bluuebunny/crossref_metadata_2025 huggingface dataset:
The utility of 18-F-fluorodeoxyglucose positron emission tomography in evaluation of bone marrow involvement by non-Hodgkin lymphoma (NHL)
Authors: Muslimani A. , Farag H. , Francis S. , Spiro T. P. , Daw H. A. , Chaudhry A. A. , Chan V. C.
Published: March 2020

8077

Introduction: In NHL, the anatomic extent of the disease is an important factor influencing the overall survival. Clinically, NHLs are classified as indolent, aggressive, or highly aggressive. Bone marrow (BM) involvement is a sign of extensive disease, and iliac crest (IC) BM biopsy (BMB) is the established method for the detection of BM infiltration. However, IC BMB is associated with a high rate of false- negative result. We assess the ability of 18F-FDG PET scan to ascertain the presence of BM involvement in NHL. Methods: We retrospectively reviewed charts from January 2002 through November 2006 of histologically proven NHLs. 87 patients (pts) were eligible for our study (38 males, 49 females; age range 42–81 years). All pts were examined by whole-body 18F-FDG-PET scan for initial staging, and all had unilateral posterior IC BMB. BM involvement was established following the result of 1) unilateral posterior IC BMB, and 2) image-guided BMB following positive 18F-FDG-PET scan in selected patients. Results: Among the PET+ / IC BMB- group, 3 pts had a positive CT-scan guided BMB at the site of involvement detected by the 18F-FDG-PET scan (2 from the humerus,1 from the femur); the remaining 7 pts did not have a site-directed biopsy. Our data demonstrate an overall sensitivity of 0.76 for the PET scan detecting BM involvement in all pts and specificity of 0.88. We point out that the 0.88 specificity may be spuriously low, this is a result of the fact that of the 10 PET+ / IC BMB- pts 7 have not had directed biopsy to the site of involvement detected by the18F-FDG- PET-scan. Further analysis revealed no significant difference between the sensitivity (P = 0.21) and specificity (p = 0.99) between I- NHL and A/HA- NHL groups. Conclusion: 18F-FDG-PET scan shows potential to detect BM involvement in NHL. In particular, image-guided repeat BMB may be considered in pts with negative initial IC BMB, whose 18F-FDG-PET scan demonstrates BM involvement in a different site.

No significant financial relationships to disclose.

[Table: see text]
Gallium, rituximab, and dexamethasone for relapsed NHL
Authors: Smith S. E. , Wren K. , Stiff P. J. , Toor A. , Rodriguez T. , van Gestel D.
Published: March 2020

8079

Background: Almost 50% of patients with intermediate grade non-Hodgkin's lymphomas (NHL) treated with standard CHOP- like therapy will have less than a complete response (CR) after treatment or will relapse after obtaining a CR. Salvage chemotherapy followed in responders by an autologous stem cell transplant (ASCT) can be curative. For many patients, this is not an option due to age, comorbidities, or lack of response. A non-cross resistant agent with activity in NHL which could salvage more patients is gallium nitrate Methods: We conducted a phase II clinical trial investigating the combination 3 non-myelosuppressive agents, gallium nitrate, rituximab and dexamethasone (GaRD) for relapsed or refractory DLBCL, MCL or transformed follicular lymphomas. Gallium is given at 200mg/m2 CIV days 1–7, rituximab 375mg/m2 IVPB day 1 and dexamethasone 40 mg po days 1–4. Eligible patients had relapsed or refractory disease and had a SWOG PS ≤3. Patients may have failed prior ASCT or allogeneic SCT. This was a 2 stage, phase II study with initial evaluation after 22 patients of whom at least 10 responders were needed for completion of the study, as determined prior to start of trial Results: We enrolled 22 patients on study. 15 had large cell, 6 had transformed follicular and 1 had mantle cell NHL. Most of these patients were refractory to one or several prior salvage regimens [13/22 (59%)]; all had prior rituximab 22/22 (100%) and 18/22 (82%) had it with there most recent treatment. No patients developed grade 3 or 4 toxicities, except grade 4 lymphopenia in 7/22 (32%). The overall response rate was 10/22 (45%); CR/CRu 8/22 (36%); PR 2/22 (9%); SD 4/22 (18%); and PD 8/22 (36%). Five patients went on to receive stem cell transplant (including 3 allogeneic and 2 ASCT). Two of the responders were patients who had failed a prior stem cell transplant: 1 ASCT failure who remains in CR >18 months and an allograft failure in CR >14 months after relapse. Of the 22, 10 (46%) are alive at a median f/u of 17.2 months, of whom 7 are currently NED Conclusions: This regimen appears to be effective and relatively non-toxic for patients with relapsed and refractory NHL, including stem cell transplant failure. As CR at ASCT may be associated with an improved outcome, a trial of GaRD combined with RICE is planned to improve cytoreduction prior to ASCT in patients with relapsed NHL.

