bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase II study of neoadjuvant biochemotherapy (BCT) for stage III malignant melanoma (MM): Results of long-term follow-up (LTFU)
Authors: Lewis K. D. , Lane A. , Anderson C. , Pearlman N. , Becker M. , Zeng C. , Baron A. , Gonzalez R. 
Published: April 2020

8035 Background: Patients (pts) with MM metastatic to regional lymph nodes (LNs) (stage 3) are at high-risk of developing systemic disease and subsequent death. High-dose adjuvant alpha interferon (IFN) has proven in randomized studies to result in significant improvement in relapse-free survival (RFS), but the benefit on overall survival (OS) is less clear. BCT (cytotoxic chemotherapy with interleukin-2 (IL-2) and IFN) has shown high response rates in pts with metastatic MM. It is, therefore, hypothesized that using BCT in earlier stage disease may result in an improvement in OS for this high-risk population. Methods: This was a pilot phase 2 study of neoadjuvant BCT in pts with stage 3 MM with a planned accrual of 50 pts. Earlier results have previously been reported (Cancer 2002;94:470–6). LTFU is now obtained and reported here. Eligibility required biopsy confirmed MM to regional LNs without previous therapeutic lymphadenectomy. Two cycles of BCT were administered prior to and after lymphadenectomy. BCT was: cisplatin 20 mg/m2 days (D) 1–4, vinblastine 1.6 mg/m2 D 1–4, dacarbazine 800 mg/m2 D 1, IFN 5 MIU/m2 D 1–5, IL-2 9 MIU/m2 continuous infusion D 1–4. The primary endpoints were RFS and OS. Results: Fifty-one pts were enrolled from 4–96 to 5–99. Three pts had stage 4 MM and are not included in this analysis. Of the remainder, 87.5% (42/48) had clinically detectable disease, while 12.5% (6/48) were sentinel lymph node positive. Twenty-five percent (12/48) had received prior IFN therapy. At a median follow-up of 75 months (mo), 54% are disease-free (26/48) and 65% are alive (31/48). The 5-year OS and RFS are 66% [95% confidence interval (CI) 50 - 78) and 56% (95% CI 41 - 69), respectively. Median survival has yet to be reached. After the 24-month time point there have been 3 relapses and 4 deaths. Toxicity was manageable. Conclusions: Neoadjuvant BCT may be an effective regimen for stage 3 MM. The LTFU of the current study shows favorable results in terms of RFS and OS when compared to historical controls. A subsequent larger, multicenter phase 2 study of neoadjuvant BCT has been completed. In addition, a cooperative group phase 3 study comparing adjuvant BCT to IFN is currently enrolling pts. [Table: see text]
High-dose IL-2 in patients with metastatic melanoma after progression on biochemotherapy (BioCT). The experience of the Hospital Sírio-Libanês, Brazil
Authors: Schmerling R. A. , William W. N. , Belfort F. A. , Buzaid A. C. 
Published: April 2020

8038 Background: There are limited data on systemic therapy after progression following BioCT (cisplatin, vinblastine, dacarbazine, interferon-alfa and IL-2) in patients with stage IV melanoma. High-dose IL-2 has a 16% response-rate as first-line therapy, with approximately 5% of the pts achieving long-term survival. Methods: We retrospectively reviewed our experience with high-dose IL-2 in pts who had metastatic melanoma and had progressed during or after BioCT from 1/2000 to 1/2005. One treatment course consisted of IL-2, 600.000 IU/kg IVP q8h for a maximum of 14 doses per cycle, followed by an identical cycle after a one week of rest. Responding patients received 2 additional courses after 6 weeks of rest between courses. All pts were treated in a regular ward setting under the assistance of specialized and trained nurses on high-dose IL-2 therapy. Results: A total of 23 pts (15 male, 8 female); median age 46 (range 21–68) were treated with high-dose IL-2. Two pts received only 1 cycle of therapy due to PD and 1 treatment-related death. The remaining 21 pts received at least 1 full course (2 cycles) of therapy. Median number of cycles was 2 and median number of IL-2 doses/cycle was 10. Response rates using RECIST were as follows: CR, 1 pt (5%); PR, 6 pts (27%). Duration of response was 1, 3, 8, 9, 10, 12, and 18 months. There were no long-term disease-free survivors. Among the 9 patients with a previous response to BioCT, 1 pt had CR and 3 pts had PR to high-dose IL-2. Among the 8 pts whose disease previously progressed on BioCT, 2 pts still achieved a PR. After a median follow-up of 36 months, all pts have presented disease progression and 20 pts have died. Median time to progression and overall survival were 2.5 mo and 9.5 mo, respectively. Conclusions: High-dose IL-2 has modest but definite activity in pts previously treated with BioCT, regardless of the response to the latter treatment, and may be an option in selected pts. No significant financial relationships to disclose.
