11 children, whereas ablative procedures were performed in 14 patients. A macroscopically complete surgical remission of all clinically detectable tumors was achieved in 24/28 patients during front line therapy. With a median follow-up of 1.7 years (4.2 years for survivors), 15/28 patients were alive. Outcome was poorer for the 28 toddlers compared to the 2,678 older patients (5-year event free survival 43% ± 10% vs. 56% ± 1%)(P = 0.02). Conclusion: Osteosarcoma is extremely rare in preschool children. These young patients often have large tumors which may require mutilating resections. Despite the high rate of ablative surgery, the prognosis, however, may be poorer compared to older patients.

No significant financial relationships to disclose.
ITCC phase I study of erlotinib as single agent in children with refractory and relapsed malignant brain tumors and in combination with irradiation in newly diagnosed brain stem glioma
Authors: Geoerger B. , Hargrave D. , Ndiaye A. , Frappaz D. , Doz F. , Leblond P. , Gentet J. , Riccardi R. , Paoletti X. , Le Deley M. , Vassal G.
Published: March 2020

9556

Background: Erlotinib hydrochloride (OSI-774), a selective inhibitor of the EGFR tyrosine kinase, may be active in childhood brain tumors, particularly in combination with irradiation. Methods: Multicenter, non-randomized phase I study with separate dose findings for erlotinib as single agent in children with refractory or relapsing brain tumors (group 1), and combined to irradiation in newly diagnosed brain stem glioma (group 2). Erlotinib was administered orally daily at 75, 100, 125 or 150 mg/m2. Dose escalation was performed in a classical 3+3 methodology for group 1 and according to the continuous reassessment method for group 2; dose-limiting toxicity (DLT) was evaluated at 3 and 6 weeks, respectively. Results: In total, 31 patients have been entered to date, 30 received treatment, 17 in group 1 (3 relapsing brain stem glioma, 4 ependymoma, 4 oligodendroglioma, 6 other) and 13 in group 2 with a median age of 9 and 6 years (range 4–16 and 2–12), respectively. Median treatment duration was 1.5 and >5 months, respectively. In group 1, 3 patients each were treated at 75 mg/m2 and 100 mg/m2, 7 at 125 mg/m2, 4 at 150 mg/m2. One patient with a glioneuronal tumor treated at 125 mg/m2 experienced G5 intra-tumoral hemorrhage at day 4 which was considered as DLT; at 150 mg/m2, 1 patient with an oligodendroglioma experienced G3 asthenia at day 18 and G3 intratumoral hemorrhage at day 29, and 1 patient with an ependymoma experienced G5 intra-tumoral hemorrhage at day 49. In group 2, 1/6 patients treated with erlotinib 75 mg/m2 and irradiation experienced seizures and died, no DLT occurred in 6 patients at 100 mg/m2. Non-hematological toxicities included G1-G2 erythema, folliculitis, dry skin, trichomegaly, G1 transaminitis, bilirubinemia, G1–3 asthenia, G1–5 intra-tumoral hemorrhage. Minor tumor response was observed in an oligodendroglioma. Pharmacokinetic and biological evaluations are ongoing. Conclusions: Erlotinib was well tolerated in children with cutaneous symptoms being the most frequent treatment toxicity. However, neurological toxicity and intra-tumoral hemorrhage was notable in these children with brain tumors. Inclusion at 125 mg/m2 is ongoing to confirm the MTD.

No significant financial relationships to disclose.
Phase III study on larynx preservation comparing induction chemotherapy and radiotherapy versus alternating chemoradiotherapy in resectable hypopharynx and larynx cancers. EORTC protocol 24954–22950
Authors: Lefebvre J. , Horiot J. , Rolland F. , Tesselaar M. , Leemans C. R. , Geoffrois L. , Hupperets P. , Lacombe D. , Bogaerts J. , Bernier J.
Published: March 2020