No significant financial relationships to disclose.
CHOP compared to THP-COP regimen: Long-term outcome in Chinese non-Hodgkin lymphoma (NHL) patients
Authors: Zhai L. , Cheng C. , Niraula S. , Huang Y. , Li Z. M. , Wang S. S. , Huang H. Q. , Lin T. Y.
Published: March 2020

8081

Background: THP-ADM (Pirarubicin) has potential to replace conventional ADM (Adriamycin) because of less severe toxicities. However, only a few studies have compared the long-term outcome between patients receiving the two drugs. A Japanese trial (JGTLE) shows the CR rate of THP-COP group was greater than CHOP group in elderly T-cell Non-Hodgkin's Lymphoma (NHL) patients. The current study was aimed at comparing the long-term outcome and toxicities between NHL patients receiving CHOP and THP-COP regimens within similar age-groups and pathological sub-types. Methods: 505 previously untreated NHL patients receiving either standard CHOP or THP-COP regimen (cyclophosphamide 750 mg/m2, doxorubicin or pirarubicin 50 mg/m2, vincristine 1.4 mg/m2and prednisone 40 mg/m2 for 5 days) were enrolled. Results: Patients’ characteristics between CHOP group(n=279) and THP-COP (n=228) group were well balanced. There were no differences in CR rate (54.8% vs. 54.0%, p=0.85) and response rate (82.1% vs. 84.1%, p=0.55). With a median follow-up of 59.7months, survival rate was similar (5-year OS: 56.7% vs. 55.8%, 5-year PFS: 43.5% vs. 47.3%, 5-year DFS: 54.0% vs. 54.7%). The incidence of cardiotoxicity(myocardial dysfunction and arrhythmia)was almost the same (10.0% vs10.2 %; P=0.958). Less Alopecia (39.1% vs. 28.8%, p= 0.015)and gastrointestinal toxicities(63.1% vs. 50.0%, p=0.003) were observed in THP-COP group. No differences between the two groups were observed within different pathological subtypes (B-cell subtype: CR rate 58.2% vs. 56.7%, 5-year OS 59.2% vs. 60.0%; T-cell subtype: CR rate 47.0% vs. 45.5%, 5-year OS 50.5% vs. 43.4%) and age-groups (<60 years group: CR rate 51.6% vs. 53.7%, p= 0.684; 5y OS 58.9% vs.61.1%, p= 0.570; =60 years group: CR rate 67.9% vs. 54.8 %, p= 0.148; 5y OS 48.0% vs. 42.1 %, p= 0.314). In the 33 elderly patients of T-cell subtype, CR rates were almost the same. (73.7% vs. 42.9%, p=0.073). Conclusions: The long-term outcome of NHL patients receiving THP-COP is similar to those receiving CHOP within similar age groups and pathologic subtypes. Cardiotoxicity occurs at a similar rate in both groups, while a lower incidence of alopecia and gastrointestinal toxicities was observed in THP-COP group.

