bluuebunny/crossref_metadata_2025 huggingface dataset:
The efficacy and safety of ipilimumab (MDX-010) in patients with unresectable stage III or stage IV malignant melanoma
Authors: Weber J. S. , Hersh E. M. , Yellin M. , Nichol G. M. , Urba W. , Powderly J. D. , O’Day S. J.
Published: March 2020

8523

Background: Ipilimumab, a fully human monoclonal antibody that blocks cytotoxic T-lymphocyte antigen-4 (CTLA-4), enhances antitumor immune responses resulting in durable objective responses. In this study we examined the efficacy and safety of different ipilimumab preparations and regimens in patients with unresectable metastatic melanoma. Methods: In this study (MDX010–15), 34 patients received either 2.8 or 5 mg/kg transfectoma- or 3 mg/kg hybridoma-derived ipilimumab on days 1, 57 and 85. Additionally, 30 patients received single doses of 7.5 (6 pts), 10 (7 pts), 15 (6 pts) or 20 mg/kg (11 pts) transfectoma-derived ipilimumab. Once single doses up to 20 mg/kg were found to be well tolerated, 24 additional patients were given up to 4 doses of 10 mg/kg ipilimumab on days 1, 22, 43 and 64. Complete or partial responses (CR, PR), stable disease (SD) and adverse events (AEs) were monitored. Results: 1 CR, 3 PRs and 10 durable SDs were confirmed in 88 treated patients at the time of analysis. ORs were durable (∼29+, 34, 38+ and 39+ weeks [w]) and ongoing in 3 patients at study completion. PR in 1 patient was observed after ∼18.5w and developed to an ongoing CR at ∼51w. In another, SD for ∼16w preceded a ∼30w+ PR. Durable SD ranged from ∼21 to 79+w and is ongoing in 4 patients. Patients with OR or SD had immune-related AEs including rash, pruritis (G1/2), diarrhea (G1/2/3) or colitis (G2). AEs were severe in 27 patients, and considered ipilimumab-related (mostly G3/G4 colitis and diarrhea) in 9 (10% of all treated patients). Conclusions: Preliminary results suggest ipilimumab is generally safe and well tolerated. Late-onset ORs can occur, sometimes preceded by months of SD. ORs and SDs tend to be durable. Drug-related AEs of an immune nature are probably related to the biologic effects of ipilimumab, and are similar to those reported previously. No obvious dose relationship to AEs has been seen to date.

[Table: see text]
A phase II study of YM155, a novel survivin suppressant, administered by 168 hour continuous infusion in patients with unresectable stage III or stage IV melanoma
Authors: Gonzalez R. , Lewis K. , Samlowski W. , Cranmer L. , Catlett J. , Kirkwood J. , Whitman E. , Lawson D. , Bartels P. , Drake T.
Published: March 2020

8538

Background: In cell line studies, YM155 showed markedly potent antiproliferative activity against melanoma with 50% growth inhibition (GI50) values ranging from 0.35 nM to 910 nM. In melanoma tumor-bearing mouse xenograft models, YM155 showed significant antitumor activity including regression of tumors, at doses ranging from 1 to 10 mg/kg/day. Methods: Chemotherapy naive patients with unresectable Stage III or IV melanoma were eligible. The primary endpoint was tumor response defined by RECIST criteria. Secondary endpoints included progression-free survival and toxicity. A Simon's two stage minimax design was utilized with the first stage requiring 1 response (N=27) and a total of 2 responses required at the conclusion of stage II (N=29). Patients were considered evaluable if they completed 2 cycles. YM155 was given as a 168-hour (7-day) continuous infusion every three weeks (1 cycle) at a dose of 4.8 mg/m2/day. Results: Enrollment is complete at 34 pts in order to reach 29 evaluable with treatment ongoing. Results are available for the first 26 pts. Median age was 59 y/o, (range 29 - 88) with ECOG PS of 0–1. There is one objective response of intrabdominal lymph nodes based on Investigator assessment at Cycle 2 confirmed at Cycle 4; another patient had a minor response (24% reduction) at Cycle 6 (currently at Cycle 8). Two subjects have shown stable disease after 6 cycles and remain on study. The median number of cycles is 3 (range 1 - 9). Two of 26 pts reported a grade 3 AE considered possibly related to YM155 (chest pain - nos and catheter related thrombosis). Nineteen of 26 pts have discontinued the study (18 PD, 1 withdrew consent). Conclusions: YM155 induced responses in 2 pts and was generally well tolerated. Given this encouraging response as a single agent, studies of YM155 combined with other agents are under consideration.

[Table: see text]
Quality of life in patients with advanced melanoma receiving vaccine therapy alone (V) or vaccine with high-dose interleukin-2 (V-HIL2)
Authors: Marden S. F. , Muehlbauer P. , Soeken K. , Kline Leidy N. , Parchen D. , Schwartzentruber D. J.
Published: March 2020

