bluuebunny/crossref_metadata_2025 huggingface dataset:
Treatment of liver toxicity in women undergoing adjuvant chemotherapy for breast cancer: A phase III, monocentric, prospective, randomised trial of ursodeoxycolic acid (UDCA) vs no treatment
Authors: Cannizzaro R. , Crivellari D. , Lombardi D. , Magri M. , Fornasarig M. , Cadelli L. , Bidoli E. , Talamini R. , Veronesi A.
Published: March 2020

9060

Background: Liver toxicity during adjuvant chemotherapy (CT) represents one of the causes of treatment delay and dose reduction, with impairment of dose intensity and of final results. UDCA, a hydrophilic bile acid, has been reported to be effective in cholestasis. Aim: to evaluate the efficacy of UDCA (12 mg/kg/die) plus CT discontinuation vs CT discontinuation alone in the treatment of liver toxicity. Methods: The study provided two arms of randomization: discontinuation of CT and administration of UDCA at the dosage of 12 mg/kg/day or discontinuation of CT. CT was resumed at normalization of liver tests. Pts with liver metastases, acute or chronic hepatopathy, heart or kidney failure, or PS<70 were excluded. During a 3 year period, 118/305 pts developed CT-induced hepatotoxicity and were enrolled into the study. Logistic multiple models and Fisher test or χ2 test and the Mann-Whitney test were used. Results: Out the 118 pts, 66% were treated with CMF, 29% with Anthracyclines alone or in sequence with CMF and 5% with Anthracyclines and Taxanes. Liver toxicity occurred respectively in 37 pts after the 1st cycle, in 35 after the 2nd, in 15 after the 3rd, in 19 after the 4th, in 9 after the 5th and in 3 after the 6th. CT was definitely stopped in 8% of pts. CT was delayed of 1 week in 53%, of 2 wks in 31% and of 3 or more in 16%. 95% of pts had a hepatocytolitic damage and nobody purely cholestatic. G1 toxicity was observed in 34%, G2 in 57%, G3 in 9%. Pts were randomized in two groups of 59 pts each. UDCA group: 3 pts (5%) stopped CT and 11 (19%) had dose reduction. Control group: 6 pts (10%) stopped CT and 7 (12%) had dose reduction. No statistically significant difference between UDCA group and control group was noted both for dose reduction (p = 0.31) and for CT stop (p = 0.30), even if twice as many pts of the control group had to stop CT (6/59). No correlation between alcohol use and liver damage was noted. Conclusions: Most cases of liver toxicity are of low or intermediate grade. No statistically significant difference was found between UDCA and control, even if there was a positive trend in reducing liver toxicity, that can have a positive impact on the final results of adjuvant CT.

No significant financial relationships to disclose.
A double-blind, randomized cross-over trial of venlafaxine versus clonidine to treat hot flashes in breast cancer patients
Authors: Mom C. , Buijs C. , Willemse P. H. , Boezen H. , Maurer J. , Wymenga A. , Nieboer P. , de Jong R. S. , de Vries E. G. , Mourits M. J.
Published: March 2020

9083

Background: Breast cancer patients who become postmenopausal due to their treatment can experience more frequent and severe hot flashes than healthy postmenopausal women. Estrogens are considered to be contra-indicated. Venlafaxine and clonidine are both used to alleviate hot flashes, with different side effects. This study compared side effects, efficacy and patient preference. Methods: In a double-blind, cross-over study women <60 years, with a history of breast cancer, and experiencing at least 14 hot flashes/week were randomized to receive venlafaxine 75 mg od (and placebo bid) for 8 weeks, followed by a 2 week wash-out period, and 8 weeks of clonidine 0.025 mg bid (and placebo od) or vice versa. Hot flash frequency and hot flash score (frequency × severity) were recorded in a diary and side effects were scored using a questionnaire during the 2nd and 8th week of both treatment periods, and these were compared to a baseline week. Results: Sixty patients were randomized to start with venlafaxine (n=30) and clonidine (n=30), 40 completed both treatment periods. Premature treatment discontinuation occurred in 15/59 patients during venlafaxine and in 5/53 during clonidine due to side effects (p<0.05). The main side effects of venlafaxine were nausea and headache, and of clonidine dry mouth. In the 8th week of treatment women reported more loss of appetite (24% vs 4%; p=0.03) and improved sleeping (55% vs 75%; p=0.03) with venlafaxine. A =50% reduction in hot flash score was found in 21 (49%) and 26 (55%) of the patients with venlafaxine and clonidine respectively (ns). The decrease in hot flash score was most marked in the first treatment period. At study completion 20 (33%) of the patients chose to continue clonidine, and 17 (29%) preferred venlafaxine (ns), whereas 23 (38%) declined further treatment. Conclusions: Venlafaxine and clonidine are both moderately and equally effective in the reduction of hot flashes. Side effects are the main reason for discontinuation, occurring more often during treatment with venlafaxine.

No significant financial relationships to disclose.
Urinary incontinence in women with gynecologic malignancies before and after primary therapy
Authors: Downs L. S. , Li Z. , Wyman J. F.
Published: March 2020