LBA6016

Background: Final analysis of a larynx preservation study comparing sequential induction chemotherapy and radiotherapy (XRT) versus alternating chemoradiotherapy in treating resectable hypopharynx and larynx cancers. Methods: Patients (pts) with untreated, resectable T3-T4 larynx or T2-T3-T4 hypopharynx, N0-N2, M0 squamous cell carcinoma (SCC) were randomized in this prospective Phase III trial. Pts received in the control arm (SEQ) 2 cycles of cisplatin/5-FU (CF), followed in case of response by 2 additional cycles of CF, followed on day 80 by XRT (70 Gy / 35 fractions / 7 weeks), or in the experimental arm a CF cycle in weeks 1, 4, 7 and 10, alternated with XRT (20 Gy / 10 fractions) during the three 2-week intervals (ALT). Pts had surgery and postoperative XRT in case of non- response. The primary endpoint was survival with a functional larynx (FLS), with events including local relapse, laryngectomy, tracheotomy, gastrostomy, feeding tube, and death. With 450 patients and 3 yrs minimum followup per pt, this trial was planned to provide 80% power to detect a difference of 11% (from 28% to 39%) in this endpoint at 3 years by 2-sided Logrank test (Type I error 5%). Results: The trial enrolled 450 pts (224 to SEQ, 226 to ALT) from July 1996 to May 2004. Median followup is 6.5 years (yrs). 76 pts discontinued treatment for toxicity (34 on SEQ, 42 on ALT). Hazard ratio (HR) for FLS was 0.84 (95% CI 0.67–1.05, p=0.12) with medians 1.6 yrs on SEQ and 2.3 yrs on ALT. OS (medians of 4.4 and 5.2 yrs) and PFS (medians of 3.0 and 3.1 yrs) were similar for SEQ and ALT, respectively. At 3 yrs, cumulative incidence of larynx events was 46% on SEQ and 38% on ALT (HR 0.79, p=0.09). Grade 3/4 mucositis was seen in 32% of pts who received RTX on SEQ, and 21% on ALT. Late severe edema and/or fibrosis was observed in 16% of pts in SEQ and 11% in ALT. Conclusion: A 8% difference in larynx function preservation rate at 3 yrs favoring ALT did not translate into statistically significant differences. ALT, as a form of chemoradiation, did not lead to increased incidence and severity of mucositis. There were no relevant long-term sequelae in either arm.

No significant financial relationships to disclose.
Does tetracycline prevent/palliate epidermal growth factor receptor (EGFR) inhibitor-induced rash? A phase III trial from the North Central Cancer Treatment Group (N03CB)
Authors: Jatoi A. , Rowland K. , Sloan J. A. , Gross H. M. , Fishkin P. A. , Kahanic S. P. , Novotny P. J. , Schaefer P. L. , Dakhil S. R. , Loprinzi C. L.
Published: March 2020

LBA9006

Purpose: Many patients who receive EGFR inhibitors develop an acneiform rash, and anecdotal reports suggest tetracycline is effective in treating it. To our knowledge, however, no rigorous trials have ever been published to substantiate this approach. This double- blinded, placebo-controlled trial was conducted to assess the role of tetracycline in preventing EGFR inhibitor-induced rash and/or reducing its severity. Methods: 61 patients were randomly assigned to tetracycline 500 mg orally twice a day×4 weeks versus an identical, similarly prescribed placebo. Eligibility criteria required all patients to have begun an EGFR inhibitor </= 7 days prior with no rash at study entry. Patients were to be followed for 8 weeks. Physician assessments of rash incidence, severity, and adverse events, occurred at 4 and 8 weeks. Patients completed a weekly rash diary, quality of life questionnaire (SKINDEX-16), and EGFR inhibitor compliance questionnaire. Thirty patients per group provides 90% power to detect a difference in rash incidence (the primary endpoint) of 40% between groups and of rejecting the null hypothesis of equal proportions with a type I error of 5% (2-sided). Results: Treatment arms were balanced on baseline characteristics, drop out rates, and rates of discontinuation of the EGFR inhibitor. Rash incidence was comparable across arms. Physicians reported that 16 tetracycline-treated patients (70%) and 22 placebo-exposed patients (76%) developed a rash (p=0.61). However, tetracycline appears to have lessened rash severity. By week 4, physician-reported grade 2 rash occurred in 17% of tetracycline-treated patients (n=4) and 55% of placebo- exposed patients (n=16); (p=0.04). Tetracycline-treated patients reported better scores on certain quality of life parameters (SKINDEX-16), such as skin burning or stinging, skin irritation, and being bothered by a persistence/recurrence of a skin condition. Adverse events were comparable across arms. Conclusion: Tetracycline did not prevent EGFR inhibitor-induced rashes. However, diminished rash severity and improved quality of life suggest this antibiotic merits further study.