8549

Background: Melanoma is a public health concern with 1 in 75 Americans diagnosed during their lifetime and 5-year survival rate of about 10% for those with advanced melanoma. With curative options limited, new regimens must be evaluated and attention given to outcomes of how patients feel and function as a result of therapy. Methods: We examined the effect of biotherapy and fatigue on health-related quality of life (HRQL) in patients with stage IV melanoma enrolled in phase II clinical trials at the NCI receiving peptide vaccines with or without high dose IL-2. Generic HRQL was measured by physical (PCS) and mental (MCS) summary scores of the Short Form-36 health survey (SF-36). The Functional Assessment of Cancer Therapy-General (FACT-G) with a fatigue scale (FS) measured disease-specific HRQL and fatigue. Higher scores on measures indicate better physical, emotional, social function and well-being and less fatigue. Between 2000–2003, patients (F=22, M=47; mean age 46 ± 11) completed measures by computer at baseline (BL) and first follow-up after 2 cycles of treatment, before discussion of response to therapy. Data were analyzed using two-way ANCOVA with biotherapy (V or V-HIL2) and fatigue (worse (W) or improved/stable (I/S)) as factors and BL HRQL as covariate. A clinically important difference on FS is reported as 3 points. Fatigue levels with decrease of 3 from BL to follow-up were classified as W and <3 as I/S. Results: Patients were Caucasian (99%), married (77%), BL ECOG 0 or 1 (99%), mean BL Hgb 13 ± 2 and received 2 prior therapies (38%) or more (42%). Adjusting for BL HRQL, there was no biotherapy (p >.30) or interaction effect (p >.60; table ). There was a fatigue effect (p <.001) with lower HRQL adjusted mean scores in W versus I/S. Conclusions: HRQL does not differ in patients with advanced melanoma ECOG 0 or 1 who receive investigational V versus V-HIL2 at follow-up evaluation. Patients’ reporting of worsened fatigue is associated with poorer HRQL, regardless of the biotherapy received.

[Table: see text] [Table: see text]
Pegylated liposomal doxorubicin plus paclitaxel as an individualized chemosensitivity-directed treatment in advanced metastatic melanoma
Authors: Ugurel S. , Neuber K. , Pfoehler C. , Mauch C. , Ulrich J. , Schadendorf D.
Published: March 2020

8551

Background: Melanoma is a cutaneous neoplasm known for its high agressiveness and its poor prognosis once metastasized. Dacarbacine chemotherapy is actually considered standard first-line treatment of metastatic melanoma, with reported response rates of 6–7%. Due to this unsatisfactory situation, a number of non-standard anti-cancer drugs have been tested for improved efficacy. The present study was aimed to test doxorubicin plus paclitaxel in metastatic melanoma patients based on in-vitro chemosensitivity of this drug combination in fresh tumor samples. Methods: The primary study endpoint was objective response, secondary endpoints were safety and overall survival. Patients with histologically confirmed metastatic melanoma (AJCC stage IV), measurable tumor parameters, and an in-vitro chemosensitivity to doxorubicin plus paclitaxel which is superior to other test drugs determined by an ATP-based luminescence viability assay, were eligible. Patients received paclitaxel 175 mg/m2 i.v. followed by pegylated liposomal doxorubicin 30 mg/m2 i.v. at d1 every 28 days. Tumor assessment was performed every 8 weeks and evaluated according to RECIST. Treatment was continued at a tumor response of stable disease (SD) or better, and stopped in case of disease progression (PD) or intolerable side effects. Results: Out of 14 patients enrolled into this study, 12 received study treatment as first-line, and two as second-line therapy. Objective response was 14.3% (1 CR, 1 PR); progression arrest was 28.6% (1 CR, 1 PR, 2 SD). Median overall survival was 9.7 months. Common slight to moderate side effects were myelosuppression and neurotoxicity. Severe toxicities (CTC grade 3/4) were experienced by three patients (21.4%), with two of them presenting severe myelosuppression, and one experiencing myocardial infarction. Conclusions: Pegylated liposomal doxorubicin combined with paclitaxel shows significant efficacy in advanced metastatic melanoma if applied in an individualized, sensitivity- directed regimen. The observed side effects were comparable to other combination chemotherapies. This treatment regimen needs further evaluation in larger clinical trials containing standard therapy control groups.

No significant financial relationships to disclose.
LDH is a prognostic factor in stage IV melanoma patients (pts) but is a predictive factor only for bcl2 antisense treatment efficacy: Re-analysis of GM301 and EORTC18951 randomized trials
Authors: Keilholz U. , Suciu S. , Bedikian A. Y. , Punt C. J. , Gore M. , Kruit W. , Pavlick A. C. , Spatz A. , Gilles E. , Eggermont A. M.
Published: March 2020

8552

Background: Two large studies with identical eligibility criteria and using serum LDH as stratification for randomization were re-analyzed in order to 1) confirm the prognostic importance of LDH in advanced melanoma; 2) to assess whether an interaction between LDH and treatment efficacy exists. Methodology: Oblimersen (OBL) trial GM301 randomized 771 pts between DTIC vs. DTIC+OBL, whereas EORTC trial 18951 randomized 365 pts between biochemotherapy vs biochemotherapy+IL2 (JCO, 2004). LDH was divided into 5 groups: 5 UNL. Cox model was used to asses the prognostic importance of LDH, treatment difference and LDH-treatment interaction regarding the main endpoint, overall survival (OS). Results: In each study LDH appeared to be of strong and incremental prognostic importance (p<0.0001): the higher the LDH the shorter the OS. Median OS in pts with LDH<0.8 UNL was ±1 yr vs. 5 UNL. In both trials, pts with LDH 0.8–1.1 UNL had already a shorter median OS (± 9 months) as compared to the <0.8 group. In each study, overall, treatment differences were not significant. However, an interaction between LDH and treatment difference was observed in GM301 (p=0.01), but not in 18951 (p=0.51). In GM301, the largest benefit in favor of OBL was confined to the LDH <0.8 UNL subgroup (see table ), whereas in EORTC18951 the trend for an IL2 advantage was spread over several LDH groups. The observation was consistent also for response and PFS, and was not related to known confounding variables including metastatic disease site and PS. Conclusion: LDH is a biomarker with remarkable prognostic value for OS in advanced melanoma, and our analysis provides evidence for its prognostic value already below the UNL. Furthermore, OBL only had an effect in pts with low pretreatment LDH levels representing more favorable biology.

No significant financial relationships to disclose.