9087

Background: There is limited data on the impact of treatment for gynecologic cancer on future urinary incontinence. Our objective is to determine degree of urinary incontinence in women previously treated for gynecologic cancer and women not yet treated. Methods: With IRB approval gynecologic cancer patients that had completed therapy over 1 year prior and those not yet receiving therapy were asked to participate. Consenting subjects completed the Incontinence Impact Questionnaire (IIQ) and Urogenital Distress Inventory (UDI). Both are scored from 0–100 with higher scores representing more incontinence. We also assessed general health. Mean scores were calculated and compared with adjustments for covariates. In established patients Kruskal-Wallis was used to test overall equality of IIQ and UDI across various diagnoses and treatments. Results: Ninety new patients and 104 established patients were enrolled. Age, parity, tobacco use and use of incontinence medications were similar between the groups. General health status was worse in the new patients (p<0.0001). Mean (± S.E.) IIQ scores were similar between new (6.87 ± 1.4) and established patients (4.76 ± 0.96), p=0.56. Mean UDI scores were also similar for new (17.2 ± 9.0) and established (13.2 ± 9.8) patients, p=0.20. After adjusting for health status, parity, age, tobacco use, prior use of incontinence medications there was no significant difference in either score. There was a significant positive association between age and incontinence as assessed by IIQ (p=0.02). We compared scores for established patients diagnosed with cervical, ovarian, uterine and vulvar cancer and found no significant difference in either IIQ (p=0.55) or UDI (p=0.76). Similarly there was no significant difference in scores for patients receiving hysterectomy, radical hysterectomy, BSO, vulvectomy, tumor debulking, chemotherapy or radiation therapy. Although not significant there was a trend toward more incontinence in patients having received radical hysterectomy. Conclusions: Urinary incontinence as measured by IIQ and UDI dose not appear to be different at the time of diagnosis of gynecologic cancer and a year from the completion of therapy. There is no apparent difference in urinary incontinence across diagnoses.

No significant financial relationships to disclose.
Prevalence of insomnia and associated symptoms in patients with cancer
Authors: Stepanski E. J. , Schwartzberg L. S. , Blakely L. J. , Fu D. , Fortner B. V.
Published: March 2020

9098

Background: High rates of insomnia have been reported in patients undergoing treatment for cancer. The etiology of insomnia in these patients is unknown, but may be related to psychological factors (anxiety or depression), pain, treatment-related toxicity, or other co-morbid medical conditions. Insomnia has been linked with increased rates of depression, decreased quality of life, and increased fatigue in other patient populations, and is therefore important to understand in the context of cancer. Methods: The Patient Care Monitor (PCM; Supportive Oncology Services, Memphis, TN) is a validated software package assessing oncology-related patient symptoms using a 11- point Likert scale. This instrument is administered routinely to patients at each office visit at most community oncology clinics within the Accelerated Community Oncology Research Network (ACORN). Cross-sectional patient-reported data from 11,445 consecutive patients evaluated at ACORN sites are presented here. Results: The mean age of the sample was 61.5 (±14.2; range 18–95), and 74.3% was female. 25% had received chemotherapy within the prior month. The sample size by tumor site was as follows: breast- 3,316; GU- 2,966; GI- 1,634; hematologic- 1,373; lung- 1,224; head and neck- 501; skin- 321. 55% of the pts reported trouble sleeping, with 26% describing this trouble as moderate or severe. Mean values from patient reported symptoms on the PCM are reported below. 21.9% of patients without insomnia had recent chemotherapy, compared with 27.5% of patients with insomnia who had recent therapy (p<.001). Conclusions: Insomnia occurs commonly in patients with cancer, and is associated with significantly increased fatigue, pain, and depressed mood. Additional research will explore changes in insomnia over the course of treatment, and relate these to possible etiological factors.

[Table: see text]

No significant financial relationships to disclose.
Radiation-induced esophagitis: A double-blind randomized clinical trial of aluminum hydroxide plus magnesium hydroxide plus oxetacaine suspension versus aluminum hydroxide plus magnesium hydroxide suspension
Authors: Bruns F. , Riesenbeck D. , Muecke R. , Klasser M. , Willich N.
Published: March 2020

9100

Background: To assess whether oral administered oxetacaine-containing suspension is effective in treating acute radiation- induced esophagitis in cancer patients. Methods: A double-blind, prospective-randomized clinical trial was conducted across 20 radiotherapy institutions in Germany. Patients [pts.] with head and neck or thoracic cancer without dysphagia/odynophagia received definitive or postoperative radiotherapy [RT] with or without chemotherapy including at least 5 cm of the esophagus in the high dose volume. Pts. were randomized to receive oral aluminum hydroxide plus magnesium hydroxide plus oxetacaine (Tepilta [T]) suspension or aluminum hydroxide plus magnesium hydroxide suspension without oxetacaine (Magaldrat [M]) as first-line treatment for acute radiation-induced esophagitis. Primary endpoint was the interval between begin of RT and failure of first-line treatment of esophagitis defined as need for additional systemic analgesics. Data on pts.’ symptoms were collected during and for at least 2 weeks after treatment. Results: A total of 158 pts. were randomized, of whom 103 had take at least one dose of the study medication for acute esophagitis = grade 2 (CTC). Of the 105 pts., 51 were randomized to receive T and 52 M. The cumulative incidence of acute esophagitis = grade 2 (CTC) was 25% for the T and 22% for the M arm. Kaplan-Meier analysis showed a statistically significant difference between the two groups regarding the need for systemic analgesics under consideration of the intake time in favor of T (p = 0.032). No statistically significant difference was found between the two groups regarding the secondary endpoints need respective delay of additional parenteral nutrition (p = 0.28 respective p = 0.12), and pts.`s and investigator`s estimation of global effectivity of the study medication (0.08 and 0.12). Conclusions: This trial demonstrated a statistically significant delay of the intake time for systemic analgesics in pts. randomized to receive oral aluminum hydroxide plus magnesium hydroxide plus oxetacaine suspension.