Phase 2 trial of talabostat and cisplatin in patients with stage IV melanoma
Authors: Cunningham C. , Pavlick A. C. , Khan K. D. , Frenette G. , O’Day S. , Stephenson J. , Gonzalez R. , Yang Z. , Vrhovac V. , Uprichard M. J. 
Published: April 2020

8040 Background: Talabostat (TAL) is an oral inhibitor of dipeptidyl peptidases such as fibroblast activation protein found on the stroma of tumors, draining lymph nodes, and in melanomas. TAL up-regulates cytokines and chemokines, leading to specific T-cell immunity and T-cell independent activity. TAL significantly enhances the activity of cisplatin (C) in mice, and reduces tumor size >60% in melanoma xenografts (A375, A2058). This trial evaluated the activity of TAL and C in patients with Stage IV melanoma. Methods: Open-label, single-arm, Phase 2 study of 4 x 3-week cycles of C-75mg/m2 (Day 1) and TAL-300mcg BID orally on Days 2–15 with dose-escalation to TAL-400mcg BID depending on tolerability. Single-agent TAL could be continued beyond 4 cycles until disease progression or unacceptable toxicity. Eligibility criteria included: ≤1 prior bio- or chemotherapy regimen, ECOG 0–2, measureable disease per RECIST, no symptomatic CNS metastases, LDH, ALT, and AST <3X ULN. Primary endpoint was disease response; secondary endpoints included PFS, duration of response, and survival. Results: 74 patients (50 men, 24 women) entered the study; median age was 58 years (range 27 to 79); 94.6% were caucasian. Most patients (71.4%) were M1c, and the majority (64.3%) had received at least 1 prior regimen; 72.9% of these had received prior cytokine treatment. A PR was reported in 5/42 evaluable patients (11.9%), and SD for at least 4 cycles in an additional 21/42 (50%). Median PFS and survival are currently estimated at 2.6 months (95% CI 2.1, 3.4) and 8.5 months (95% CI 5.4, infinity), respectively in the ITT population. Most frequent AEs were nausea (46%), fatigue (35%), and vomiting (34%); the high unevaluability rate patients was due to non-compliance related to C-associated N/V (thus the dose of C was reduced mid-study from 100 to 75mg/m2). Grade 3 toxicities were neutropenia, fatigue, and dehydration, all at 3.4%. Grade 4 toxicities were organ failure, renal failure, and PD (1 patient each). 4 patients died due to PD, and 1 each due to renal and organ failure. Conclusions: The combination of TAL and C is active in patients with Stage IV melanoma. Most AEs were related to C-associated nausea and vomiting, limiting the oral delivery of TAL. Additional studies of TAL in melanoma with other drug combinations are warranted. [Table: see text]
Molecular dissection of the RAS/RAF/MAPK pathway in primary and metastatic melanoma
Authors: Rother J. , Bailey J. , Alvarado G. , Prieto V. G. , Lazar A. J. , Jones D. , Hwu W. J. 
