bluuebunny/crossref_metadata_2025_split huggingface dataset:
Randomized phase II study of dacarbazine with or without sorafenib in patients with advanced melanoma
Authors: McDermott D. F. , Sosman J. A. , Hodi F. S. , Gonzalez R. , Linette G. , Richards J. , Jakub J. K. , Beeram M. , Patel K. , Cranmer L. 
Published: March 2020

8511 Background: Sorafenib (SOR), a potent and selective multi-kinase inhibitor, exerts its anti-tumor and anti-angiogenic effects via inhibition of VEGFR-1, -2, -3, PDGFR-a, -β, and Raf. Dacarbazine (DTIC) is an FDA-approved cytotoxic agent for advanced melanoma. Phase I/II results of SOR + DTIC were encouraging and prompted this randomized phase II study. Methods: This was a multi- center, double-blinded, placebo-controlled study; eligibility criteria included measurable disease by RECIST, no prior cytotoxic chemotherapy, and no active brain metastases. Advanced melanoma patients (pts) stratified by stage (unresectable III vs IVM1a/M1b vs M1c) and ECOG PS (0 vs 1) were randomized to receive DTIC 1,000 mg/m2 q 21 days + oral placebo (PL) or oral SOR 400 mg bid continuously until the occurrence of progressive disease or intolerable toxicity. The primary endpoint was progression-free survival (PFS) of DTIC+SOR vs DTIC+PL. Using a two-sided test with a = 0.05, 77 PFS events were needed to detect a hazard ratio (HR) of 0.5 (SOR/PL) with 86 % power. The secondary endpoint was overall survival and tertiary endpoints were objective response rate (ORR), time to progression, and duration of response. Results: 101 pts were enrolled over 12 months (51 DTIC+SOR, 50 DTIC+PL). Treatment arms were balanced for age (median 58 yrs), gender (male 70%), PS (ECOG 1 39%), stage (Stage IV M1c 52%) and baseline LDH (>ULN 29%). At the time of analysis by independent assessment, the median PFS of DTIC+PL vs DTIC+SOR was 11.7 wks (95% CI 6.1, 17.9) vs 21.1 wks (95% CI: 16, 28); HR 0.67 [p=0.07]; PFS rate at Day 180 was 18% vs 41%; and ORR was 12% vs 24%. Survival data are immature. Toxicities of Grade 3 or higher (DTIC+PL vs DTIC+SOR) included neutropenia (12% vs 33%), leukopenia (6% vs 14%), thrombocytopenia (18% vs 35%), thrombosis/embolism (0% vs 6%), hypertension (0 vs 8%), hand-foot skin reaction (0 vs 4%), and CNS hemorrhage (0% vs 8%). 3 of the 4 pts with CNS hemorrhage had new brain metastases. No treatment-related deaths occurred in either arm. Conclusions: DTIC+SOR was well tolerated and showed a strong efficacy trend compared with DTIC+PL in median PFS, PFS rate at 6 months and ORR in chemotherapy-naïve pts with advanced melanoma. This regimen warrants further evaluation in larger clinical trial settings. No significant financial relationships to disclose.
Improved survival following lymphadenectomy for nodal metastasis from an unknown primary melanoma
Authors: Lee C. C. , Faries M. B. , Wanek L. A. , Morton D. L. 