No significant financial relationships to disclose.
Prophylactic oral glutamine for docetaxel or paclitaxel associated taste alterations in cancer patients: A randomised, parallel, placebo-controlled, double-blind study
Authors: Strasser F. , Demmer R. , Boehme C. , Schmitz S. , Thuerlimann B. , Cerny T. , Gillessen S.
Published: March 2020

9104

Background: Taste alterations (TA) can occur as side-effects of taxane-based chemotherapy (T-Ch) and studies suggest that glutamin can reduce neurotoxicity. We compared in patients (pts) with a first time T-Ch oral glutamin (G) with placebo (P) for occurrence and severity of TA. Methods: Pts were randomised for 30g per day G or P (maltodextrin) (Baxter, Switzerland) from the first day of T-Ch. Subjective TA (dysgeusia) was measured daily by VAS, at baseline 3 times. On each cycle of T-Ch, objective (sour, sweet, salty, bitter) and subjective (4-categorical scale of 4 tastes) TA, and toxicity (NCI CTC V.3) were assessed. Stomatitis and zinc deficiency were screened for and treated. Of 47 pts receiving at least one day G or P, three (2 G, 1 P) died to tumor progression and three (2 G, 1 P) withdraw consent in the first cycle of T-Ch. For primary outcomes, repeated dysgeusia scores were analyzed by linear mixed model and repeated binary values of each objective taste item by generalized estimating equation using logit link function. Results: G (n=21) and P (n=20) pts groups were comparable for demographics (f:m 5:16, median age 67 [49,83], 9 prostate, 3 lung, 3 breast, 6 other cancer; 8:12, 63 [40,73], 2, 6, 6, 6), and T-Ch drug (docetaxel 11/paclitaxel 10; 7/13), schedule (weekly 18/3-weekly 3; 14/6), or goal (adjuvant 1/palliative 20; 5/15). At baseline, average median dysgeusia was 11 in both groups (0,90; SD 23. 0,99; 22), 4 tastes were recognized by 12, 16, 13, and 15 pts in G (n=16) and 16, 19, 17, 19 in P (n=20). Study duration was 73 days for G (median; 4, 385) and 74 for P (7, 187). 19 of 39 pts (11 G, 8 P) developed peripheral neuropathy G1 or G2, none G3. Maximal (mean) dysgeusia was 31 (1, 100) in G and 33 (4, 74) in P; increase from baseline was 20 (1, 100) and 22 (1, 63). No effect of G or P on dysgeusia was detected (p=ns), linear time effect was p=0.46. Baseline dysgeusia effect was significant (p<0.0001), two group analysis (dysgeusia =11) did not alter results. Objective taste tests (no baseline effect) or subjective TA were not different, as were adverse events. Conclusions: Oral glutamin at the dose given did not decrease subjective taste disturbances or altered taste perception associated with T-Ch compared to placebo.

No significant financial relationships to disclose.
Prospective study of specialist oncology community nursing resulting in improvements in key patient supportive care outcomes
Authors: Sussman J. , Howell D. , Whelan T. , Brazil K. , Pyette N. , Bainbridge D.
Published: March 2020

9107

Background: Cancer patients report ongoing significant gaps in supportive care. To date few interventions have been shown to improve supportive care outcomes in cancer. Research in other areas suggests that specialist nursing interventions in the community may address gaps in unmet need, continuity of care and quality of life. This study prospectively studied a community based nursing intervention for cancer patients. Methods: Patients were followed using a longitudinal cohort design, with assessments at baseline (T1), four (T2) and eight (T3) weeks, upon enrollment in a specialist nursing program. The nursing intervention included a comprehensive supportive care assessment and subsequent care delivery or linkage to appropriate services in the community. Validated patient assessment outcomes included: Supportive Cancer Needs Survey Short Form 34, Quality of Life (EORTC QLC-30(v3)), Continuity and Coordination of Care (CCCQ), and a service utilization instrument. Results: 72 of 109 enrolled patients completed all study measures. The majority had advanced stage disease. Median age was 59 years. Disease categories for participants included: breast (33%), gastrointestinal. (18.1%), lung (13.9%), ovarian (9.7%), and head and neck (8.3%). All participants received a baseline comprehensive assessment and had a mean of 1.7 home visits with a mean of 3.9 telephone contacts. We observed significant reductions in most supportive care need domains ( Table ). There were trends to improvement in domains of quality of life and continuity of care. We also observed reductions in acute care services use and increased community agency use. Conclusions: This is one of the first prospective studies in cancer patients that demonstrates improvements in a number of supportive care outcomes through a community based specialist nursing intervention. A randomized study to confirm these findings is currently underway.

[Table: see text]

No significant financial relationships to disclose.
Efficacy of a 1-day 3-drug antiemetic regimen for prevention of acute and delayed nausea and vomiting induced by moderately emetogenic chemotherapy
Authors: Grunberg S. M. , Dugan M. , Muss H. B. , Wood M. , Burdette-Radoux S. , Weisberg T.
Published: March 2020

9111

Background: Serotonin antagonists, NK-1 antagonists (NKA) and corticosteroids (C) have all shown efficacy against chemotherapy-induced nausea and vomiting. However these agents are commonly used in cumbersome and inconvenient multiple day regimens that can also raise questions of compliance. Palonosetron is a serotonin antagonist with a 40 hour half-life, requiring only one dose for several days of exposure. Single high doses of NKA and C can also be used to simulate drug exposures achieved with a multiple day regimen. We have therefore evaluated a 1-day 3-drug antiemetic regimen for 5 day efficacy against moderately emetogenic chemotherapy. Methods: Patients with solid tumors receiving their first cycle of cyclophosphamide and/or doxorubicin were eligible to receive a single pre-treatment dose of palonosetron 0.25 mg IV/dexamethasone 20 mg PO/aprepitant 285 mg PO. Nausea and vomiting were evaluated over the following 5 days with a patient diary including vomiting episodes, use of rescue medication, and daily nausea visual analogue scale (VAS). Patients were urged to begin rescue medication for nausea, vomiting, or related discomfort. Endpoints included Complete Response (CR) (no emesis or rescue), No Emesis (NE), and No Significant Nausea (NSN) (VAS<25) during the acute period (A) (Day 1), the delayed period (D) (Days 2–5), and the overall period (O) (Days 1–5). Adverse events were recorded and tabulated for at least 14 days. Results: 32 of 40 planned patients have been entered on study. 31 women and 1 man with breast cancer receiving adjuvant chemotherapy with median age 52 years (range 34–74) have been treated and all are evaluable. CR for A/D/O was 78%/59%/50%. However NE for A/D/O was 100%/97%/97%, and NSN for A/D/O was 75%/62%/56%. Only 8 patients had more than one day of Significant Nausea. The most common treatment-related adverse events were fatigue and mild headache. Conclusions: A 1-day 3-drug antiemetic regimen is feasible and effective, and should be tested against a multiple day standard antiemetic regimen.