[Table: see text]
Reliability and validity of the Functional Assessment of Cancer Therapy-melanoma (FACT-M)
Authors: Cormier J. N. , Webster K. , Cella D. , Ross M. I. , Gershenwald J. E. , Lee J. E. , Mansfield P. F. , Kim K. B. , Camacho L. H. , Palmer J. L.
Published: March 2020

8554

Background: Our group has developed a disease-specific module for the Functional Assessment of Cancer Therapy (FACT) instrument to assess quality of life (QOL) in melanoma patients. The purpose of this study was to assess the reliability and validity of the melanoma subscale (MS) and melanoma surgery subscales (MSS) as well as the total FACT-M, which includes the FACT combined with the MS and MSS. Methods: 273 melanoma patients (stages I-IV) attending an outpatient melanoma clinic completed a battery of questionnaires at baseline assessment. The scores from the MS, MSS, and total FACT-M were compared to patient performance status (ECOG and Karnofsky scales), disease stage, treatment status, and other instruments with related domains including the Profile of Mood States, Marlowe-Crowne Social Desirability Scale, and the EORTC Quality of Life Questionnaire - melanoma module. Patients were assessed 1 week after baseline to assess test-retest reliability, and 163 patients completed assessments at 3 months to evaluate the responsiveness to change in performance status. Results: Internal consistency and test-retest reliability for the MS (Cronbach's a = 0.85, r = 0.81), MSS (a = 0.85, r = 0.82), and the total FACT-M (a = 0.95, r = 0.90) were excellent. Overall, the scales correlated with other measures and correlations were in the hypothesized direction. As predicted, FACT-M, MS, and MSS scores were lower for patients with advanced (stage III/IV) melanoma, patients with poor performance status, and patients who were receiving active treatment. In addition, total FACT-M, MS, and MSS scores were highly sensitive to changes in performance status (p = 0.0012, 0.0004, and 0.0006, respectively). Conclusions: The FACT-M is a reliable and valid QOL assessment tool for patients with melanoma. This disease-specific instrument should be utilized for melanoma QOL assessment in clinical trials.

No significant financial relationships to disclose.
Patient-specific vaccines derived from proliferating autologous tumor cell lines and dendritic cells: Results of a phase II trial in metastatic melanoma
Authors: Dillman R. O. , Selvan S. R. , Schiltz P. M. , DePriest C. , Peterson C. , DeLeon C. , McClay E. F. , Barth N. M. , Sheehy P. F. , Allen K.
Published: March 2020

8555

Background: Patient-specific vaccines utilizing proliferating tumor cells, or tumor stem cells, may be the ideal products for active specific immunotherapy. Methods: Eligible patients had recurrent or metastatic melanoma from which a cell line was established, expanded to 200 million cells, incubated with interferon-gamma, irradiated and cryopreserved. Autologous dendritic cells (DC) were derived from peripheral blood mononuclear cells cultured in IL-4 and GM-CSF. DC were incubated with the irradiated tumor cells, then cryopreserved in 20- million-cell aliquots, which were thawed, washed and suspended in 500 micrograms of GM-CSF for injection. Treatment consisted of s.c. injections weekly × 3, then monthly × 5 in a 2-stage phase II trial with two stratifications. Patients were characterized as having objectively measurable disease (OMD) or non-measurable disease (NMD). Plans were to enroll 30 to 80 patients: 15 to 40 with OMD, 15 to 40 with MD. Objectives were to determine safety, frequency of conversion of delayed type hypersensitivity (DTH) reactions to irradiated autologous tumor cells, objective response rate (ORR) using RECIST criteria, progression-free survival (PFS), overall survival (OS), and comparison to a historical control group. Results: Between January 2001 and April 2006, 55 patients were enrolled; 53 were eligible and evaluable. The 30 men and 23 women had a median age of 50 years; 15 had OMD and 38 NMD. Patients received an average of 7.4 vaccinations out of a possible 8. Treatment was well- tolerated. 25% had a positive tumor DTH test: 1 at baseline, 7 after 3 injections, 5 after 8 injections. ORR was 0/15. Follow up for the 39 surviving patients ranges from 7 to 67 months with a median of 30 months. Median PFS is 7.1 months with 24 patients remaining progression-free. Only 14 patients have died; median OS has not been reached. 5-year projected survival is 70%; 20 patients are alive 2.5 to 5.5 years from start of vaccine. OS is better than observed for 48 comparable patients that we treated previously in a trial with irradiated tumor cells without DC (p=0.016). Conclusion: This patient-specific vaccine approach is feasible, safe, associated with encouraging survival, and warrants further investigation.

No significant financial relationships to disclose.
Safety data on adjuvant treatment of cutaneous melanoma patients with interferon-alpha2b and pegylated interferon-alpha2b: An interim analysis of 285 patients treated in Germany
Authors: Eigentler T. K. , Gutzmer R. , Hauschild A. , Vogt T. , Linse R. , Garbe C.
Published: March 2020