Published: March 2020

8515 Background: It is not possible to identify a primary site in 10–20% of melanoma patients presenting with palpable nodal metastases. The explanation for this phenomenon is unknown but could reflect an endogenous antimelanoma immune response that causes complete regression of the primary melanoma. If so, then these patients should have a better survival than patients whose primary melanoma has been identified. Methods: We reviewed our 13,000-patient prospective melanoma database (1971–2005) to identify patients managed with regional lymphadenectomy for palpable nodal metastases from unknown primary melanoma (MUP) or known primary cutaneous melanoma (MKP). Multivariate analysis was performed to identify prognostic factors significant for survival. MUP and MKP patients were then matched by significant covariates. Overall survival (OS) was estimated by Kaplan-Meier method and compared by log-rank analysis. Results: Among 1571 patients with palpable nodal metastases who underwent regional lymphadenectomy, multivariate analysis identified 5 significant covariates: age (HR=1.294, P=0.0017), sex (HR=1.335, P=0.0004), nodal tumor burden (HR=1.256, P<0.0001), decade of diagnosis (HR=0.989, P=0.0131), and unknown/known primary (HR=1.507; 95% CI=1.220 to 1.862; P=0.0001). Five-year OS was significantly higher for the 262 MUP patients than 1309 MKP patients (55±6% vs. 44±3%; P=0.0021). Computerized matching of MUP and MKP patients by four significant covariates (age, sex, nodal tumor burden, and decade of diagnosis) yielded 221 matched pairs. Median OS and 5-year OS rates were 165 months and 58±7%, respectively, for MUP as compared with 34 months and 40±6%, respectively, for MKP (P=0.0008). Conclusions: Our results strongly support the effectiveness of lymphadenectomy for nodal metastasis from MUP. Risk of death dropped significantly when regional lymphadenectomy was performed for metastases from MUP as compared with MKP. This result is compatible with an immunologic rejection of the primary melanoma due to a strong host antitumor immune response. Immunologic studies to identify cell-mediated and antibody components of this response are underway. No significant financial relationships to disclose.
Updated results of a randomized phase II study comparing two schedules of temozolomide in combination with sorafenib in patients with advanced melanoma
Authors: Amaravadi R. , Schuchter L. M. , McDermott D. F. , Kramer A. , Giles L. , Troxel A. B. , Medina C. A. , Nathanson K. L. , O'Dwyer P. J. , Flaherty K. T. 
Published: March 2020

8527 Background: The preliminary results for 90 patients (pt) on this 4-arm phase II trial testing sorafenib (SO), an oral Raf kinase/VEGFR2 inhibitor, and temozolomide (TEM) in pt with metastatic melanoma (MM) were presented in 2006. Since then 88% of target accrual is completed and the study is open at a second institution. The primary objective of this study is to estimate the duration of progression- free survival (PFS). Secondary objectives are to determine the optimal dosing of TEM, response, and toxicity rates. Correlative studies include BRAF genotyping and assessment of intratumoral Raf inhibition, and apoptosis. Methods: Pt with MM and ECOG PS<2 are eligible. Prior therapy is allowed. Target accrual is 167 pt in 1 stage. All pt receive SO 400 mg po bid continuously. After 1 week of SO alone, pt without brain metastasis or prior TEM (A+B) are randomized to receive either extended dosing (ED): TEM 75 mg/m2 po qd for 6/8 weeks (Arm A), or standard dosing (STD): TEM 150 mg/m2 po qd for days1–5/28 (Arm B). Pt with prior TEM are treated with ED (Arm C) and pt with brain metastasis without prior TEM are treated with STD (Arm D). Responses are assessed using RECIST. Results: Accrual is complete for arms A and B. Results for 147 pt were evaluated ( Table ). SO + TEM resulted in a 19% overall response rate (ORR) [95% CI 11–30%] for pt on arms A+B. In this group, 3/78 pt (4%) developed CNS metastases while on study. Pt on arm D had a 17 % ORR [95% CI 7–34%]. Common grade 3 toxicities were hand-foot syndrome (14%), rash (9%), nausea (9%), and diarrhea (5%). Grade 3 lymphopenia was more common in arm A v. B (43% v. 16%, p=0.01). No significant difference in PFS was found between pt with WT v. mutant BRAF (n=33). Therapy-induced apoptosis was found in 8/9 serial biopsies. Analysis of MAPK phosphorylation in serial biopsies is planned. Conclusions: Updated results confirm the encouraging antitumor activity and tolerability of SO + TEM in pt with MM without a prior history of TEM. No significant financial relationships to disclose. [Table: see text]
Biochemotherapy versus chemotherapy for metastatic malignant melanoma: A meta-analysis of the randomised trials
Authors: Ives N. J. , Stowe R. L. , Lorigan P. , Wheatley K. 