[Table: see text]
High rates of psychosocial stress among Hispanic breast cancer survivors
Authors: Apollo A. J. , Crew K. D. , Campbell J. , Greenlee H. , Jacobson J. S. , Grann V. , Raptis G. , Ortiz Y. , Hershman D. L.
Published: March 2020

9113

Background: Due to early detection and improved treatments, women with breast cancer are living longer. We conducted a survey of attitudes about physical health, psychosocial issues, and health-related behaviors among female breast cancer survivors. Methods: Consecutive women with early-stage breast cancer who were ≥3 months post-completion of primary treatment and had no evidence of residual disease were asked to complete a 127-item self-administered questionnaire assessing physical/emotional health, complementary/alternative medicine use, and employment/financial concerns. Baseline demographic and clinical data were collected, including stage, tumor characteristics, and treatments. Endpoints were differences in responses between Hispanic and white patients on a 5-point scale, or dichotomized for each item. Results: Of 133 respondents, 66 were white and 67 were Hispanic. Their median age was 54 (26–90) years, and their median time since diagnosis was 3 (1–20) years. Compared to whites, Hispanic patients were younger (age <45, 34% vs. 9%, p=0.01), less educated (40% vs. 5% not completing high school, p<0.0001), and more likely to have a yearly household income <$10,000 (58% vs. 7%, p<0.0001). Hispanics were more likely than whites to report depression (31% vs 8%, p=0.0008) and depression-related symptoms and stressors such as: anorexia, pain, financial stress, and infidelity by spouse ( Table 1 ). Hispanics were also more likely to have religious beliefs that helped them cope with cancer. Differences between groups in fatigue, memory loss, and anxiety were not statistically significant. Conclusions: Our study suggests that Hispanic breast cancer survivors may have higher rates of depression and psychosocial stressors than white women. Further research is warranted to assess factors that contribute to depression in cancer survivors, and interventions to diagnose and treat it effectively.

[Table: see text]

No significant financial relationships to disclose.
Risk assessment model for first-cycle chemotherapy-induced anaemia (CIA) in patients with solid tumours (ST): DELFOS Study
Authors: López-Pousa A. , Rifà J. , Casas Fernández de Tejerina A. , González Larriba J. L. , Iglesias C. , Gasquet J. A. , Carrato A.
Published: March 2020

9122

Background: CIA, a major side effect of systemic cancer chemotherapy, is directly associated with concomitant morbidity, mortality and costs, and therefore has a strong impact on both patient health and healthcare systems. The objective of the present research study is to determine a predictive model for first-cycle CIA in patients with ST in Spain. This will help to establish appropriate protocols in routine patient care, hence improving clinical decision making. Methods: Data were obtained from the DELFOS Study, a multicentre non- interventional prospective-cohort study in Spain. This study has completed enrolment and data were available for this planned analysis. To obtain the predictive logistic regression model (LRM), the hierarchical principle was followed as a way to enable results replication. The model was implemented for CIA defined as anaemia grade = 2 (haemoglobin [Hb]<10 mg/dL). Anaemic patients at baseline according to this criterion were excluded from the studied sample to avoid bias. A receiver operating characteristics (ROC) Curve was used to determine the model's sensitivity and specificity. Results: A total of 1,140 pts (57.3 % female; mean age: 58 yrs [SD: 12]; ECOG = 2) with ST (breast, 38.1%; lung 17.5%; colorectal, 14.3%; other 30.1%) and baseline Hb>10mg/dL were included from 88 Spanish medical oncology health centres. The LRM obtained predicting CIA (pChi-sq < 0.0005) contained the following factors: gender, baseline haemoglobin, platinum-based chemotherapy (PBC) and baseline bilirubin. Risk factors and size effects included: male gender (p=0.003, OR=2.41, 95%CI (1.34, 4.31)), low baseline Hb (p<0.0005, OR=3.32, 95%CI (2.52, 4.39)), PBC as treatment (p=0.017, OR=2.04, 95%CI (1.13, 3.66)) and baseline bilirubin (p=0.029, OR=1.93, 95%CI (1.07, 3.49)). Inherent sensitivity and specificity of the equation were, respectively, 77.6% and 79.2%. Conclusions: A risk predictive model for first-cycle chemotherapy-induced anaemia in patients with ST in Spain was implemented. Four predictive factors were identified. Baseline Hb values were inversely associated with toxicity. Male gender, platinum-based chemotherapy and high bilirubin values showed themselves as risk factors for anaemia.