8561

Background: A multicenter, prospective randomized, phase III trial (EADO 2002/CMII) evaluating efficacy of interferon-a2b (IFNa) and of pegylated interferon-a2b (PEGIFNa) was carried out in cutaneous melanoma patients. Patients were eligible for this trial after local excision of an intermediate risk cutaneous melanoma (tumor thickness >1,5mm) & the absence of regional nodal macrometastases). Methods: Interferon-a2b (IFNa) for 18 months (3x3MIU sc/week), and pegylated interferon-a2b (PEGIFNa) for 36 months (100 μg sc/week) were evaluated in 285 patients treated in Germany; 141 pts treated with PEGIFNa and 144 pts with IFNa. Safety data was analyzed and adverse events of the IFN-a treatment were monitored. Results: All relevant AEs appeared within the first year of treatment. The leading clinical adverse events observed in both arms were fatigue (27.7%) & myalgia (19.7%) (NCI-CTC2–3). There were no significant differences between both treatment arms in frequency and intensity for depression, fever, weight loss, erythema at injection site, nausea, constipation, hair loss, pain, cardiovascular function, pulmonal & nervous status (NCI-CTC2–3). There were no significant differences in terms of anemia, thrombocytopenia, bilirubinaemia, SGOT, SGPT, BUN & proteinaemia (NCI-CTC3). Leukocytopenia (NCI-CTC3) occurred in 2.4% of all cases, and was observed more frequently in the PEGIFNa arm (3.1% vs. 0.8%; p=0.09). Granulocytopenia (NCI-CTC3) was present in 6.7% of all treated patients, appearing more frequent in the PEGIFNa arm (11.0% vs. 2.3%; p=0.05), also. One patient in the PEGIFNa arm developed a grade 4 leuko- and granulocytopenia. In another case in the IFNa arm a grade 4 increase of the SGPT was observed. In 23.7% of all treated patients a dose reduction was performed. Conclusions: Both PEGIFNa and IFNa are well tolerated using these regimens for these treatment durations. There were few differences in the tolerability between PEGIFNa 100 μg sc/week and IFNa 3x3MIU sc/week. Only an increased myelosuppressive effects such as leuko- and granulocytopenia have been observed. A prolongation of PEGIFNa treatment to 3 years was not associated with an increase in AEs.

No significant financial relationships to disclose.
Prognostic factors for survival after embolization of hepatic metastases in uveal melanoma
Authors: Yamamoto A. , Chervoneva I. , Sullivan K. , Eschelman D. , Gonsalves C. , Mastrangelo M. J. , Berd D. , Feeney K. , Terai M. , Sato T.
Published: March 2020

8562

Background: Liver is the most common site of metastasis (>80%) in patients with uveal melanoma. Embolization of the hepatic artery has been used to control hepatic metastases. Methods: Uveal melanoma patients with hepatic metastases embolized with iodized poppy seed oil and gelatin sponge, and either BCNU (chemoembolization, CE) or GM-CSF (immunoembolization, IE) during periods when each of these drugs was the agent of first choice, were evaluated. Prognostic factors that predict OS and progression free survival (PFS) in the liver (PFS-L) and in the extra-hepatic systemic organs (PFS-S) were analyzed univariately using the log-rank test and multivariately using Cox proportional hazards model. The following parameters were evaluated: age, gender, pre-existing extrahepatic metastases (EHM), LDH, AST, ALP, and treatment modality (CE or IE). Results: A total of 53 uveal melanoma patients with < 50% liver involvement with melanoma were analyzed. In comparison to the 19 patients (14 males/5 females) who underwent CE, the 34 patients who underwent IE (12 males/22 females) have significantly better OS (14.1 vs. 9.7 months, p=0.012) and PFS-S (10.2 vs. 4.8 months, P=0.013) in univariate analyses. Female patients outlived male patients (14.2 vs. 9.7 months, p=0.005). In Cox model, the shorter OS was associated with male gender (hazard ratio (HR)=2.1; 95% CI, 1.1–4.0; p=0.020), and marginally related to EHM (HR=1.8; 95% CI, 1.0–3.4; p=0.052). Independent predictors of shorter PFS-S included older age (HR=1.04 per year; 95% CI: 1.01–1.06; p=0.007), EHM (HR=2.1; 95% CI, 1.1–3.8; p=0.017), and CE (HR=2.1; 95% CI, 1.2–3.8; p=0.012). The gender-by-treatment interaction was also considered in all Cox models, but it was not significant. None of the covariates was a predictor of PFS-L in univariate or multivariate analyses. Conclusions: IE and female gender were found to be positive prognostic factors for survival after embolization of hepatic metastases.

No significant financial relationships to disclose.
Effect of granulocyte macrophage-colony stimulating factor (GM-CSF, sargramostim) administration on serum S100B and its subtypes in melanoma patients
Authors: De Gast B. , Korse C. , Weber R. , Trautveter S. , Bonfrer J. , Spitler L.
Published: March 2020

8563

Background: Serum S100B is a tumor marker for malignant melanoma (MM) and is also a histological marker for Dendritic Cells (DC). Previously study we found that DC only expressed the S100BB subtype, whereas MM expressed both the S100A1B and BB subtypes. As GM-CSF can induce activation of DC, we studied if such therapy also increased serum S100B and analysed the subtype of the increased S100B. Methods: Forty-three patients with MM were treated after surgical cytoreduction with adjuvant GM-CSF, 125 μg/m2 subcutaneously for up to 1 year in 28-day cycles of 14 days on followed by 14 days rest. Serum S100B was measured before therapy (d0), following 14 days on GM-CSF (d15), and after 14 days off GM-CSF (d29), as well as d155. If serum S100B was increased, subtype analysis was performed with immunoassays for S100A1B and S100BB. Results: In 39 patients with a normal serum S100B at d0 (mean 0.04 ± sd 0.02 μg/l), a significant rise of serum S100B occurred at d15 (mean 0.09 ± sd 0.04 μg/l), returning to normal at d29 (mean 0.05 ± sd 0.02, p<0.001 for d15 versus d0 and d29). Analysis of the increased S100B at d15 showed increased levels of S100BB in 7/13 patients and no increase in the levels of S100A1B. In 4 patients S100B was increased at d0, of the S100A1B subtype in 2 with rapidly progressive disease. The other 2 had only increased S100BB levels. In 28 patients a significant increase occurred at d155. Overall, 18 patients have remained without evidence of disease all without S100A1B. Four patients developed metastatic disease and had increased levels of S100A1B; however 6 additional patients also developed metastasis without an increase in S100A1B. Conclusions: Administration of GM- CSF causes an increase of S100BB suggestive of activation of DC. Increased levels of S100A1B were indicative of active MM, but the absence of elevated S100A1B did not exclude metastasis.