Published: March 2020

8544 Background: Metastatic melanoma is associated with a poor survival rate. High response rates have been reported for both chemotherapy and biochemotherapy. To assess whether adding interferon-a (IFN) ± interleukin-2 (IL-2) to chemotherapy is advantageous, a published data meta-analysis of trials of biochemotherapy versus chemotherapy has been performed. Methods: Standard published data meta-analysis methods were used to assess response rates (partial, complete and objective (i.e. partial+complete)) and overall survival (OS), with odds ratios (OR) and 95% confidence intervals (CI) calculated. The only subgroup analysis performed was by type of immunotherapy, with trials divided according to the type of immunotherapy given in the biochemotherapy arm - IFN or IFN+IL-2. Results: Data were available from 18 trials (11 trials of chemotherapy ± IFN and 7 of trials chemotherapy ± IFN+IL-2). Nearly 2500 patients were included in the analysis, with 555 responses and 2,039 deaths observed. There was a clear benefit for biochemotherapy for partial response (OR=0.67, CI=0.54–0.83, p=0.0002), complete response (0.50, 0.35–0.73, p=0.0003) and objective response (0.60, 0.49–0.73, p<0.00001). For objective response, these benefits were significant for both the IFN (0.60, 0.46–0.79, p=0.0002) and IFN+IL2 (0.60, 0.45–0.78, p=0.00002) subgroups. In contrast, there was no benefit on OS (0.99, 0.91–1.08, p=0.9), and there was also evidence of heterogeneity of treatment effect between the individual trials (p=0.006). Conclusions: This meta-analysis shows that biochemotherapy clearly improves response rates, but this does not appear to translate into a survival benefit. Single agent chemotherapy is considered the standard of care for the majority of patients receiving treatment for advanced melanoma outside a clinical trial, and the result of this meta-analysis shows no reason to change this. No significant financial relationships to disclose.
Survival and long-term toxicities of biochemotherapy for metastatic melanoma
Authors: Minor D. R. , Miller J. , Kashani-Sabet M. 
Published: March 2020

8553 Purpose: Because long-term survival after therapy for advanced stage IV melanoma is rare, we thought it would be useful to examine our series of survivors treated with biochemotherapy for melanoma to analyze the characteristics of survivors and their chronic toxicities. Patients and Methods: We reviewed our previously reported (J Clin Oncol. 2005:23:16s suppl, abstract 7547) consecutive series of 38 patients treated between 9/02 and 7/04. They received 6 cycles of inpatient temozolomide, cisplatin, vinblastine, decrescendo high- dose iv IL-2 , and interferon followed by maintenance immunotherapy using IL-2 and sargramostim using the O’Day regimen (Clinical Cancer Res. 2002:8:2775).Two of the ten long-term survivors received surgery for resection of residual disease after achieving a partial response with biochemotherapy. Maintenance immunotherapy was given for 6 to 24 months after biochemotherapy. Results: The median progression- free survival was 7.3 months. No patient developed progression later than 17 months after the start of therapy with the progression-free survival curve level at 24%. Median overall survival was 16.2 months. 10 of the 38 patients are alive and disease-free off therapy after an average of 3.3 years follow-up. Durable complete responses were seen in visceral sites including lung, bone, and pericardium, with 8 of 10 long- term survivors having M1B or M1C disease. 3 patients have significant lymphedema related to prior surgery, radiation therapy, or both. 2 patients, one with pre-existing diabetes, have significant persisting neuropathy. 5 of the 10 patients are hypothyroid. Menstrual function returned in the three women under age 45 in this study. Conclusion: This series supports the findings from other series that biochemotherapy, like high-dose IL-2, can give prolonged disease-free survival. Survivors have a high incidence of hypothyroidism but neuropathy and lymphedema, which affected a minority of patients, were the most bothersome long-term toxicities. No significant financial relationships to disclose.