No significant financial relationships to disclose.
Diarrhea events in cancer patients (pts) treated with lapatinib
Authors: Koehler M. , Chan S. , Newstat B. O. , Preston A. , Burris H. A.
Published: March 2020

9125

Introduction: Lapatinib (L) is an oral dual ErbB1/ErbB2 tyrosine kinase inhibitor administered to > 5,000 pts in clinical trials. Low grade gastrointestinal adverse events: diarrhea, nausea and vomiting were recorded. We characterize here the diarrhea events related to L. Methods: Diarrhea events were recorded in 1,514 pts from 8 completed MBC and non-breast cancer clinical trials. Non-L treated pts in these trials were the comparator for analysis of toxicity grades, relationship to dose, time to onset, duration, required interventions and outcomes. Results: The L dose ranged from 1,000–1,500mg daily as monotherapy (n=928) or in combination with chemotherapy (n=198). Capecitabine alone (n=191)and tamoxifen alone (n=197) pts served as controls. For L and non-L groups the per pt diarrhea rates were: any grade 50%v33%; of those G1 54%v53%; G2 30%v30%; G3 15%v17%; G4 <1%v0% and SAEs 3% v 3%; respectively. There were no fatal L-related SAEs. For L, early diarrhea presentation <6 days(d) was 2x more frequent (44%v21%). In the non-L grp, diarrhea presented at 6–14 d in 30% pts. Delayed onset (>28 d) was similar: 22% on L v 26%, non-L. Initial G3 diarrhea or progression from G1/G2 to G3 was similar (Lv non-L): 4%v 3% and 4% v3%, respectively. The median number of events/pt (2) was the same for both groups and median duration was 5d (L) v 6d (non-L). Events (L v non-L) resolved in 89%v93%; and resolved with sequelae <1% v 1%; resolution was not recorded in 7%v4%. Events were managed in approximately 30% of pts with standard anti-diarrhea medications (loperimide and lomitil) and when more sever with hydration, octreotide & antibiotics. Majority of G1/G2 events were not treated. Most pts (85%) did not have L interrupted or dose adjusted and both group only 2% (L)v 2% (non-L) discontinued therapy due to diarrhea. Conclusions: Diarrhea related to L therapy (mostly used as monotherapy in this analysis) is usually mild to moderate, frequently does not require intervention, but pts monitoring is crucial. Importantly, L-related diarrhea appears as early events (before day 6) and is generally responsive to standard interventions. Analyses are ongoing to further identify its natural history, characteristics and pts at risk for serious events.

No significant financial relationships to disclose.
Relationship between performance status and malnutrition in non-selected cancer patients: A nation-wide one-day survey
Authors: Mateus C. , Cacheux W. , Lemarié E. , Michalet M. , Beauvillain de Montreuil C. , Hébuterne X. , Goldwasser F. ,   French Nutrition Oncology Study Group
Published: March 2020

9126

Background: The evaluation of the performance status (PS) is universally used in oncology and a PS of 2 is known as associated with reduced survival and increased risk of toxicity following chemotherapy. The aim of the present study was to evaluate the prevalence of malnutrition in a non selected population of cancer patients (pts) and how malnutrition correlates with poor PS. Methods: A prospective one-day prevalence survey was carried out in 154 wards of private or public hospitals in 24 cities in France. Height, present and usual body weight were assessed in outpatients and inpatients who were present that day. Malnutrition was defined as a Body Mass Index <18.5 or <21 in pts of 75 yrs or more and/or as a loss of body weight >10% from the beginning of the disease. The prevalence of malnutrition was studied in the overall population and stratified for the type of cancer and the PS. Results: 2,068 pts (1,189 men and 879 women) aged 60±13 yrs were evaluated and nutritional status was available in 1,903 pts. The PS was 0 or 1 in 52.3% of pts, 2 in 25.3%, 3 or 4 in 22.4%. Overall, 38% of pts were malnourished. Prevalence of malnutrition according to the primary tumor was: pancreas (n=42): 67%, oesophagus (n=41): 61%, stomach (n=41): 59%, head and neck (n=366): 49%, lung (n=247): 45%, ovary/uterus (n=87): 45%, colon/rectum (n=191): 39%, leukemia/lymphoma (n=377): 34%, breast (n=229): 21%, prostate (n=72): 14%. The prevalence of malnutrition was 14.4%, 31.4%, 52.3%, 53.6%, and 65.3% in pts with a PS ranging from 0 to 4, respectively. In comparison to PS-0 pts, Relative risk (RR) of malnutrition was 2.5 (p < 0.0001) in PS-1 pts and 6.4 in PS-2 pts (p<0.0001). Conclusions: Malnutrition is diagnosed in >50% of PS-2 pts. Systematic screening and care of malnutrition is mandatory to improve the PS and subsequently treatment tolerability in these pts.

No significant financial relationships to disclose.
Clinical significance of CXC chemokine receptor-4 (CXCR4) and c-Met in childhood rhabdomyosarcoma (RMS) tumors
Authors: Diomedi Camassei F. , McDowell H. P. , De Ioris M. A. , Altavista P. , Cozza R. , Donfrancesco A. , Inserra A. , Callea F. , Dominici C.
Published: March 2020

9510

Background: Both CXCR4/SDF-1 and c-Met/HGF axes promote invasive growth of RMS cells in experimental models, but no data are available on their expression and significance in RMS tumors. Expression for CXCR4 and c-Met (and their ligands) was evaluated in primary RMS tumors and correlated with clinical features, marrow involvement at diagnosis, overall (OS) and progression-free survival (PFS). Methods: Forty newly diagnosed pts, aged 2–180 months (median 58), with embryonal (n. 20) or alveolar (n. 20) RMS admitted between 1994 and 2004 were retrospectively enrolled. The only selection criterion was availability of data on marrow involvement at diagnosis as assessed by cytomorphology and immunocytochemistry for MyoD1 and myogenin. Primary site was favorable (orbit, paratesticular, uterus/vagina) in 7 pts and unfavorable (all the others) in 33. Pts were entered as group I/II (n. 5), III (n. 28) or IV (n. 7) (IRS grouping system). Marrow was infiltrated at diagnosis in 16 pts. Treatment was according to Italian RMS protocols. Expression for CXCR4, SDF-1, c-Met and HGF proteins was investigated by immunohistochemistry. Three separate counts (each >5,000 tumor cells) were performed without knowledge of clinical features and outcome; results expressed as mean percentage of immunostained tumor cells. Student t test, log-rank test, Kaplan-Meier survival analysis were applied. Institutional informed consent and ethical approval were obtained. Results: As of December 2006, median follow-up was 60 months, with 25 pts DF, 1 AWD and 14 DOD. CXCR4 and c-Met were expressed in =5% of tumor cells in all cases, but 14/40 tumors showed =50% tumor cell positivity (high expression) for either markers. High CXCR4 expression correlated with alveolar histology (p=0.006), unfavorable primary site (p=0.009), advanced group (p<0.001), marrow involvement (p=0.007), shorter OS and PFS (p<0.001). High c- Met expression with alveolar histology (p=0.005), advanced group (p=0.04), marrow involvement (p=0.02). SDF-1 and HGF were expressed by a lower percentage of tumor cells (1–95% of cells positive for the correspondent receptor). Conclusions: CXCR4/SDF-1 and c-Met/HGF pathways are clinically relevant in children with RMS and represent novel targets for disease-directed therapy.