Published: April 2020

8050 Background: Given the reported presence of frequent mutation in NRAS and BRAF in many melanocytic lesions, the association of mutations activating the RAS/RAF/MAPK pathway with tumor progression in melanoma remains unclear. We compared the NRAS and BRAF mutation status with the levels of activated MAPK in paired primary and metastatic melanomas. Methods: 15 patients with material from both primary and metastatic lesions were assessed. Four patients had metastasis at initial diagnosis, the remaining patients developed metastasis from 8.5 to 66 months (mos) following initial diagnosis (median 24.1 mos). Mutations in BRAF (exons 11 and 15) and KRAS and NRAS (exons 1 and 2) were assessed by quantitative pyrosequencing. MAPK levels were assessed by immunohistochemistry on paraffin sections using phosphor-44/42 (Thr202/Tyr204) polyclonal antisera. Results: Activating NRAS point mutations were found in 3 of 15 patients, with 2 detected in the metastatic lesions; both of these had upregulation of activated MAPK compared to the primary lesions. BRAF V599 point mutations were found in 3 of 15 patients and present in both the primary and cognate metastatic lesions. All cases with BRAF or NRAS mutations had moderate to high levels of activated MAPK, as compared to only 2 of 9 patients without such mutations. The correlation of mutational status and clinical course revealed that NRAS/BRAF mutations and/or MAPK activation did not negatively impact overall survival. Conclusions: Molecular alterations in the RAS signaling pathway are associated with activated MAPK in both primary and metastatic melanoma. NRAS mutations and MAPK activation may be preferentially associated with disease progression, as opposed to BRAF mutations. However, neither NRAS/BRAF mutation nor activation of MAPK signaling pathway in primary and/or metastatic melanoma was significantly associated with poor disease outcome. Further molecular dissection using the archived material from two large melanoma neoadjuvant trials conducted in 1988 and 1994 is ongoing to determine the prognostic and predictive power of these biomarkers. No significant financial relationships to disclose.
Natural history of metastatic melanoma patients with CNS metastases
Authors: Davies M. A. , Bedikian A. Y. , McIntyre S. , Smith T. , Kim K. , Hwu W. , Papadopoulos N. , Hwu P. 
Published: April 2020

8054 Background: Melanoma has a high rate of CNS metastasis (mets). The objective of this study was to evaluate the characteristics and outcomes of melanoma patients (pts) who develop CNS mets. Methods: 333 pts with a diagnosis of CNS mets were identified from databases of 743 chemotherapy naïve metastatic melanoma (MM) pts enrolled on clinical trials between 1986 and 2004. Their clinical and pathological characteristics were reviewed. Results: The site of primary melanoma was head or neck (60/333; 18%), trunk/abdomen (144/333; 43%), limbs (66/333; 20%), ocular (2/333; 1%), or unknown (61/333; 18%). Median Breslow thickness (BT) = 2.2 mm; BT < 1 mm = 39/217 (18%); and BT < 2 mm = 95/217 (44%). Median Clark level (CL)= IV; CL I = 0/180 (0%); CL II = 14/180 (8%); CL III = 70/180 (39%); and CL IV = 96/180 (53%) . The median interval from diagnosis of primary melanoma to CNS mets = 29.6 (range 0.3–393) months (mos). Median survival (MS) from CNS diagnosis = 4.6 (range 0–120) mos. MS was highest for pts with brain mets (n=307; 4.8 mos) compared to pts with brain mets plus leptomeningeal disease (LMD) (14; 2.0 mos) or pts with LMD alone (11; 1.2 mos) (p=.0048 for pts with LMD vs. without). MS varied for pts with 1 (6.6 mos), 2 (4.2 mos), 3 (5.9 mos) or >3 (3.5 mos) brain lesions at diagnosis of CNS mets. Among pts diagnosed with CNS mets at or prior to systemic therapy, MS was longer for pts with CNS mets only (n=20; 14.3 mos) compared to pts with CNS mets concurrent with extracranial mets (63; 7 mos) (p=.003). Patients who developed CNS mets after starting chemotherapy for extracranial mets (n=250; 3.7 mos) had a shorter MS than those diagnosed at or before systemic therapy (83; 7.9 mos, p<.001). Among pts diagnosed after starting systemic therapy, CNS mets were detected ≤ 12 months from the start of chemotherapy in 30% of pts (MS = 3 mos), 12–24 mos in 37% of pts (MS = 4.6 mos), and > 36 mos in 32% of pts (MS = 11.1 mos, p=.044 vs. other groups). Conclusions: This study represents one of the largest cohorts of pts with melanoma CNS mets. The presence of LMD, or development of CNS mets after starting systemic therapy, is associated with a worse prognosis. Among pts diagnosed with CNS mets at or before starting systemic therapy, the presence of concurrent non-CNS mets also portends for a worse outcome. Supported in part by Carol Courtney Memorial fund and Chiron Corporation. No significant financial relationships to disclose.