No significant financial relationships to disclose.
Freedom from progression (FFP) by adding paclitaxel (T) to doxorubicin (A) followed by CMF as adjuvant or primary systemic therapy: 10-yr results of a randomized phase III European Cooperative Trial in Operable Breast Cancer (ECTO).
Authors: Zambetti Milvia , Baselga José , Eiermann Wolfgang , Guillem Vicente , Semiglazov Vladimir , Lluch Ana , Sabadell Dolores , Bozhok Alla , Byakhov Mikhail J. , Ojeda Belen , Mansutti Mauro , Mariani Gabriella , Moliterni Angela , Cortes-Funes Hernan , Colozza Marian , Pienkowski Tadeusz , Magazzu Domenico , Valagussa Pinuccia , Bonadonna Gianni , Gianni Luca
Published: March 2020

537

Background: At the time the ECTO was designed in 1996, taxanes were only indicated for patients with metastatic breast cancer. However, paclitaxel and docetaxel were still to be tested in the adjuvant setting. In addition there was relatively scarce information on the comparative efficacy of neoadjuvant and adjuvant regimens. The ECTO trial was designed to evaluate the addition of paclitaxel to an anthracycline-based adjuvant regimen and to compare this combination with the same regimen given as primary systemic (neoadjuvant) therapy. Methods: A total of 1,355 women with operable breast cancer were randomized to one of three treatments: 1) surgery followed by adjuvant single agent doxorubicin (A) followed by CMF (arm A); 2) surgery followed by adjuvant paclitaxel plus doxorubicin (AT) followed by CMF (arm B); 3) AT followed by CMF followed by surgery (arm C). The two co-primary objectives were to assess the effects on freedom from progression (FFP) of: 1) the addition of paclitaxel to post-operative chemotherapy (arm B versus arm A); and 2) primary versus adjuvant chemotherapy (arm B versus arm C). Results: At 10 years, in the adjuvant setting FFP remained statistically significant in favor of AT followed by CMF (arm B, HR 0.77, P=0.045). Distant FFP was similarly improved but overall survival was not (HR 0.82, P=0.24). There was no significant difference in FFP when chemotherapy was given after surgery compared with the same regimen given before surgery (arm B vs arm C, HR 0.79, P=0.07). In the primary chemotherapy arm, patients who achieved a pathological complete remission (pCR) had improved distant FFP (P < 0.001) compared to patients who did not achieve pCR. When given as primary systemic therapy, the paclitaxel-containing regimen allowed breast-sparing surgery in a significant percentage of patients, which did not translate in an increased risk of ipsilateral breast recurrence compared to the risk observed in patients in the adjuvant arms. Conclusions: Incorporating paclitaxel into anthracycline-based adjuvant therapy resulted in a significantly improved FFP and DFFP.
Phase 2 study of the CDK4 inhibitor abemaciclib in dedifferentiated liposarcoma.
Authors: Dickson Mark Andrew , Koff Andrew , D'Angelo Sandra P. , Gounder Mrinal M. , Keohan Mary Louise , Kelly Ciara Marie , Chi Ping , Antonescu Cristina R. , Landa Jonathan , Qin Li-Xuan , Crago Aimee Marie , Singer Samuel , Tap William D.
Published: March 2020