Profiling cytochrome P450 CYP1 enzyme expression in primary melanoma and disseminated disease utilizing spectral imaging microscopy (SIM)
Authors: Everett S. A. , McErlane V. M. , McLeod K. F. , Daley F. M. , Barber P. R. , Vojnovic B. , Nathan P. D. , Richman P. I. , Pearl R. A. , Linge C. , Grover R. 
Published: March 2020

8556 Background: The aim of this study was to profile cytochrome CYP1 family (CYP1A1/1A2, and CYP1B1) mono-oxygenase enzymes during the malignant progression of primary melanoma and metastatic disease. Methods: Tissue microarrays of primary (n = 75), and metastatic (n = 104) melanoma were constructed with the patient demographics: (1) primary melanoma; age 22 to 93 (median 59); sex M/F 36/44; Breslow thickness 0.4 to 15 mm (median 2.5 mm); ulceration 25/80, and (2) metastatic melanoma; age 26 to 92 (median 60 mm); sex M/F 54/49; ulceration 30/104; number of nodes 1 to 15 (median 2); extra-capsular spread 20/95. CYP1 protein was detected by IHC using validated selective poly- and monoclonal antibodies. Vector SG (grey) stain for CYP1 was used with nuclear fast red counterstain to aid spectral resolution from background melanin. Staining intensity was scored visually (negative 0, weak 1, moderate 2, strong 3) and using SIM at every pixel of a captured image of each melanoma core. Reference spectra of individual chromophores were used to spectrally ‘un-mix’ CYP1 staining before the mean normalised absorbance intensity was determined. Grading was by the 2002 AJCC classification system: primary stage I n = 27 (1A 8, 1B 19), and stage II n = 48 (2A 22, 2B 16, 2C 10), lymph node metastasis stage III n = 98 (3B 53, 3C 45), visceral metastasis stage IV n = 6. Normal skin (n = 27), benign naevi (n = 14), and dysplastic naevi (n = 21) were also included. Results: CYP1B1 was not in normal skin but was over-expressed in both primary and metastatic melanoma (visual: 71% & 65%, SIM: 91% & 83%). Primary melanoma (stage I & II) was significantly greater (p = 0.004) than metastasis (stage III & IV). CYP1B1 did not correlate with ulceration or Breslow thickness but did correlate with N stage lymph node metastasis (p = 0.005). CYP1B1 expression in dysplastic naevi indicated up-regulation at an early stage of melanoma progression. CYP1A1/1A2 was not expressed in normal skin nor primary/metastatic melanoma. Conclusions: CYP1B1 protein expression is maintained with advancing AJCC stage from primary through to visceral metastasis. Future work will seek to correlate protein expression with functionality with a view to exploiting CYP1B1 in the enzyme/prodrug therapy of malignant melanoma. No significant financial relationships to disclose.
A phase II trial of biochemotherapy with cisplatin, vinblastine, dacarbazine, interleukin-2, interferon, and digoxin in melanoma matients
Authors: Khan M. I. , Taft B. , Rasku M. A. , Laber D. , Chesney J. , Miller D. M. 