No significant financial relationships to disclose.
Ifosfamide versus cyclophosphamide: Long term gonadal effects in 166 male survivors of childhood cancer
Authors: Ridola V. , Defachelles A. S. , Schmitt C. , Fawaz O. , Gentet J. C. , Aubier F. , Michon J. , Bergeron C. , Béhar C. , Oberlin O.
Published: March 2020

9515

Background: Alkylating agents are associated with a risk of male gonadal damage, even in patients treated during childhood. The purpose of this work was to compare this risk after treatment by ifosfamide vs cyclophosphamide during childhood. Methods: Evaluation was based on basal FSH measurement known for its correlation with spermatogenesis. LH and testosterone were also measured in most of the patients. 159 males were evaluated after treatment of a soft tissue sarcoma (79), osteoasarcoma (39), ewing (10), lymphoma (28), other (3). 100 patients received ifosfamide as unique alkylating agent and the other 59 received cyclophosphamide as the other unique alkylating agent between 1973 and 2000. Median age at treatment was 11.2 years (0–18 yrs). Median interval after the end of the treatment was 10.7 years (4.1–20.2 yrs), median age at evaluation was 21.4 years (17.5–36.1 yrs). Median dose of ifosfamide was 54 g/m2 (18- 114), median dose of cyclo was 8.3 g/m2 (4.6–22). Age at treatment and at evaluation were similar in both groups. Results: All males but two (17.5 and 26.5 yrs) had normal testosterone levels. LH was elevated in 14% of the patients. FSH was above laboratory upper limit in 28 of the 59 males (47.5%) treated with cyclophosphamide and was within the normal range in 94 of 100 patients (94%) treated with ifosfamide. Eight patients treated with cyclophosphamide fathered children. The median dose of cyclo was 5.6 g/m2 (4.8 - 10.8 g/m2). Six patients who received 51 to 54 g/m2 fathered children. The risk of abnormal FSH increased with the cumulative dose of cyclophosphamide: only 2/16 boys (12%) who received more than 12 g/m2 had a normal dosage of FSH, while 29/43 (67%) of the boys who received lower doses of cyclo did so. Conclusions: These results show a low risk of gonadal dysfunction in men exposed to ifosfamide (median dose 54 g/m2) compared to the results for males treated with cyclophosphamide. The risk of abnormal FSH increased with the cumulative dose of cyclophosphamide.

No significant financial relationships to disclose.
A phase I study of clofarabine in combination with cyclophosphamide and etoposide: A new regimen in pediatric patients with refractory or relapsed acute leukemia
Authors: Hijiya N. , Franklin J. , Rytting M. , Cooper T. , Chu R. , Barry E. , McCarthy C. , Abichandani R. , Carroll W.
Published: March 2020

9529

Background: Clofarabine is a promising new agent in the treatment of childhood leukemia as evidenced by single agent activity in previous phase I and II studies. We conducted a pilot phase I study of clofarabine used in combination with cyclophosphamide and etoposide to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLT). Methods: Patients between 1 and 21 years old with relapsed or refractory acute lymphoblastic leukemia (ALL) and acute myelogenous leukemia (AML) were enrolled. A standard 3+3 design was followed to determine the safe dose when used in combination. All drugs were administered by IV infusion daily for 5 consecutive days in induction and 4 days in consolidation. Patients received up to 2 induction cycles depending on the response, followed by consolidation cycles (maximum of 8 total cycles). The initial doses (cohort 1) were as follows: clofarabine: 20 mg/m2/day, etoposide 75 mg/m2/day and cyclophosphamide 340 mg/m2/day. Once etoposide and cyclophosphamide were escalated to their target dose (100 mg/m2/day and 440 mg/m2/day respectively in cohort 3), clofarabine was then increased to 30 mg/m2/day in cohorts 4 and would be increased to 40 mg/m2/day in cohort 5. Results: Thirteen patients (10 ALL; 3 AML) were enrolled in the first 4 dose cohorts to this date. The median number of prior regimens was 2. Response data (based on investigator assessment) are available for the first 8 patients: 6 patients (including 1 patient with AML) achieved either complete remission (CR) or complete remission without platelet recovery (CRp), for an overall response rate of 75%. Four patients proceeded to HSCT. One patient in cohort 4 experienced a DLT which resolved (grade 3 elevation of lipase) and possible veno-occlusive disease leading to cohort expansion. Common toxicities noted include febrile neutropenia and fever. Conclusions: The phase I study is ongoing until determination of MTD for this combination but these early results indicate that this combination shows significant activity in children with refractory or relapsed acute leukemias and is well-tolerated.