11004

Background: The oncogene cyclin-dependent kinase 4 (CDK4) is amplified in > 90% of de-differentiated liposarcomas (DDLS). We previously demonstrated that treatment with the CDK4 inhibitor palbociclib results in favorable progression-free survival (PFS) in DDLS. Abemaciclib is a newer and more potent CDK4 inhibitor. This single-arm phase 2 study was designed to test the activity of abemaciclib in DDLS. Methods: Participants were adults with advanced DDLS, measurable disease by RECIST 1.1, any (or no) priory therapy, and progression by RECIST in the 6 months prior to study entry. The primary endpoint was PFS at 12 weeks. Based on historical data, promising drugs have 12-week PFS of ≥ 40% and not promising ≤ 20%. This study would be positive if 12-week PFS was ≥ 60%. The study was approved by the Institutional Review Board of Memorial Sloan-Kettering Cancer Center and all patients provided written informed consent. The study was registered at Clinicaltrials.gov (NCT02846987) and study drug was provided by Eli-Lilly. Results: Treatment was abemaciclib 200 mg by mouth twice daily continuously. 30 patients were treated and 29 were evaluable for the primary endpoint. Patient characteristics: Median age 62 (range 39-88), 60% male. Lines of prior therapy: 0 (50%); 1 (33%); ≥ 2 (17%). The observed PFS at 12 weeks was 76% (95% CI 57-90%). Median PFS was 30.4 weeks (95% CI 28.9-NE). There was one partial response. A further 3 patients had > 10% decrease in tumor size by RECIST but did not meet the criterion for partial response. Grade 3-4 toxicity included anemia (37%), neutropenia (20%), thrombocytopenia (17%) and diarrhea (7%). Conclusions: This study met its primary endpoint. In patients with advanced progressive DDLS, abemaciclib treatment results in favorable PFS and objective tumor response with manageable toxicity. Updated response data and results of paired tumor biopsies will be presented. Clinical trial information: NCT02846987.
Prediction of treatment (tx)-induced fatigue in breast cancer (BC) patients (pts) using machine learning on genome-wide association (GWAS) data in the prospective CANTO cohort.
Authors: Lee Sangkyu , Deasy Joseph O. , Oh Jung Hun , Di Meglio Antonio , Boyault Sandrine , Rousseau-Tsangaris Marina , Besse Celine , Thomas Emilie , Boland-Augé Anne , Cottu Paul H. , Tredan Olivier , Levy Christelle , Martin Anne-Laure , Everhard Sibille , Ganz Patricia A. , Partridge Ann H. , Michiels Stefan , Deleuze Jean-Francois , Andre Fabrice , Luis Ines Maria Vaz Duarte
Published: March 2020

11515

Background: Many BC survivors report fatigue. The relevant genomic correlates of fatigue after BC are not well understood. We applied a previously validated machine learning methodology (Oh 2017) to GWAS data to identify biological correlates of fatigue induced after tx. Methods: We analyzed 3825 BC pts with GWAS data (Illumina InfiniumExome24 v 1.1) from the CANTO study (NCT01993498). The outcome of this study was post-tx fatigue 1 year after the end of primary chemotherapy/radiotherapy/surgery using the EORTC C30 fatigue subscale (overall fatigue) and the EORTC FA 12 fatigue domains (physical/emotional/cognitive). For each domain, we limited the study group to those with zero baseline fatigue and defined severe fatigue change as score increase above the third quartile. We tested univariate correlations between severe fatigue in each domain and 496539 SNPs as well as relevant clinical variables. The machine learning prediction model based on preconditioning random forest regression (PRFR) (Oh et al., 2017), was then built using the SNPs with ancestry adjusted univariate p-value < 0.001 and clinical variables with Bonferroni adjusted p-value < 0.05. The model was validated in a holdout subset of the cohort. Gene set enrichment analysis (GSEA) was performed using MetaCore to identify key biological correlates relevant to tx-induced fatigue. Results: Distinct results were found by fatigue domain (table). GSEA showed that the cognitive fatigue model SNPs included biomarkers for cognitive disorders (p = 1.6 x 10-12) and glutamatergic synaptic transmission (p = 1.6 x 10-8). Conclusions: A SNP based model had differential performance by fatigue domain, with a potential genetic role on risk and biology for tx induced cognitive fatigue. Further research to explore biomarkers of tx induced fatigue are needed. [Table: see text]
Acupuncture versus cognitive behavioral therapy for cognitive impairment in cancer survivors with insomnia: Implications for personalized medicine.
Authors: Mao Jun J. , Liou Kevin , Root James , Li Qing Susan , Bao Ting , Garland Sheila N. , Ahles Tim
Published: March 2020