No significant financial relationships to disclose.
Allogeneic stem cell transplantation (allo-SCT) in T-cell lymphomas: A French national survey from the Société Française de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC)
Authors: le Gouill S. , Milpied N. , Buzyn A. , Socié G. , Mothy M. , Vernant J. , Ifrah N. , Haioun C. , Michallet M. , Volteau C. , Blaise D.
Published: March 2020

8095

Background: T- and NK-cell lymphomas represent 10–15% of non-Hodgkin's lymphoma in adults.Despite intensive chemotherapy including or not autologous stem cell transplantation upfront, a majority of patients experience relapse. Methods: We retrospectively analyzed T-cell lymphomas patients transplanted from a related or unrelated HLA identical sibling donor with myeloablative or non-myeloablative conditioning regimen. Patients younger than 15 years at the time of transplantation, HIV positive patients or lymphoblastic lymphomas were excluded. We present the results of this study based on the SFGM-TC data-base. At the present time, we analyzed 57 cases from 10 french centers. Results: Diagnosis was PTCL (n=19) , AITL (n=8), anaplastic large cell lymphoma (ALCL) (n=20), hepatosplenic γ/d lymphoma (n=2), T-cell granular lymphocytic leukemia (n=1) and localized nasal NK/T cell lymphoma (n=3), NK/T cell lymphoma (n=1), HTLV1 cell lymphoma (n=2) and enteropathy-associated T-cell lymphoma (n=1). There were 38 males and 19 females. Median age at diagnosis was 38 years (13 - 61 y). At diagnosis, 51 patients had IPI score > or = 3. Median time from diagnosis to transplantation was 12 months (4.6–17). All patients but 15 underwent myeloablative conditioning regimen. Source of stem cells was BMSC (n=38), peripheral stem cells (n=18) or cord blood (n=1). Transplantation was performed from a related HLA-matched sibling donor in 53 cases. Disease status at the time of transplantation was CR in 25 cases, PR in 19 cases and SD/PD/refractory in 13 cases. Eleven patients presented acute GVH grade 3/4. After transplantation, 91% of patients were in CR compared to 43 % before. Six patients experienced relapse and eighteen patients died because toxicity related mortality. Conclusions: Preliminary results show that allo-SCT is an attractive option in aggressive T-cell lymphomas and confirm the role of a graft versus T-cell lymphoma effect. Ongoing analysis will identify prognostic factors and be presented at the time of the meeting. The present study will provide usefull tools for clinicians to evaluate the role of allo-SCT in the specific field of adult T- cell lymphomas.

No significant financial relationships to disclose.
Pegylated liposomal doxorubicin (PLD) as an alternative treatment of cutaneous T-cell lymphoma
Authors: Quereux G. , Khammari A. , Nguyen J. M. , Benmiloud M. , Dreno B.
Published: March 2020

8096

Background: Therapy of cutaneous T-cell lymphoma (CTCL) at early stages consists of various modalities. The advanced or transformed stage of CTCL is treated by the CHOP regimen as standard chemotherapy; has a 40% response rate and relapses within 6 months in > 60% of pts. Methods: A prospective open multicentre Phase II study to evaluate the use of PLD as a CTCL therapeutic agent, with 25 pts, (59±12 years). Eligibility criteria: Pts with histologic proof of CTCL stage II to IV, unresponsive to at least 2 lines of therapy; transformed CTCL or non epidermotropic lymphoma CD30 + or CD30. PLD was administered i.v., 40 mg/m2 every 4 wks for 8 cycles. Objective of study was overall response rate (ORR); secondary objectives were safety, disease-free survival (DFS) and overall survival (OS). Results: Phase II study of 14pts with CTCL stage IIb/III, and 11pts with transformed CTCL, at baseline. Treatment duration was 8 cycles in 13 pts, 2–6 cycles in 10pts, and 2 pts were withdrawn during cycle 1 due to anaphylactic-like reactions. Among 23 treated pts, 5pts (22%) achieved a complete response (CR), 9pts (39%) a partial response (PR), with 61% ORR. DFS was 18 ± 4.5 mos; longest treatment duration was 24 mos. Median OS was 28 ± 3 mos. In general, PLD treatment was well tolerated. The main adverse events were grade 3 neutropenia (4%); grade 3 septicemia (8%) and 1 case of bilateral grade 3 pneumopathy. There were only 3 cases of grade 1 palmoplantar erythrodysesthesia. Conclusions: This is the first prospective multicentric study investigating activity and tolerance of 40 mg/m2 q28days of PLD in CTCL. The current study confirmed effectiveness of PLD(∼61%) in CTCL treatment, but did not show improved efficacy with dose increases (Wollina, Cancer, 2003). This data combined with Wollina’s data, support the use of PLD as a promising therapy in advanced stages of CTCL. The duration of response is superior to that achieved with CHOP. This has been confirmed in a small, trial, and needs to be confirmed in a larger trial.