No significant financial relationships to disclose.
A phase I study of oxaliplatin (OXA) and irinotecan (IRN) in pediatric patients with refractory solid tumors: A Children's Oncology Group study
Authors: McGregor L. M. , Spunt S. L. , Furman W. L. , Stewart C. F. , Krailo M. D. , Speights R. , Houghton P. J. , Ivy S. P. , Blaney S. M. , Adamson P. C. ,   Children's Oncology Group Phase I Consortium
Published: March 2020

9546

Background: Platinum analogues in combination with topoisomerase 1 inhibitors have been shown in in vitro studies to have synergistic anti-tumor activity. This study estimated the maximum tolerated dose (MTD) of OXA in combination with a protracted schedule of IRN in children with refractory solid tumors. Methods: OXA was administered over 2 hrs on days 1 and 8 in combination with IRN iv over 1 hr on days 1–5 and 8–12 of a 21-day cycle. An oral cephalosporin was administered daily to ameliorate IRN-associated diarrhea. Pharmacokinetic studies of OXA and UGT1A1 genotyping were performed during course 1 in consenting patients. Results: 13 patients (median age 16 yrs, 4 M) were enrolled. Dose-limiting diarrhea (n=3), serum lipase elevation (n=3), serum amylase elevation (n=2), colitis (n=1), abdominal pain (n=1) and headache (n=1) occurred at the 1st dose level (60 mg/m2/dose OXA; 20 mg/m2/dose of IRN) in the first 3 patients. Only 1/7 patients treated with reduced doses of both agents (40 mg/m2/dose OXA; 15 mg/m2/dose IRN) experienced DLT, diarrhea. When the OXA dose (60 mg/m2) was increased with the reduced IRN dose (15 mg/m2) 2/3 patients had DLT (1 diarrhea, 1 hypokalemia). Myelosuppression was minimal at all dose levels. One patient with alveolar rhabdomyosarcoma previously treated with irinotecan (dose level 2: 40 mg/m2/dose OXA; 15 mg/m2/dose IRN) had an unconfirmed complete response of her breast metastases and one patient with refractory neuroblastoma had disease stabilization through 6 courses of therapy. The frequency of 6/6, 6/7, and 7/7 UGT1A1 promoter genotypes were 5/10, 4/10, and 1/10, respectively. Conclusions: The MTD using this schedule with oral cephalosporin support was oxaliplatin 40 mg/m2/dose with irinotecan 15 mg/m2/dose. There was some evidence of benefit but significant toxicity, both expected (diarrhea) and unexpected (elevation in pancreatic enzymes), was also observed.

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Newly diagnosed high-risk malignant brain tumors with leptomeningeal dissemination in young children: A final update on Head Start II Regimen A2 intensified with high-dose methotrexate
Authors: Chi S. , Gardner S. , Ji L. Y. , Sposto R. , Dhall G. , Finlay J.
Published: March 2020

9552

Background: The prognosis for young children with newly diagnosed malignant brain tumors with leptomeningeal dissemination remains poor. From Jan 1997 to Mar 2003, “Head Start II” Regimen A2, intensified with high-dose methotrexate, was offered to this high-risk population. Methods: Eligibility: patients < 10 yrs of age; confirmed diagnosis of medulloblastoma (MB), primitive neuroectodermal tumor (PNET), ependymoma and choroid plexus carcinoma (CPC); and high-risk status as determined by neuroaxis dissemination. Patients with atypical teratoid/rhabdoid tumor (ATRT), regardless of stage, were also eligible. Treatment: 5 cycles of vincristine (0.05 mg/kg/week × 3 doses), cisplatin (3.5 mg/kg), etoposide (4 mg/kg/day × 2 days), cyclophosphamide (65 mg/kg/day × 2 days), and methotrexate (400 mg/kg) with leucovorin. Children without progressive disease (PD) by the end of induction underwent a single consolidation cycle (carboplatin, etoposide, thiotepa) with autologous stem cell rescue. Reduced dose RT (2340cGy CSI and focal boost) was reserved for any with residual disease at the end of induction or for the older patient (>6 yrs of age). Results: 40 patients were enrolled (MB, 22; PNET, 6; ependymoma, 5; AT/RT, 6; CPC, 1), med age at diagnosis 38 mos (range 5 to 119 mos). Significant toxicities of this intensified regimen included GI toxicities and infections. Among the entire cohort, there were 26 CR, 6 PR, 2 with stable disease and 4 with PD (and 2 toxic deaths), for a CR +PR response rate of 82%. For disseminated MB (4 M1; 2 M2; 16 M3), the CR rate alone is 77% (17/22). The 5-year EFS and OS for disseminated MB are 45% (95% CI, 24 % to 64%) and 54% (95% CI, 31% to 72%), respectively. Of note, 6/12 MB survivors (all M3) did not receive RT and all are NED >5 years from diagnosis. In addition, there are 3 AT/RT survivors, 12, 54 and 66 mos post-diagnosis who did not receive RT. Conclusions: This intensified regimen is feasible and tolerable. For patients with disseminated MB, the majority of whom had M3 disease at diagnosis, the impressive response rate and outcomes suggest that the addition of methotrexate is justified for future studies. Long- term neuropsychological outcomes are being studied at this time.

No significant financial relationships to disclose.
A clinical trial simulation study of a new pediatric phase I trial methodology: The rolling six design
Authors: Skolnik J. , Jayaraman B. , Patel D. , O'Connor E. , Barrett J. S. , Adamson P. C.
Published: March 2020

9564

Background: Phase I cancer trials have traditionally used the 3+3 study design in which cohorts of three patients at a time are enrolled. The study is suspended to accrual with every 3rd patient, and again suspended to replace inevaluable patients. As the pediatric phase I starting dose is based on adult phase I safety data, we hypothesized that pediatric study timelines could be shortened without increasing risk using a novel rolling six design, in which up to 6 patients are concurrently enrolled per dose level. Methods: A trial simulation approach comparing the standard 3+3 design to the rolling six design was performed. Discrete time events (accrual/enrollment, evaluation and/or time to dose limiting toxicity (DLT) or inevaluability) with outcome probabilities (DLT/inevaluability) assigned to each subject based on historical data from phase I pediatric oncology trials. The probability of DLT was a function of dose level and varied distributions were used to assign discrete time elements. Metrics for study efficiency (time to complete study, total number of patients required) were determined for each design. Simulated trials and decision rule logic were coded using PC/Windows SAS v9.1. Results: The rolling six design outperformed the 3+3 design for the most relevant metrics. Average (±SD) time to study completion was 373±90 days vs. 431±98 days and the total number of patients required was 20±5 vs. 17±4 for the rolling six vs. 3+3 designs, respectively. There was no difference in the number of DLTs per study (3±1) between designs. Conclusions: The rolling six design is predicted to shorten pediatric phase 1 study timelines and will be tested prospectively in upcoming COG phase I trials.