11522

Background: Cognitive impairment is a prevalent condition among cancer survivors that lacks effective treatment and can be maintained and exacerbated by poor sleep. This study explored whether treating insomnia with acupuncture or Cognitive Behavioral Therapy for Insomnia (CBT-I) improves subjective and objective cognitive functions in cancer survivors. Methods: We analyzed cognitive outcomes from a pragmatic randomized trial comparing acupuncture versus CBT-I for cancer survivors with insomnia. Analysis was limited to those reporting cognitive impairment at baseline. Acupuncture and CBT-I were delivered over 8 weeks. Perceived cognitive ability was assessed using the Brown Attention-Deficit Disorder Scale (BADDS). Objective cognitive function was evaluated with the Buschke Selective Reminding Test (BSRT). All outcomes were evaluated at baseline, Week 8 (end of intervention), and Week 20 (12 weeks post-intervention). Results: Among 99 cancer survivors, mean age was 60.4 years, 56.6% were women, and 26.3% were non-white. The most common cancer types were breast (31.3%) and prostate (19.2%). Perceived cognitive ability improved in both acupuncture and CBT-I groups at weeks 8 and 20 relative to baseline (all P < 0.001). No significant between-group differences were noted in BADDS total score (p = 0.28), but the CBT-I group demonstrated a better BADDS attention subscale score than the acupuncture group at weeks 8 and 20 (p = 0.031). With regards to objective cognitive functions assessed by BSRT, acupuncture improved attention (p = 0.017), learning (p = 0.040), and memory (p = 0.0020) at Week 8, whereas CBT-I only improved attention at Week 20 (p = 0.0002); between-group differences were not statistically significant. Conclusions: Among cancer survivors with insomnia, both acupuncture and CBT-I improved cognitive impairment relative to baseline, but their relative effects differed: the CBT-I group showed slightly better subjective attention, whereas the acupuncture group may have improved objective memory. Further investigation of these two therapies may lead to effective and personalized interventions for cancer survivors. Clinical trial information: NCT02356575.
Safety, tolerability, and PK of topical calcitriol formulation for treatment of chemotherapy-induced alopecia (CIA) in patients receiving taxane-based regimen: Final results.
Authors: Lacouture Mario E. , Sarangarajan Rangaprasad , Jimenez Joaquin Juan , Kiebish Michael A. , Narain Niven R. , Berman Brian , Goldfarb Shari Beth
Published: March 2020

11608

Background: Chemotherapy-induced alopecia (CIA) following taxane-based treatment regimen is due to direct toxicity of these agents on rapidly dividing cells within hair follicles. Currently no oral or topical agents have been approved for prevention of CIA. In murine studies, topical calcitriol reduced CIA, likely due to arrest of cell cycle in healthy hair follicles, and reduction in the sensitivity of follicular epithelium to chemotherapy. Methods: A 3+3 dose-escalation strategy was used in this Phase 1 study with 3-6 patients at six dose levels (5/10/20/40/60/80 μg/mL) were assessed for safety and tolerability of BPM31543. Patients with a diagnosis of breast cancer, gynecologic cancer or sarcomas receiving a taxane-based chemotherapy regimen applied 1mL of the formulation to the scalp BID, ≥ 5 days prior to starting chemotherapy for at least 3 months or until treatment completed. Safety and efficacy assessments included AE monitoring, PK analysis, blinded photographic assessments and patient self-assessment. Results: 22/23 (95.7%) female patients receiving treatment and included in the safety population experienced at least one TEAE. The most frequently experienced TEAEs were alopecia (14 pts; 60.9%), fatigue (11 pts; 47.8%), nausea (9 pts; 39.1%), peripheral sensory neuropathy (7 pts; 30.4%), and maculopapular rash and vitamin D increased each in six patients (26.1%). Of these, elevated vitamin D and rash were possibly or probably related to treatment. Fatigue, nausea, and neuropathy were likely due to chemotherapy. In 18 patients included in the post-dose versus pre-treatment comparison, there was no dose-dependency on systemic levels of calcitriol. Hair loss < 50% from baseline was observed in 8 patients at week 7 that was maintained at week 15 in 2 patients. Conclusions: Study results showed BPM31543 applied topically twice daily to the scalp in patients receiving taxane-based chemotherapy was safe and well-tolerated. No DLT was observed up to 80 µg/mL dose and no MTD level was reached. There was a signal of potential efficacy detected at each dose level. A seamless Phase 2/3 trial strategy for clinical development is planned. Clinical trial information: NCT01588522.
Advanced cancer patients’ changes in terminal illness understanding (TIU) and their psychological well-being.
Authors: George Login S. , Shen Megan Johnson , Maciejewski Paul K. , Epstein Andrew S. , Prigerson Holly Gwen
Published: March 2020