Methods of detection of recurrence in patients with cutaneous melanoma
Authors: Dalal K. M. , Panageas K. S. , Brady M. S. , Jaques D. P. , Coit D. G. 
Published: April 2020

8057 Background: The patterns and methods of identification of initial recurrences of melanoma in patients staged with sentinel lymph node biopsy (SLNB) were studied. Methods: Stage I/II melanoma patients who underwent SLNB from 1991–2004 were identified from a prospective single-institution database. Detection of recurrence by self (awareness of symptoms or abnormal physical findings) or physician (discovered on routine physical exam or scheduled test) and timing of clinic visit were recorded. Postoperative followup included physical exam every 3–4 months for the first year, 3–6 months for the second, and 6–12 months thereafter. Serum LDH and CXR were obtained annually. CT and PET were performed on a selective basis. Results: Of 1062 patients who underwent SLNB, 211 patients (20%) experienced a total of 242 initial sites of recurrence. Recurrence was more common in SLN+ patients (47% vs. 14%; p< 0.001, respectively). There were 198 patients evaluable for follow-up (median 35 months). Symptoms and self-detected physical findings were present in 109 patients (55.1%; table); 85 patients (42.9%) were seen earlier than their scheduled visit. Self-detected physical findings commonly identified in-transit (13%) and nodal (13%) disease. Physician detection occurred in 89 patients (44.9%); nearly half of these were detected by a scheduled radiographic test (CXR, n=14 [7%]; CT, n=26 [13%]; PET, n=1 [0.5%]). Detection of recurrence by an abnormal blood test was uncommon (n=2; 1%). Post-recurrence survival was associated with site of recurrence (table; p<0.0001). In multivariate analysis, independent predictors of post-recurrence survival were site of recurrence and method of detection (p<0.05). Conclusions: The most common site of recurrence following accurate nodal basin staging and management is systemic. Recurrent melanoma is self-detected by half of the patients. Systemic recurrence is detected by patient symptom or routine radiologic test, but it is associated with a less favorable outcome than recurrence detected by physical exam. [Table: see text] No significant financial relationships to disclose.
Trajectory of cognitive impairment during breast cancer treatment: A prospective analysis
Authors: Wagner L. I. , Sweet J. J. , Butt Z. , Beaumont J. , Havlin K. A. , Sabatino T. , Cella D. 