No significant financial relationships to disclose.
HLA class II alleles predict recurrence and pattern of failure in early-stage melanoma patients
Authors: Chun Y. S. , Wang Y. , Gershenwald J. E. , Ross M. I. , Johnson M. M. , Liu P. , Schacherer C. W. , Reveille J. D. , Lee J. E.
Published: March 2020

8503

Background: Prior reports have suggested a link between specific HLA class II alleles, including HLA-DRB1*1101, and melanoma recurrence. We therefore investigated the relationship between HLA class II alleles and clinical outcome in a large population of patients who presented with localized melanoma. Methods: HLA class II alleles were determined by typing of genomic DNA from patients who presented with localized melanoma (AJCC stage IA-IIC). Patients found to have occult regional disease by sentinel node biopsy were excluded. Log-rank and Cox analysis of outcome versus standard prognostic factors and common HLA class II alleles (=5% of the population) was performed. Results: 1,241 patients underwent HLA typing. The median primary tumor thickness was 1.1 mm, 16% were ulcerated, and the median follow-up was 56 months. Tumor thickness, ulceration, and Clark level were independent predictors of recurrence. The HLA class II allele HLA-DRB1*1101 (11% of the population) independently predicted a higher risk of recurrence [hazard ratio (HR) 2.04, P=0.004] while HLA-DRB1*0401 (20% of the population) predicted a lower risk of recurrence (HR 0.42, P=0.004). HLA- DRB1*1101 was a particularly strong predictor of recurrence in stage I patients (HR 2.73, P<0.0001). Among patients who recurred, HLA- DRB1*1101 was an independent predictor of local-regional vs. distant recurrence (HR 2.7, P=0.007), and was more common in those whose first recurrence was isolated to the regional nodal basin, compared to those whose first recurrence was elsewhere or in multiple locations (24% HLA-DRB1*1101-positive vs. 14%, P<0.009). Conclusions: These results confirm that HLA-DRB1*1101 is a genetic marker of increased risk of melanoma recurrence, while HLA-DRB1*0401 is a marker of decreased risk of recurrence. HLA-DRB1*1101 is a particularly strong marker among the group of patients predicted clinically to be at the lowest overall risk for recurrence, and independently predicts pattern of recurrence (regional nodal failure). This information is of value in the development of surveillance strategies for melanoma patients, as well as the selection, stratification and randomization of early-stage melanoma patients for clinical trials.

No significant financial relationships to disclose.
EORTC 18991: Long-term adjuvant pegylated interferon-alpha2b (PEG-IFN) compared to observation in resected stage III melanoma, final results of a randomized phase III trial
Authors: Eggermont A. M. , Suciu S. , Santinami M. , Kruit W. , Testori A. , Marsden J. , Punt C. , Hauschild A. , Gore M. , Keilholz U.
Published: March 2020