11617

Background: Although accurate TIU is necessary for informed treatment decision-making, clinicians worry that patients’ recognition of the terminal nature of their illness may lower psychological well-being. This study examines if such recognition is associated with lowered psychological well-being, that persists over time. Methods: Data came from 87 advanced cancer patients, with a life expectancy of less than 6 months. Patients were assessed pre and post an oncology visit to discuss cancer restaging scan results, and again one month later (follow-up). TIU was assessed at pre and post as the sum of four indicator variables — understanding of terminal nature of illness, curability, stage, and life-expectancy — and a TIU change score was computed (post minus pre). Psychological well-being (psychological symptoms subscale, McGill questionnaire) was assessed at pre, post, and follow-up, and two change scores were computed (post minus pre; follow-up minus post). Results: Changes toward more accurate TIU was associated with a corresponding decline in psychological well-being ( r = -0.33, p < .01), but thereafter was associated with subsequent improvements in psychological well-being ( r = .40, p < .001). This pattern persisted even after adjustment for relevant demographic factors, prognostic discussion, scan results, and physical well-being change. TIU change scores ranged from positive to negative, with some participants showing improvements in TIU ( n = 19), some showing decrements in TIU ( n = 14), and others showing stable TIU ( n = 54). Among patients with improved TIU, psychological well-being initially decreased, but subsequently recovered [7.03 (2.23) to 6.30 (1.80), to 7.63 (2.08)]; the stable TIU group showed relatively unchanged well-being [7.34 (2.37) to 7.45 (2.32), to 7.36 (2.66)], and the less accurate TIU group showed an initial improvement followed by a subsequent decline [6.30 (2.62) to 7.36 (2.04), to 5.63 (3.40)]. Conclusions: Improved TIU may be associated with initial decrements in psychological well-being, followed by patients rebounding to baseline levels. Concerns about psychological harm may not need to be a deterrent to having prognostic discussions with patients.
Efficacy of platinum-pemetrexed combination chemotherapy in ALK+ non-small cell lung cancer refractory to second-generation ALK TKIs.
Authors: Lin Jessica Jiyeong , Schoenfeld Adam Jacob , Zhu Viola Weijia , Yeap Beow Y. , Chin Emily , Rooney Marguerite , Plodkowski Andrew J. , Digumarthy Subba , Dagogo-Jack Ibiayi , Gainor Justin F. , Ou Sai-Hong Ignatius , Riely Gregory J. , Shaw Alice Tsang
Published: March 2020

9067

Background: Second-generation (gen) ALK tyrosine kinase inhibitors (TKIs) are standard first- and second-line therapies in patients (pts) with advanced ALK+ non-small cell lung cancer (NSCLC). After progression on second-gen TKI(s), standard options include platinum (PT)-based chemotherapy (chemo) or the third-gen ALK TKI lorlatinib. The efficacy of PT-based chemo is established in treatment-naive pts but is undefined in pts who have failed prior ALK TKIs. Here we evaluate the efficacy of PT/pemetrexed (pem)-based chemo in pts with ALK+ NSCLC refractory to second-gen TKIs. Methods: A retrospective study was performed at three institutions. Pts were eligible if they had advanced ALK+ NSCLC refractory to ≥1 second-gen TKI, and received PT-pem-based chemo. Medical records and imaging were reviewed to determine outcomes. Results: Among 55 eligible pts, chemo regimens included: PT/pem (31/55, 56%), PT/pem/bevacizumab (bev) (6/55, 11%), PT/pem/PD-1 inhibitor (3/55, 5%), PT/pem with ALK TKI (8/55, 15%), PT/pem/bev with TKI (6/55, 11%), and PT/pem/PD-1 inhibitor with TKI (1/55, 2%). Pts had received one (6/55, 11%), two (38/55, 69%), or more (11/55, 20%) prior TKIs. Six pts (11%) previously received adjuvant or neoadjuvant chemo. Radiographic data for response evaluation was available for 39 pts. Among 36 pts with measurable baseline disease, confirmed ORR was 31% (11/36; 95% CI, 16-48%); 13 (36%) had stable disease. The median duration of response was 5.4 months (95% CI, 1.5-7.1 months). The median progression-free survival (PFS) for the entire cohort was 4.0 months (95% CI, 2.8-4.6 months). Chemo (PT/pem +/- bev or PD-1 inhibitor) plus ALK TKI (n = 15) was associated with a significant increase in PFS compared to chemo without TKI (n = 40) (median PFS 6.8 vs 3.2 months; HR 0.306; p = 0.002). Similarly, PT/pem plus ALK TKI (n = 8) was associated with increased PFS compared to PT/pem without TKI (n = 31) (median PFS 6.8 vs 2.9 months; HR 0.358; p = 0.036). Conclusions: The efficacy of PT-pem-based chemo is limited after failure of second-gen ALK TKIs but may be higher in pts who receive chemo plus ALK TKI, suggesting a potential role for ongoing ALK inhibition. The modest benefit of PT-pem-based chemo highlights the need for other therapeutic strategies for pts refractory to second-gen TKIs.
Substandard Cisplatin Found While Screening the Quality of Anticancer Drugs From Addis Ababa, Ethiopia
Authors: Eberle Madeline S. , Ashenef Ayenew , Gerba Heran , Loehrer Patrick J. , Lieberman Marya
Published: March 2020