Published: April 2020

8500 Background: Several studies havedocumented cognitive impairment in cancer patients; however these reports are primarily based on cross-sectional comparisons. Prospective evaluation would better elucidate the onset and course of cognitive dysfunction related to chemotherapy. Methods: Of 72 breast cancer patients enrolled, 51 completed a comprehensive neuropsychological battery before chemotherapy (T1), on Day 1 of Cycle 4 (T2), and at 6-month follow-up (T3). Participants scoring ≥ 1 SD below the normative mean on ≥ 3 neuropsychological tests OR ≥ 2 SD below on 1 test were classified as impaired. Reliable change indices (RCI) conservatively estimated significant change over time. Results: Participants were White (70.6%) females (96.1%) with a mean of 15.9 ± 2.3 years of education. Mean age was 51.6 ± 8.6 years and most had Stage II (78%) or Stage III (16%) disease. Hospital Anxiety and Depression Scale scores were in the normal range at all assessments and were unrelated to T1 cognitive impairment. Consistent with previous research, 9 (17.6%) of patients met criteria for cognitive impairment at T1. By T2, 14 (27.4%) were cognitively impaired; however, at T3 follow up only 5 (9.8%) were impaired. As noted in the table, most impairment occurs during chemotherapy. Among patients not impaired before chemotherapy it was uncommon for impairment at T2 to persist at follow-up. Conclusions: Some breast cancer patients indeed develop cognitive impairment during treatment, much of which appears to resolve at 6 months. Domains most affected include attention, visuospatial skills, and working memory. Attention problems resolved by 6 months, while working memory and visuospatial deficits persisted. [Table: see text] No significant financial relationships to disclose.
The effect of depression on survival in patients with newly diagnosed advanced non-small cell lung cancer (NSCLC)
Authors: Temel J. S. , Jackson V. A. , Billings A. , Prigerson H. G. , Fidias P. , Lynch T. J. , Pirl W. 
Published: April 2020

8511 Background: The impact of emotional distress on cancer-related mortality is unclear. Divergent results in studies are due, in part, from heterogeneous populations in terms of type of cancer, stage of disease, and time of emotional assessment. This study examined the effect of depression and anxiety on a well-defined cohort of patients with newly diagnosed advanced NSCLC. Methods: 46 patients with advanced NSCLC were recruited within eight weeks of diagnosis to participate in a feasibility study of early palliative care. Participants completed the Hospital Anxiety and Depression Scale (HADS) at baseline and were followed for six months. The primary study endpoint was survival at six months. The effects of depression and anxiety were evaluated first by Kaplan-Meier survival analysis and then by Cox regression to control for other variables. Results: Three patients (6%) had stage IIIB with effusions and the remaining 43 (93%) had stage IV disease. The median age of patients was 65.5 years and 28 of the 46 (61%) were women. 34 patients had a PS 1 (74%), 11 (24%) had PS 0 and one (2%) had PS 2. 96% of the patients completed the baseline HADS. 23% met HADS criteria for probable cases of depression (8 or greater) at baseline and 34% met HADS criteria for probable cases of anxiety (8 or greater). Using Kaplan-Meier survival analysis, patients with depression were less likely to have survived at 6 months than non-depressed patients (50% versus 80%, log rank p=0.01). Baseline anxiety did not appear to impact survival. Using Cox proportional hazard regression analyses to control for stage, ECOG performance status, age, and gender, the effect of depression remained significant at p=0.03. Conclusion: Depression in newly diagnosed advanced NSCLC patients was associated with inferior survival in this well-defined patient population. Conversely, anxiety did not appear to be associated with mortality. These findings strengthen the argument that emotional distress influences survival. Larger prospective studies are needed to confirm this conclusion, explore possible mediators, and investigate the effects of treatment for depression. No significant financial relationships to disclose.
Randomized phase II trial of the neurokinin-1 receptor antagonist (NK-1 RA) casopitant mesylate with ondansetron (ond)/dexamethasone (dex) for chemotherapy-induced nausea/vomiting (CINV) in patients (pts) receiving highly emetogenic chemotherapy (HEC)
Authors: Rolski J. , Ramlau R. , Dediu M. , Russo M. W. , Ross G. A. , Mather R. A. , Bandekar R. R. , Grunberg S. M. 