8504

Background: EORTC 18991 is the largest adjuvant trial ever conducted in stage III melanoma. It assessed the efficacy and toxicity of long term PEG-IFN vs Observation (Obs.). Methods: PEG-IFN (Induction at 6μg/Kg/wk, sc, 8 weeks; followed by Maintenance at 3μg/Kg/wk, sc) for a total treatment duration of 5 years was compared to Obs. in 1256 patients (pts) with stage III melanoma (anyTN1–2M0 without in-transit metastases). Randomization was stratified for nodal involvement N1 (microscopic) vs N2 (palpable nodes), # of nodes, Breslow and ulceration of primary, sex and center. Distant Metastasis-Free Survival (DMFS) was the primary endpoint. Relapse-Free Survival (RFS) was the pre-specified regulatory primary endpoint. Overall survival (OS) was the secondary endpoint. Intent-to-treat analysis was performed. Results: Median follow-up was 3.8 yrs: HR = Hazard Ratio; NR = Not Reached In N1-pts (n=543) the benefit of PEG-IFN seemed more pronounced than in N2-pts (n=713): RFS (HR 0.73 p=0.02 and HR 0.86 p=0.12 for N1 and N2, respectively), DMFS (HR 0.75 p=0.03 and HR 0.94 p=0.53) and OS (HR 0.88 p=0.43 and HR 1.01 p=0.91). PEG-IFN therapy relative dose intensity (actual/planned dose while treated) reached median 88% (induction) and 83% (maintenance). 251 pts (40 %) stopped PEG-IFN because of toxicity. Grade 3–4 - mostly grade 3 - toxicities were reported in 45% (PEG-IFN), vs 12% (Obs.), including most frequently fatigue (15%), hepatotoxicity (10%) and depression (6%) with ECOG 0–1 Performance Status maintained in 83% of pts during maintenance. Conclusions: Long term PEG-IFN therapy in stage III melanoma had a significant and sustained impact on RFS, but not on DMFS and OS. Pts with only microscopic nodal involvement (Sentinel Node positive) seemed to have greater benefit in terms of both RFS and DMFS. Similar better effects of adjuvant IFN therapy in pts with lower disease burden are observed in 2 consecutive EORTC trials (18952 and 18991) involving 2644 pts.

[Table: see text] [Table: see text]
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.
Mammography use in women age 80 and older with breast cancer
Authors: Giordano S. H. , Badgwell B. , Duan Z. , Bedrosian I. , Hortobagyi G. , Babiera G.
Published: March 2020

9039

Background: The guidelines for screening mammography use in patients age 80 years and older are not clear. The purpose of this study was to determine the effect of mammography use on stage and tumor size at breast cancer diagnosis. Methods: The study is a retrospective cohort using the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database. We evaluated 14,976 women aged 80 and older diagnosed with breast cancer between 1996–2002. Patients were divided into three cohorts based on screening mammography use in the 60 months prior to diagnosis: nonusers, non-regular users (1–2 mammograms), and regular users (3+). The effects of screening on tumor stage (0-I vs. II-IV) and size were determined by logistic regression and multivariate analysis of variance. Results: Regular mammography use for the age groups 80–84, 85–89, and >= 90 was 29%, 19%, and 9%, respectively. Among regular users of mammography, 26% presented with stage II or greater cancer while 64% of non-users presented with stage II or greater disease. On multivariate analysis, non-users were 4.7 (95% CI 4.26–5.14) times more likely to present with high-stage cancer. Non-users, non-regular users, and regular users had an adjusted mean tumor size of 5.08 (4.44–5.72), 3.26 (2.57–3.95), and 2.77 (2.02–3.51), respectively. Conclusions: Regular screening mammography among women aged 80 years and older is associated with earlier stage at presentation and smaller tumor size compared to mammography nonusers. Health care providers should consider discussing potential benefits of screening mammography with their older patients particularly for those without significant comorbidity.

No significant financial relationships to disclose.
Fosfomycin prevents cisplatin-induced ototoxicity: Results of a randomized, double blind, placebo controlled trial
Authors: Green D. , Chavez-Mac Gregor M. , Sosa-Sanchez R. , Andraca R. , Enriquez L. , Leon E. , Ponce de Leon S.
Published: March 2020