No significant financial relationships to disclose.
A pharmacokinetic comparison of the Marqibo 3 and 5 vial injection kits in metatastic melanoma patients
Authors: Hwu P. , Papadopoulos N. , Kim K. , Vardeleon A. G. , Campbell S. , Namdari R. , Choy G. , Berk G. , Bedikian A.
Published: March 2020

8575

Background: In nonclinical and clinical studies, liposomal encapsulation of vincristine sulfate (VCR) increased the circulation time and accumulation of VCR at the tumor site, and thus improved antitumor efficacy in comparison to VCR. Marqibo (vincristine sulfate liposomes injection) may be administered safely at doses exceeding that typically employed by VCR, with a manageable pattern of clinical toxicities consistent with VCR. Methods: We conducted a phase I, single-center, open-label, randomized, 2-arm crossover study designed to compare the pharmacokinetics (PK) of Marqibo utilizing the 3- and 5-vial kits administered 2 mg/m2 IV infusion once every 2 weeks in histologically confirmed, surgically nonresectable Stage III or IV metastatic cutaneous, mucosal, or choroidal melanoma patients. Patients randomized to receive the 3-vial kit at Cycle 1 were crossed over to receive the 5-vial kit at Cycle 2 or vice versa. The 3-vial kit was used for all patients at all cycles from Cycle 3 to end of treatment. Antitumor activity was assessed by CT scan every 4 cycles. Blood samples for PK analysis was collected at pretreatment, during infusion, end of infusion, and at various time points within 96 hours post end of infusion at Cycles 1 and 2. Total VCR concentration and released vincristine concentration was measured using HPLC-MS/MS method. Results: Fifteen patients were enrolled and treated; 11 were evaluable for the PK analysis. Median number of cycles received was 4 (1- 24). Objective response was observed in 13% (1 CR, 1 PR) or stable disease (20%, 3 SD) as their best response. The 90% CI (0.83–1.12) on the ratio of the means of the AUC0-inf of the 3- and 5-vial kits was within the interval of 0.80–1.25 confirming the bioequivalence of the two kits. Seventy-three percent discontinued treatment due to disease progression and 13% discontinued due to adverse events. Adverse events included hypoesthesia or paresthesia, constipation, numbness, weakness, fatigue, nausea, vomiting. Conclusions: Single agent Marqibo demonstrated moderate activity in advanced Stage IV melanoma patients and was generally well tolerated with similar adverse event profile to VCR. The 3- and 5-vial kits produced similar bioequivalent PK profiles.

No significant financial relationships to disclose.
Improved long-term survival in patients with intermediate thickness primary melanoma managed by sentinel node biopsy
Authors: Scheri R. P. , Wanek L. , Essner R. , Morton D.
Published: March 2020

8576

Background: Although improved disease-free survival (DFS) with sentinel node biopsy (SNB) for clinically localized melanoma was observed at the interim analysis from the first Multicenter Selective Lymphadenectomy Trial (MSLT-I) there was not yet an improvement in overall survival (OS). We hypothesize this was due to the few observed early deaths. To investigate this we simulated the MSLT-1 protocol using our institutional database. Methods: 3,800 patients undergoing wide excision with or without SNB were matched by primary stage/ulceration/site and patient demographics. Patients with positive sentinel nodes (SN) underwent immediate completion lymphadenectomy (CLND) whereas non-SNB patients managed by nodal observation underwent delayed CLND at nodal recurrence. Survival was determined by the Kaplan-Meier method. Significance was determined using log-rank and Cox regression analysis. Results: Among matched pairs of SNB and non-SNB patients with 1.2–3.5 mm primaries, projected 10-year OS was 76% with SNB versus 63% without SNB (p=0.0008). There was no corresponding statistically significant difference between all 2001 SNB patients and 1799 non-SNB patients, or within the thin primary and thicker primary groups. By multivariate analysis, only SN status (p<0.0001), Breslow thickness (p<0.0001) and ulceration (p=0.0001) were independently predictive of OS. Conclusions: Our long-term data suggest that performing SNB will improve OS in patients with intermediate thickness melanoma but not with thicker or thinner melanomas as compared to observation and delayed CLND.

No significant financial relationships to disclose.

[Table: see text]
What do redox metabolism, printers/lithographers, and hip replacements have to do with the prevention of melanoma?
Authors: Meyskens F.
Published: March 2020

8583

Our studies of the properties of reactive oxygen species(ROS) in melanomagenesis led us to explore the role of heavy metals in this process. A systematic experimental exploration of the effect of ROS on melanin and melanosomes in melanocytes and melanoma cells using biophysical techniques including electroparamagnetic resonance to measure free radicals and electron microscopy suggests that the conversion of melanin from an anti-oxidant and reducing agent to a pro-oxidant and photoreactive compound is an early pathogenic event that is accompanied by melanosomal disruption that serves as an ongoing organelle source of free radical generation. The involvement of selected heavy metals enhances this process and in conjunction with ultraviolet light can lead to phenotypic changes in normal human melanocytes that resemble dysplatic nevi melanocytes in culture. A re-examination of the non-genetic risk factors for melanoma has identified a large(and neglected) epidemiology that implicates heavy metals and includes markedly increased risks for melanoma in printers/lithographers(4 large studies), electrical industry workers (3 large studies), and hip replacements patients(a large meta-analyses and 2 cohort studies). High levels of cobalt are present in this latter group post-replacement that lasts for years (?indefinitely) Clinical observations (imaging studies) and studies that document the importance of metallothionein expression in primary melanoma and prognosis also offers ancillary support for the involvement of metals in the pathogenesis of melanoma Based on these considerations and the role of copper in the melanin synthesis pathway and the binding characteristics of metals to melanin we propose that the most likely culprits that accounts for a significant contribution to the etiology and pathogenesis of melanoma are Cu+2 and Co+2 and suggests that chelation may be a reasonable strategy for the prevention of melanoma.