PURPOSE

A postmarket evaluation of chemotherapy dosage forms in Ethiopia was conducted to test the accuracy of the chemoPAD, a paper analytical device for drug quality screening.

MATERIALS AND METHODS

In September of 2018 in Addis Ababa, Ethiopia, 41 anticancer drug dosage forms (representing 4 active ingredients, 5 brands, and 7 lot numbers) were collected and were rapidly screened for quality using a chemotherapy paper analytical device (chemoPAD). Confirmatory analysis via high performance liquid chromatography was conducted.

RESULTS

The chemoPAD showed that the correct active pharmaceutical ingredient was present in doxorubicin, methotrexate, and oxaliplatin injectable dosage forms. However, 11 of 20 cisplatin samples failed the screening test. Confirmatory assay by high-performance liquid chromatography showed that all 20 cisplatin samples—comprising three lot numbers of a product stated to be Cisteen—were substandard, containing on average 54% ± 6% of the stated cisplatin content. Inductively coupled plasma optical emission spectroscopy analysis of five representative samples found 57% to 71% of the platinum that should have been present. The sensitivity of the chemoPAD for detection of falsified products could not be measured (as none were present in these samples), but the selectivity was 100% (no false positives). The sensitivity for detection of substandard products was 55%, and the selectivity was 100% (no false positives).

CONCLUSION

Although instrumental analysis by pharmacopeia methods must remain the gold standard for assessing overall drug quality, these methods are time consuming and patients could be exposed to a bad-quality drug while clinical workers wait for testing to be performed. The chemoPAD technology could allow clinicians to check at the point of use for serious problems in the quality of chemotherapy drugs on a weekly or monthly schedule.
The FSH–HIF-1α–VEGF Pathway Is Critical for Ovulation and Oocyte Health but Not Necessary for Follicular Growth in Mice
Authors: Li Chengyu , Liu Zhaojun , Li Weijian , Zhang Liangliang , Zhou Jilong , Sun Minghong , Zhou Jiaqi , Yao Wang , Zhang Xuan , Wang Honghui , Tao Jingli , Shen Ming , Liu Honglin
Published: March 2020

Follicle-stimulating hormone (FSH)-induced growth of ovarian follicles is independent of follicular vascularization. Recent evidence has indicated that follicular vascularization is critical to ovarian follicle development and survival. FSH, a gonadotropin that induces follicular growth and development, also acts as the major survival factor for antral follicles. FSH has been reported to stimulate angiogenesis in the theca layers mediated in part by the vascular endothelial growth factor A (VEGFA) and the transcription factor hypoxia inducible factor 1α (HIF-1α). However, it remains largely undetermined whether FSH-dependent growth and survival of antral follicles relies on FSH-induced vascularization. Here, we first demonstrated that induction of angiogenesis through the FSH–HIF–1α-VEGFA axis is not required for FSH-stimulated follicular growth in mouse ovary. FSH increased the total number of blood vessels in mouse ovarian follicles, which was correlated with elevated expression of VEGFA and HIF-1α in granulosa cells. In contrast, blocking of follicular angiogenesis using inhibitors against the HIF-1α-VEGFA pathway repressed vasculature formation in follicles despite FSH administration. Interestingly, by measuring follicular size and ovarian weight, we found that the suppression of angiogenesis via HIF-1α–VEGFA pathway did not influence FSH-mediated follicular growth. However, inhibition of FSH-induced follicular vascularization by PX-478, a small-molecule inhibitor that suppresses HIF-1α activity, blocked ovulation and triggered atresia in large follicles. On the other hand, PX-478 injection reduced oocyte quality via impairing the meiotic apparatus, showing a prominently defective spindle assembly and actin dynamics. Collectively, our findings unveiled a vascularization-independent effect of FSH on follicular growth, whereas follicular survival, ovulation, and oocyte development relies on FSH-mediated angiogenesis in the follicles.