Published: March 2020

8573 Background: Patients with stage IV metastatic melanoma have limited treatment options. Epidemiological studies have demonstrated that there is a lower death rate from breast cancer in patients who are on digoxin therapy (6%) when compared with patients who are not on digoxin therapy (34%). Recent in vitro studies have shown that digoxin inhibits growth and causes apoptosis in multiple cell lines including breast cancer cells (MCF-7), non-small cell lung cancer cells, HeLa cells, renal adenocarcinoma cells (TK-10), neuroblastoma cells, and prostate cancer cells. In addition digoxin enhances the efficacy of chemotherapy against melanoma cells in vitro. Consequently, the addition of digoxin may augment the cytotoxic effects of bio-chemotherapy against stage IV melanoma. Methods: Twenty-seven patients with stage IV melanoma without CNS metastasis with a median age of 51 years (25–69), were enrolled in this open label phase II clinical trial. ECOG performance status was 0 to 1. Patients had normal cardiac, pulmonary, renal and liver function tests. Patients received digoxin 0.25 mg daily throughout all cycles. Patients were hospitalized in ICU for 5 days to receive the therapy and supportive care. Treatment schedule: dacarbazine, IV, 800 mg/m2 on day 1; cisplatin, IV, 20 mg/m2 on days 1–4; vinblastine, IV, 1.2 mg/m2 on days 1–4; IL-2, IV over 24 hours, 9 M IU/m2 on days 1–4; interferon, SC, 5 MU/m2 on days 1–5. After completing 2 cycles (28 days per cycle) patients were evaluated for response by CT and/or FDG-PET imaging studies. Patients who experienced a SD, PR, or CR then completed 2 more cycles of this therapy. There was no treatment related mortality. Results: Seven patients achieved CR (25.9%), five patients had a PR (18.5%), and six patients had a SD (22.2%). The overall clinical benefit was 66.6%. Nine patients (33.3%) experienced progressive disease and were taken off the protocol. Eleven patients (40%) are alive and sixteen patients (60%) have died. Conclusions: Our preliminary data demonstrate that the addition of digoxin to bio-chemotherapy may have a synergistic effect on patients with melanoma. Accrual to this trial is on-going and final overall survival and progression free survival will be evaluated in the future. No significant financial relationships to disclose.
The cognitive effects of modafinil in breast cancer survivors: A randomized clinical trial
Authors: Kohli S. , Fisher S. G. , Tra Y. , Wesnes K. , Morrow G. R. 
Published: March 2020

9004 Background: Patients receiving treatment for cancer can experience a diminution of their cognitive abilities which can persist for many years after. The present study examined the potential of modafinil as a cognitive enhancer on memory and attention in a randomized clinical trial in breast cancer patients following completion of treatment. Methods: Breast cancer patients who reported a score of = 2 on the Brief Fatigue Inventory (BFI) an average of 22.8 months following completion of chemotherapy were enrolled. In Phase 1, patients received 200mg modafinil open-label once daily for 4 weeks. In Phase 2, patients with a positive response following Phase 1 were randomized either to an additional 4 weeks of modafinil or to placebo. Tests of memory and attention selected from the Cognitive Drug Research (CDR) computerized cognitive assessment were performed at baseline (before modafinil) and after completing Phase 1 and 2. The difference between scores at baseline and scores at Phase 1 and Phase 2, were subjected to a Wilcoxon's signed rank test. Results: Of the 82 women enrolled, 68 completed all 3 CDR assessments in the study (range=33–83 years, median age=54 years). At the end of Phase 1 (week 4), modafinil had a significant effect on the Speed of Memory Index (p=0.0047) and the Digit Vigilance Test (p=0.0014) but showed no significant effect on Quality of Working Memory (p=0.3528) nor on Power of Attention (p=0.8953). At the end of phase 2 (week 8), the group that continued modafinil demonstrated improved Mean Continuity of Attention (p=0.0002) compared with the placebo group and also demonstrated significantly greater improvements in Quality of Episodic Secondary Memory relative to placebo (p<0.005). This improvement was observed at week 4, and was maintained throughout the study. Finally, continued modafinil demonstrated significantly greater improvement in Speed of Memory relative to placebo (p=0.009). Conclusions: Modafinil provides significant improvements in attention and speed of memory for breast cancer patients following their treatment of cancer. Although further study is needed, these findings suggest that modafinil may enhance quality of life in this patient population. Supported by a grant from Cephalon, Inc and NCI Grants U10-CA37420 and R25- CA102618. No significant financial relationships to disclose.
Effect of percutaneous biliary drainage (PBD) for malignant biliary obstruction (MBO) on quality of life (QoL)
Authors: Robson P. M. , Heffernan N. , Holmes R. , Gonen M. , Schubert J. , Getrajdman G. I. , Brody L. A. , Brown K. T. , Covey A. M. , Blumgart L. H. 