No significant financial relationships to disclose.
Phase III study of gemcitabine [G] plus cetuximab [C] versus gemcitabine in patients [pts] with locally advanced or metastatic pancreatic adenocarcinoma [PC]: SWOG S0205 study
Authors: Philip P. A. , Benedetti J. , Fenoglio-Preiser C. , Zalupski M. , Lenz H. , O'Reilly E. , Wong R. , Atkins J. , Abruzzese J. , Blanke C.
Published: March 2020

LBA4509

Background: Epidermal growth factor receptor [EGFR] pathway is a rational target for therapeutic intervention. This study tested the efficacy of an anti-EGFR monoclonal antibody and gemcitabine [G] combination in the Phase III setting in patients with advanced PC. Methods: Eligibility included locally advanced unresectable or metastatic PC; adequacy of organ function; performance status (PS) 0- 2; no prior EGFR therapy; no prior systemic chemotherapy except for adjuvant chemotherapy; and submission of tumor for EGFR immunostaining. The primary endpoint was overall survival. Secondary endpoints included objective response, time to progression, pain control, and quality of life. Assuming 6 months median survival, the study was designed to detect a median improvement to 8 months (1.33 hazard ratio) with 90% power, based on a one-sided 0.0125 test, and 704 eligible patients. Primary analyses used a Cox regression model, stratified for factors used in the randomization. Patients were stratified by PS, stageand prior pancreatectomy, and randomized to either G alone or G plus C. G was given at a dose of 1,000 mg/m2/wk for seven weeks out of 8, then 3 weeks on and one week off. C was given as a loading dose of 400 mg/m2 on week 1 and then 250 mg/m2 weekly. Results: 766 pts (735 eligible) with a median age of 64 (30–91) were enrolled by SWOG and CTSU between January 2004 and April 2006. Of those, 51% were males, 21.5% had locally advanced disease, and 13% had PS of 2. The study closed with full accrual. The median survival was 6 months in the G arm and 6.5 months in the G plus C arm for an overall HR of 1.09 (95% CI 0.93–1.27, p= 0.14) . The corresponding PFS was 3 months and 3.5 months, for G and G+C arms, respectively (HR =1.13, 95%CI .97–1.3, p=.058). The confirmed response probabilities were 7 % in each arm, and inclusion of unconfirmed responses yielded 14% in the G arm and 12% in the G + C arm.702 pts were evaluable for toxicity. 90 pts experienced at least one grade 4 toxicity; 14% on the G plus C, 11% on G alone. Conclusions: This study failed to demonstrate a clinically significant advantage of the addition of cetuximab to gemcitabine for overall survival, PFS and response in advanced PC.

No significant financial relationships to disclose.
Single agent, canfosfamide (C, TLK286) vs pegylated liposomal doxorubicin (D) or topotecan (T) in 3rd-line treatment of platinum (P) refractory or resistant ovarian cancer (OC): Phase 3 study results
Authors: Vergote I. , Finkler N. , del Campo J. , Lohr A. , Hunter J. , Matei D. , Spriggs D. , Kavanagh J. , Vermorken J. , Brown G. L. , Kaye S.
Published: March 2020

LBA5528

Background: Canfosfamide (C) is a novel glutathione analog prodrug activated by glutathione S-transferase P1–1. P resistant OC has a poor prognosis and non-P agents are used for palliation. C reported objective responses in multicenter Phase 2 OC trials. Methods: Pts with P resistant OC who progressed after D or T, measurable disease (RECIST), adequate liver/renal/bone marrow function were eligible. Randomization was stratified by prior D or T treatment, ECOG PS (0 or 1 vs 2) and presence or absence of bulky disease (= 5cm). Patients received C at 1000 mg/m2 IV q3wks, or to D at 50 mg/m2 IV q4wks or T at 1.5 mg/m2 IV daily × 5 q3wks until progression. The trial had a 90% power to detect a 29% reduction in the relative risk of death. Results: 461 pts (C=232 and D or T=229) received 1052 cycles [median 3; range (r) 1–33], 699 (median 4; r 1–32), and 469 (median 5; r 1–21) for C, D and T respectively. Most common Grade 3–4 AEs for C were: nausea (31.6%), vomiting (8.7%), fatigue (6.1%), and anemia (5.6%), for D/T were: nausea (55.3%), anemia (15.2%), fatigue (6.9%), neutropenia (23.5%), thrombocytopenia (12.4%), febrile neutropenia (6%), stomatitis (6%), and PPE syndrome (6%). ORR for C was 4.3% including a CR, vs 10.9% ORR for D/T. Median survival (MS) was 8.5 mos for C, 13.6 mos for D/T (p=0.0001). Median progression-free survival was 2.3 mos for C and 4.4 mos for D/T, (p=0.0001). D/T MS was 14.2/10.8 mos, respectively. Conclusions: Canfosfamide did not meet the primary endpoint. C demonstrated single agent activity in P refractory or resistant OC and was well tolerated. C in combination with standard agents in less heavily treated OC trials are in progress.

No significant financial relationships to disclose.