Published: April 2020

8513 Background: A combination of a 5-HT3 receptor antagonist (5-HT3 RA) + dex is standard for prevention of CINV due to HEC. However, NK-1 RAs are now also of interest. The current trial evaluated casopitant mesylate, a potent, oral, selective NK-1 RA, in a triple therapy regimen with a 5-HT3 RA and dex in pts receiving HEC. Methods: In this multicenter, randomized, double-blind, placebo-controlled, dose-ranging, parallel group study, pts receiving HEC were stratified by gender and randomized among six arms. HEC consisted of regimens including cisplatin ≥ 70 mg/m2 IV over 1–4 hours (h) day 1 (D1). All pts received ond 32mg IV D1 and dex PO D1–4 with either placebo control, casopitant 50mg QD D1–3, casopitant 100mg QD D1–3, or casopitant 150mg QD D1–3. Pts on exploratory arms received ond/dex plus either casopitant 150 mg D1 only or aprepitant 125mg D1 and 80mg D2–3. The primary endpoint was complete response (CR) rate (no vomiting, retching, rescue medications or premature withdrawals) during the first 120 h following initiation of HEC. Target intent-to-treat (ITT) group enrollment was 82 pts per arm. Results: 493 enrolled patients comprised the ITT group. CR rate was 60% in the control arm; 76% for casopitant 50mg; 86% for 100mg; and 77% for 150mg (p=.0036, Cochran-Armitage trend test). CR rate was 75% with casopitant 150 mg D1 and 72% for 3-day aprepitant. CR rates at 24 h were similar in all groups (86%-96%). Casopitant prolonged time to emesis (p=.0029) and increased the proportion of pts without vomiting (p=.0122) relative to control. There were no differences in rates of nausea or use of rescue medication among groups. Adverse events were similar across all arms, with neutropenia, nausea, and hiccups (≤ 17%) as most common. All casopitant doses were generally well tolerated. Conclusions: The addition of casopitant to ond/dex at all doses tested and in 1- or 3-day administration regimens was well tolerated and significantly reduced CINV rates over a 5-day period in pts receiving HEC. The results of the exploratory 1-day regimen are of particular interest for future evaluation. [Table: see text]
Effect of nausea vs. vomiting on patients’ quality of life during chemotherapy
Authors: Hickok J. T. , Roscoe J. A. , Morrow G. R. , Giguere J. K. , Colman L. K. , Malcolm A. 
Published: April 2020

8514 Background: Antiemetic guidelines are based largely on the presumption that vomiting is of greater concern to cancer patients, and impacts their quality of life (QOL) more strongly, than nausea. We examined the relative influence of chemotherapy-induced nausea and emesis on patients’ overall QOL and on the specific domains of social, emotional, physical and functional well-being. Methods: 667 patients enrolled in a three-arm, randomized, controlled Phase III study that detected no difference in the ability of a serotonin receptor antagonist vs. prochlorperazine (given regularly three times daily or taken only as needed for symptoms) to control the severity of nausea, completed the FACT-G before treatment and on the third day following their first infusion of anti-cancer chemotherapy containing doxorubicin (Day 4 of cycle 1). 93% were female, and 90% had breast cancer. Results: There was a significant reduction in overall QOL and in physical and functional well-being, but no significant change in emotional or social well-being, over the four day period. In a stepwise linear regression analysis predicting change in overall QOL, average nausea severity entered first and accounted for 24% of the variance in reduced QOL (p < 0.001). Occurrence of vomiting (yes, no) accounted for a non-significant less than 1% of additional variance (p = 0.240). No other factors (gender, age, the degree to which patients expected to experience nausea or vomiting, whether or not nausea or vomiting occurred, and maximum nausea severity over the four days) were significant predictors of the reduction in QOL. Similar results were obtained when the relative influence of nausea and vomiting on physical and functional decline were studied. Conclusions: Severity of nausea, not the occurrence of vomiting, was the key factor in patients’ perceived decline in quality of life in the days immediately following chemotherapy infusion. Nausea severity should be a primary outcome measure in studies evaluating antiemetic efficacy. Supported in part by NCI Public Health Service grant U10 CA37420 and ACS grant RSG-01–071-PBP No significant financial relationships to disclose.