No significant financial relationships to disclose.
Role of low molecular weight heparin (LMWH) in central venous catheter antithrombotic prophylaxis
Authors: Tassinari D. , Scarpi E. , Rupoli S. , Leoni P.
Published: March 2020

9010

Background: To assess the role of LMWH in antithrombotic prophylaxis in cancer patients with a central venous catheter. Methods: A systematic review of literature in the MEDLINE and EMBASE data bases from 1966 to October 2006, using “anticoagulants/*administration & dosage” [MeSH term], “cancer patient” [MeSH term], “catheterization, central venous/*adverse effect” [MeSH term], “catheters, indwelling/adverse effects” “central venous catheter” [MeSH term], “dalteparin/*administration and dosage” [MeSH term], “enoxaparin/*administration and dosage” [MeSH term], “low molecular weight heparin/*administration and dosage” [MeSH term], “nadroparin/*administration and dosage” [MeSH term], “neoplasm/drug therapy” [MeSH term], “reviparin/*administration and dosage” [MeSH term], “venous thrombosis/*etiology/*prevention & control/radiography” [MeSH term], a search was performed independently by two authors (DT and ES). All the randomized phase III trials comparing LMWH and placebo were considered eligible and included into the analysis. The risk reduction (RR) of upper limb venous thrombosis (ULVT) was the primary outcome of the analysis. Heterogeneity between the trials was analysed using the Mantel-Haenszel test, and the outcome analysis was performed using a random effects model and an alpha error lower than 5%. Results: 5 trials met the selection criteria and were included into the analysis. The outcome of 1,367 patients (793 treated with LMWE and 574 treated with placebo) was compared in the pooled analysis. A significant heterogeneity was documented between the trials (p=0.005), while no heterogeneity was observed when a trial with a low quality in the presented data was excluded from the analysis (p=0.777). No significant differences in RR were observed both when all the trials were included into the analysis (RR=−2.4%, p=0.456) and when we excluded a trial for the low quality of presented data (RR=0.2%, p=0.896). Conclusion: Antithrombotic prophylaxis with LMWH does not reduce the risk of ULVT in oncologic patients with central venous catheter, and its routine use seems to be not-recommended in clinical practice.

No significant financial relationships to disclose.
Aminoglycoside-induced deafness in leukemic patients: Cost-effectiveness of prevention by genetic testing
Authors: Bitner-Glindzicz M. , Osei-Lah V. , Colvin I. , Sirimanna T. , Lucas D. , MacArdle B. , Webb D. , Shankar A. , Kingston J. , Jenkins L. , Rahman S.
Published: March 2020

9014

Background: Aminoglycosides are highly-effective, inexpensive antimicrobials widely used in empirical combination therapy for fever in children with severe neutropenia, including patients receiving treatment for acute leukemia. Some genetically predisposed individuals are exquisitely sensitive to the cochleotoxic effects of these drugs, even when levels are within the therapeutic range. This genetic susceptibility is maternally inherited and caused by mutation of the MT-RNR1 gene encoding mitochondrial 12S rRNA at base position 1555, termed m.1555A>G. Methods: Retrospective analysis of m.1555A>G positive cases in the Regional Diagnostic laboratory to determine how many were revealed by aminoglycoside treatment for cancer treatment-related sepsis. Results: Three unrelated mutation positive individuals were identified in a two year period. All were children with acute lymphoblastic leukemia who experienced rapidly progressive hearing loss during their treatment. Two of the three children have a post-lingual hearing loss of sufficient severity to merit cochlear implantation. None had a significant family history of deafness. Conclusions: Initial estimates of the prevalence of the m.1555A>G mutation were based upon extrapolation back from its contribution to the cause of hearing loss amongst hearing-impaired people and were thought to be low. However, recent small studies of the prevalence of m.1555A>G in the general population suggest that prevalence is much higher than previously calculated (1 in 206 in New Zealand (n=206), 1 in 1,161 in Texas (n=1,161)) but that penetrance, at least in the absence of aminoglycosides, is low. Using estimates of the lifetime cost of pediatric cochlear implantation we suggest that screening for the m.1555A>G mutation at the time of diagnosis of leukemia would be cost effective and therefore suggest that all children diagnosed with leukemia should be screened for this mutation prior to receiving aminoglycoside therapy.

No significant financial relationships to disclose.
Subclinical cardiac toxicity and health-related quality of life (hql) in childhood cancer survivors
Authors: Cox C. L. , Rai S. N. , Rosenthal D. , Phipps S. , Hudson M. M.
Published: March 2020

9018

Background: Despite substantial information about late cardiotoxicity, little is known about its impact on the adolescent/young adult survivor's health-related quality of life (HQL). Using cross-sectional data, we assessed how HQL and New York Heart Association (NYHA) functional classification are related to survivors’ cardiac performance, cardiac risk factors, and treatment history. Methods: HQL indicators were examined in 164 long-term survivors of pediatric cancer (age 16–40 years), who had (n=132; 10 years (mean) after diagnosis of predominantly leukemia or lymphoma) or had not (n=32; 11 years (mean) after diagnosis of predominantly solid tumors) received anthracyclines and/or thoracic irradiation. Survivors underwent extensive noninvasive clinical and laboratory cardiac risk evaluation and completed a self-report questionnaire on selected subscales of the SF-36 (HQL). Results: Reported general health was lower in the cardiotoxic-therapy group (P = 0.05). Sex, current age, time since diagnosis, cardiac function, and cardiac risk factors were independent predictors of HQL subscales and NYHA class in multivariable analysis. Female sex and higher LDL cholesterol interacted to predict diminished reported vitality (P = 0.04) and physical health (P = 0.05) shown in table . Conclusions: Even in the absence of clinically evident cardiotoxicity, cardiac dysfunction and cardiac risk were strongly linked to decreased HQL and NYHA class, particularly among female survivors. Reduced HQL may be an indicator of unidentified sequelae that should be investigated and monitored.