9041

Background: Cisplatin is one of the most frequently used chemotherapy agents. The main dose-limiting toxicity for its use is hearing-loss, present in 40–100% of patients. To date, no treatment has proven efficacy in preventing or reducing cisplatin acoustic damage. Fosfomycin, acting as a free-radical scavanger, has shown to reduce cisplatin-induced ototoxicity and nephrotoxicity in animal models, without affecting its antineoplastic activity. This trial evaluated the effect of fosfomycin in cisplatin-induced ototoxicity. Methods: 22 chemotherapy naive patients with normal audition, scheduled to receive cisplatin-based chemotherapy (cumulative dose =200mg/m2) were randomized to receive placebo (n=11) or 1g of IV fosfomycin concurrent with each cisplatin administration (2–4 cycles). Primary outcome was ototoxicity when comparing audiometric studies (low and high frequencies and otoaccustic emissions) at baseline and at completion of chemotherapy. With β=0.8 and a=0.05 the study was powered to detect differences =20 dB at any given frequency. Fisher's test, Wilcoxon and Mann-Whitney test were used. Results: Groups were balanced for baseline characteristics, cisplatin dose and response rates. No differences were found when comparing ototoxicity at low frequency ranges. When analyzing high frequencies and otoaccustic emissions, 9 patients (82%) in the placebo group developed ototoxicity vs 4 (36%) in the fosfomycin group (p=0.04). The degree of hearing-loss, evaluated by comparing percentage of change in each evaluated frequency, was significantly lower in patients receiving fosfomycin (p=0.04). Other chemotherapy toxicities were similar in both groups. Conclusions: In patients with audiometric integrity, the concurrent administration of fosfomycin with cisplatin significantly reduces ototoxicity. The degree of hearing-loss is lower in patients receiving fosfomycin than in those receiving placebo. The use of fosfomycin in combination with cisplatin is safe and does not interfere with its antineoplastic activity. To our knowledge this is the first clinical-trial that demonstrates prevention and reduction of cisplatin-induced hearing-loss.

No significant financial relationships to disclose.
Assessing adherence to the American College of Chest Physicians’ (ACCP) recommendations for thromboprophylaxis in hospitalized cancer patients
Authors: Amin A. N. , Stemkowski S. A. , Lin J. , Yang G.
Published: March 2020

9047

Background: This study evaluates whether clinicians are providing appropriate VTE prophylaxis to at-risk surgical and non- surgical cancer patients in accordance with ACCP guidelines. Methods: Premier's inpatient administrative data were used to assess VTE prophylaxis rates in fourteen cancer types. Patients age 40 or older, with a minimum length of stay of six days, and no contraindications for anti-coagulation were included in the study. Two rates were determined; the rate of discharges receiving any level of anticoagulation and the rate of patients receiving appropriate prophylaxis by comparing daily use of anti-coagulants and compression devices, dosage, and prophylaxis duration with ACCP recommendations. The 6th guidelines were used due to their release prior to the study period. Rates based on the 7th guidelines were calculated for the same patient cohort to assess how the revised guidelines affect our findings. Trends were assessed by comparing prophylaxis rates by quarter. Results: 72,391 discharges from 225 hospitals between January 2002 and September 2005 met the inclusion criteria. 29% of all at-risk cancer discharges received the recommended prophylaxis regimen. Rates varied by cancer type ranging from 18.7% in prostate to 36.3% in colorectal cancer discharges. 55% did not receive any anti-coagulation prophylaxis, 9.5% received insufficient dosage and 5.8% did not receive prophylaxis for the appropriate duration. The appropriate VTE prophylaxis rate is higher for surgical cancer than for non-surgical cancer discharges (32.3% vs. 27.7%). Trends suggest a slight increase in appropriate prophylaxis rates for all types of cancer discharges. Appropriate prophylaxis rates based on 7th guidelines are lower than rates based on the 6th guidelines due to the more specific recommendation in the 7th guidelines. Conclusions: Cancer patients are known to have significant risk for VTE, yet VTE prophylaxis for at-risk non-surgical cancer patients in hospitals is not optimal. Rates for surgical cancer patients were only slightly higher. Using the 7th recommendations results in lower prophylaxis rates. More effort is required to increase awareness of the ACCP recommendations for thromboprophylaxis in cancer patients.

No significant financial relationships to disclose.