Published: March 2020

9029 Background: PBD is routinely performed to relieve MBO. The clinical effects of drainage have been well documented, but little has been reported about how PBD effects a patient's QoL. Methods: Between October, 2004 and December, 2006, eligible patients (>18 years old, English speaking, clinical diagnosis of MBO) scheduled to undergo PBD at a comprehensive cancer center were invited to participate in a prospective study evaluating QoL using the Functional Assessment of Cancer Therapy Hepatobiliary (FACT-Hep) instrument, comprised of 5 subscales (physical, emotional, functional and social well being, and disease-specific concerns). FACT is the total score of the first four items; FACT-Hep is the total score of all 5 subscales. Patients completed the instrument at baseline, one week and four weeks following PBD. Instruments were scored following FACT guidelines; changes in QoL between these time points were analyzed using a mixed effect model with time as a categorical variable. Results: One hundred twenty five patients consented to participate in this study. Sixteen were not evaluable and were withdrawn from the study. One hundred nine (60 male / 49 female) patients completed the baseline instrument (100%), 57% at one week and 39% at four weeks. Thirty four patients (31%) completed all time points. The most common diagnoses included cholangiocarcinoma (30%), pancreatic cancer (29%), and metastatic colorectal cancer (17%). Mortality was 10% (N=11) at 4 weeks and 28% (N=30) 8 weeks following PBD, with one patient dying from a procedure related complication. The mean FACT scores are indicated in the table below. A declining score is associated with a decline in QoL. Conclusions: PBD for MBO does not improve overall QoL following PBD. Patients have significant disease related mortality within eight weeks of the procedure. [Table: see text] No significant financial relationships to disclose.
High prevalence of restless legs syndrome in cancer patients undergoing chemotherapy: Relationship with anxiety, depression and quality of life perception
Authors: Saini A. , Ostacoli L. , Sguazzotti E. , Capogna S. , Castronovo C. , Dongiovanni V. , Gorzegno G. , Furlan P. M. , Dogliotti L. , Berruti A. 
Published: March 2020

9032 Background: The Restless Legs Syndrome (RLS) is one of the commonest neurological sensorimotor disorders consisting in periodic limbs movements during the sleeping time that lead to severe insomnia and quality of life deterioration. The prevalence of RLS in normal population is 7 and 11% in males and females respectively. RLS correlated with female sex and iron deficiency. Chronic pain, sensory polineuropathy and the use of dopamine antagonist drugs can induce or exacerbate RLS. Dopamine agonists are extremely active drugs in controlling RLS. The prevalence of RLS in cancer patients is unknown. Methods: The presence of RLS, by means of the essential diagnostic criteria provided by the International RLS Study Group (Allen RP, Sleep Med; 2003), was tested in 257 consecutive cancer patients (119 males and 138 females) with different malignancies belonging to two different Medical Oncology centres. All patients were receiving chemotherapy. Functional Assessment of Cancer Therapy General (FACT-G), Hospital Anxiety and Depression Scale (HADS) and Mini Mental Adjustment to Cancer Scale (Mini-MAC) questionnaires were administered concomitantly to assess the impact of RLS on quality of life, anxiety or depression and styles of coping, respectively. Results: RLS was present in 47 patients (18.3%), 14 males (11.8%) and 33 females (23.9%); (p=0.01). RLS directly correlated with pain (p<0.0001), nausea (p<0.001), worse physical well-being (p=0.007), emotional well- being (p=0.001) and functional well-being (p=0.02). RLS affected patients showed higher levels of anxiety (p<0.001) and depression (p=0.001). The styles of coping consisting in anxious preoccupation and hopeless were also more represented in the RLS affected patients (p=0.04 and p=0.02 respectively) than their counterparts. Conclusions: RLS is frequent and underdiagnosed in cancer patients. It may cause anxiety, depression and quality of life deterioration. Early RLS detection and prompt introduction of dopamine agonists may improve patient quality of life. No significant financial relationships to disclose.