No significant financial relationships to disclose.

[Table: see text]
Interval between first palliative care consultation and death in patients with advanced cancer
Authors: El Osta B. , Palmer J. , Paraskevopoulos T. , Pei B. , Roberts L. , Poulter V. , Chacko R. , Bruera E.
Published: March 2020

9028

Background: Most referrals to acute palliative care (PC) services occur late in the trajectory of the disease, although an earlier intervention can decrease patients’ (pts) symptoms distress. The purpose of this study was to determine the time interval between first palliative care consultation (PC1) and death (D) in pts diagnosed with advanced cancer (aCA) at our comprehensive cancer center and whether such interval has increased over time. Methods: The study group was 2,868 consecutive pts who had their PC1 during a 30-month period. We reviewed the charts for information about demographics, cancer type, date of cancer diagnosis, aCA diagnosis, PC1, and D. aCA was defined as locally recurrent or metastatic. Results: 1,404 pts (49%) were female, 1,791 (62%) were < 65 years old, 2,563 (89%) had solid cancer, and 2,004 (70%) were white. The median PC1-D, aCA- PC1, and aCA-D intervals were 40, 114, and 243 days respectively. The median PC1-D interval (days) was: 47 for pts with solid cancer vs 14 for pts with hematological malignancy (p < 0.0001); 44 for pts < 65 years old vs 36 for pts = 65 years old (p = 0.002); 45 for females vs 37 for males (p = 0.004); 40 for white pts vs 41 for pts from other ethnicities (p = 0.42). The median PC1-D interval in 5 consecutive half-years was 46, 56, 42, 41, and 34 days respectively (p = 0.02). The total number of pts referred for PC1 in this period increased 20%, from 544 to 654. The ratio of PC involvement period in the aCA-D interval (PC1-D/aCA-D) decreased from 0.30 to 0.26 over the 5 half-year periods (p = 0.0004) ( Table ). Conclusions: Patients with solid cancers, younger pts, and females pts were referred earlier to acute PC. Referral timing was not affected by ethnicity. The interval between first palliative care consult and death has decreased over time. Education is needed among referring physicians to increase this interval. Further research on increasing acute PC access and its impact on PC1-D interval is needed.

[Table: see text]

No significant financial relationships to disclose.
Prediction of early death risk in the elderly with cancer: Results of a prospective multicentric study of 364 patients under chemotherapy
Authors: Soubeyran P. , Rainfray M. , Mathoulin-Pélissier S. , Blanc-Bisson C. , Mertens C. , Blanc J. , Ceccaldi J. , Imbert Y. , Dauba J. , Fonck M.
Published: March 2020

9040

Background: When it is time to decide for or against chemotherapy in elderly patients (pts) with cancer, physicians face the difficult balance of risks and benefits. Too much often, decision is based on empirical feelings rather than reliable and objective factors which are frequently lacking. Yet, elderly pts can benefit from chemotherapy in many situations. Method: To help physicians in the decision process of chemotherapy through identification of factors predicting early death (< 6 months) from the onset of chemotherapy, we performed a prospective accrual of pts older than 70 with various types of cancer treated by 1st line chemotherapy. Baseline geriatric assessment (GA) (MMS, Get up and go, ADL, IADL, MNA, GDS15 , CIRS-G). Treatment was applied by the oncologist according to current standards disregarding GA results. Factors tested were: age, sex, advanced disease, renal and cardiac function, blood counts, performance status (PS), comorbidities and GA data. Results: 364 pts were accrued in 12 centres. Localisations were: lymphomas (110), colon (101), stomach (37), lung (37), pancreas (23), prostate (20), bladder (18), ovary (14) and unknown origin carcinomas (4). Main characteristics: median age (77.5 y. - range: 70- 99), sex ratio H/F (1.43), advanced tumours (66% - metastatic cancer or aaIPI 2–3 for lymphomas), PS>1 (28%), creatinine clearance <50 ml/mn (42%). GA showed 32% of pts ADL-dependent, 70% IADL-dependent, risk of falls in 12.4%, 19.2% MMS<24, 30% GDS15 >6, 63.4% MNA<23.5, 38.2% = 1 CIRS-G gr. 3–4 category. 357 pts have been followed up for more than 6 months and 59 pts died during this period. Only advanced disease (OR: 4.2 - CI95:1.7–10.3) and MNA score (OR: 4.5 - CI95: 1.75–11.6) predicted early death in logistic regression model. In advanced tumours, risk of early death varied from 11% in pts with MNA>23.5 to 40% in pts with MNA<17. Conclusions: In pts older than 70 with cancer, disease extension and MNA could predict for early death. MNA, performed by a trained nurse, should probably be added to routine pre- treatment work-up in these pts to screen for multidisciplinary assessment and management by oncologists and geriatricians. Sponsored by PHRC, sanofi-aventis, Amgen, Pfizer

[Table: see text]
Clinically significant fatigue in recurrence-free prostate cancer survivors
Authors: Storey D. J. , McLaren D. , Shipway M. , Butcher I. , Liggatt S. , O'Dea R. , Smyth J. F. , Sharpe M.
Published: March 2020

9044

Background: In the absence of definitive evidence of best disease control, treatment decisions for early prostate cancer should consider likely long term side effects and quality of life. Fatigue is an acute side effect of treatment but there are no data about long term clinically significant fatigue (CSF) in recurrence free prostate cancer survivors. This study presents the prevalence, associations and predictors of CSF after radical prostatectomy (RP) or radiotherapy (XRT). Methods: A postal questionnaire survey of 416 recurrence free men treated at a regional cancer centre >1 year previously. CSF was defined as global Brief Fatigue Inventory score >3. Other measures: Hospital Anxiety and Depression Scale (HADS), International Prostate Symptom Score (IPSS), European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire, clinical and demographic information. Relationships between these factors and CSF were explored in univariate and then multivariate logistic regression analyses. Results: 91% (377/416) of questionnaires were analyzable. Mean age was 72 years (SD 6.1) and median time since treatment was 56 months (range 13–233). The prevalence of CSF was 29% (108/377) overall; 22% (29/133) post RP and 33% (79/244) post XRT. Univariate and multivariate associations of CSF predictors are shown below. Patients with CSF also had poorer quality of life, physical, role, and social function (all p<0.001). CSF was not associated with age, social deprivation category or time since treatment. Conclusions: Almost a third of recurrence free prostate cancer survivors have CSF. RP is associated with less CSF post treatment than XRT, but treatment type did not remain statistically significant in a multivariate analysis controlling for other factors. Depression at outcome had the strongest association with CSF. Other associated variables were IPSS>7, comorbid medical conditions and anxiety. Care should focus on optimising the identification and management of these conditions to improve fatigue.

[Table: see text]

No significant financial relationships to disclose.
Second neoplasm and cerebrovascular disease in over five-year survivors with CNS germ cell tumor
Authors: Sugiyama K. , Arita K. , Kurisu K. , Sawamura Y.
Published: March 2020

9046

Background: Survivors of childhood and adolescent brain tumors are at risk for long-term effects of treatment (Tx). This study investigates details on second neoplasm and cerebrovascular disease of long-term survivors with CNS germ cell tumors (CNSGCTs). Methods: The authors reviewed clinical data on 203 institutional patients (pts) who had a CNSGCT and survived more than 5 years. Median age of initial Tx was 15.0 years and median follow-up period was 168 months (60–448 months). Results: Among these pts, 32 pts (15.4%) suffered from second neoplasm and/or cerebrovascular disease. Median age of 32 pts was 14.6 years at the initial Tx. Median interval to event was 151 months (24–456 months). The secondary events, therefore, occurred at the third decade of age. The second neoplasm included 8 cavernous angiomas, 7 GBMs, 3 meningiomas, 2 G-III glioma, 1 hemangiopericytoma, and 1 leukemia. Four cavernous angiomas caused a hematoma. The cerebrovascular disease included 14 steno-occlusive diseases of circle of Willis, 1 aneurysm, and 1 dural AVF. Four pts sufferred from both neoplasum and cerebrovascular disease. All 32 pts had previously received radiotherapy and 6 pts had undergone chemotherapy. Radiation field included whole ventricle system or whole brain involving basal cistern with the dose of more than 40 Gy, except for one who received 24 Gy followed by P-E chemotherapy. Eight of 32 pts died and 14 pts had additional sequelae due to these secondary events. Conclusions: The risk of lethal malignant neoplasm and disabling cerebarovascular disease after Tx for CNSGCTs is extremely large. Long-term follow-up system to monitor and prevent late sequelae should be established.

No significant financial relationships to disclose.
Incidence and significance of thromboembolic events (TE) in patients with gastrointestinal (GI) and non-GI malignancies on systemic cytotoxic therapy
Authors: Asmis T. R. , Templeton M. , Trocola R. , Pincus N. , Randazzo J. , Marinela C. , Kelsen D. P. , Shah M. A.
Published: March 2020

9049

Background: Although venous thromboembolic events (TE) are commonly associated with solid tumor malignancies, the precise incidence and significance of TE in cancer patients has not been well established. We previously reported a high incidence of TE in patients with GI malignancies enrolled on clinical studies at Memorial Sloan Kettering (MSKCC) (Asmis, GI ASCO 2007), and now explore the prognostic impact of TE in GI and non-GI malignancies. Methods: All patients above the age of 18 enrolled on prospective, investigator-initiated therapeutic clinical trials at MSKCC from January 1, 2003 to December 31, 2005 were reviewed. Serious adverse event monitoring was recorded prospectively and patients were followed regularly as per their protocol. All patients with Grade 3–4 TE were identified and confirmed at chart review. 100 patients without TE were audited to verify TE status, and 4 patients with TE were identified(sensitivity 96.8%, 95%CI 92.1–99.1%; specificity 100%, 95%CI 96.2–100%). Patients were followed for survival. All records were reviewed for baseline anticoagulation use, prior therapy, and date of cancer diagnosis. Results: 2482 patients with solid tumor malignancies were enrolled from 2003 to 2005: median age 58 (range 18–90), 43% female, 7% baseline anticoagulation, 44% previously untreated. 122 (4.8%, 95%CI 4%- 5.7%) had a TE. TE is associated with decreased median survival in patients with non-GI malignancy (10 months vs. 19.5 months) (p=0.0003), whereas the development of TE was not associated with reduced survival in GI malignancies (16.7 months vs 15.6 months (p=0.45)). Conclusions: In patients with non-GI solid tumors, the development of a venous thromboembolism is significantly associated with poor survival. Understanding why this is the case may provide insight to tumor biology and an opportunity to positively impact patient survival.

[Table: see text]

No significant financial relationships to disclose.