The European Society for Medical Oncology (ESMO) held a consensus conference on melanoma on 5–7 September 2019 in Amsterdam, The Netherlands. The conference included a multidisciplinary panel of 32 ...leading experts in the management of melanoma. The aim of the conference was to develop recommendations on topics that are not covered in detail in the current ESMO Clinical Practice Guideline and where available evidence is either limited or conflicting. The main topics identified for discussion were (i) the management of locoregional disease; (ii) targeted versus immunotherapies in the adjuvant setting; (iii) targeted versus immunotherapies for the first-line treatment of metastatic melanoma; (iv) when to stop immunotherapy or targeted therapy in the metastatic setting; and (v) systemic versus local treatment for brain metastases. The expert panel was divided into five working groups to each address questions relating to one of the five topics outlined above. Relevant scientific literature was reviewed in advance. Recommendations were developed by the working groups and then presented to the entire panel for further discussion and amendment before voting. This manuscript presents the results relating to the management of metastatic melanoma, including findings from the expert panel discussions, consensus recommendations and a summary of evidence supporting each recommendation. All participants approved the final manuscript.
•A melanoma consensus conference, organised by the ESMO Guidelines Committee, was attended by 32 experts from 14 countries•The experts compiled recommendations (with supporting evidence) on controversial topics in melanoma management•Recommendations for metastatic melanoma in this manuscript include the following:○targeted versus immunotherapy○treatment sequencing and duration○management of brain metastases•A separate manuscript presenting results relating to the management of locoregional melanoma is also available
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background
One‐fifth of patients with a preoperative diagnosis of ductal carcinoma in situ (DCIS) have invasive breast cancer (IBC) on definitive histology. Sentinel lymph node dissection (SLND) is ...performed in almost half of women having surgery for DCIS in Sweden. The aim of the present study was to try to minimize unnecessary SLND by injecting superparamagnetic iron oxide (SPIO) nanoparticles at the time of primary breast surgery, enabling SLND to be performed later, if IBC is found in the primary specimen.
Methods
Women with DCIS at high risk for the presence of invasion undergoing breast conservation, and patients with DCIS undergoing mastectomy were included. The primary outcome was whether this technique could reduce SLND. Secondary outcomes were number of SLNDs avoided, detection rate and procedure‐related costs.
Results
This was a preplanned interim analysis of 189 procedures. IBC was found in 47 and a secondary SLND was performed in 41 women. Thus, 78·3 per cent of patients avoided SLND (P < 0·001). At reoperation, SPIO plus blue dye outperformed isotope and blue dye in detection of the sentinel node (40 of 40 versus 26 of 40 women; P < 0·001). Costs were reduced by a mean of 24·5 per cent in women without IBC (€3990 versus 5286; P < 0·001).
Conclusion
Marking the sentinel node with SPIO in women having surgery for DCIS was effective at avoiding unnecessary SLND in this study. Registration number: ISRCTN18430240 (http://www.isrctn.com).
Sentinel lymph node dissection (SLND) is overperformed in ductal carcinoma in situ (DCIS) owing to lack of credible prognostic factors for invasion or when mastectomy is planned. In the SentiNot cohort study, marking the sentinel node with superparamagnetic iron oxide (SPIO) nanoparticles was shown to be an efficient way to spare unnecessary SLND procedures, with a good detection rate at reoperation and favourable effect in containment of incremental costs. SN, sentinel node; BD, blue dye.
Nearly 80 per cent avoided node dissection
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The majority of extracellular vesicle (EV) studies conducted to date have been performed on cell lines with little knowledge on how well these represent the characteristics of EVs in vivo. The aim of ...this study was to establish a method to isolate and categorize subpopulations of EVs isolated directly from tumour tissue. First we established an isolation protocol for subpopulations of EVs from metastatic melanoma tissue, which included enzymatic treatment (collagenase D and DNase). Small and large EVs were isolated with differential ultracentrifugation, and these were further separated into high and low-density (HD and LD) fractions. All EV subpopulations were then analysed in depth using electron microscopy, Bioanalyzer®, nanoparticle tracking analysis, and quantitative mass spectrometry analysis. Subpopulations of EVs with distinct size, morphology, and RNA and protein cargo could be isolated from the metastatic melanoma tissue. LD EVs showed an RNA profile with the presence of 18S and 28S ribosomal subunits. In contrast, HD EVs had RNA profiles with small or no peaks for ribosomal RNA subunits. Quantitative proteomics showed that several proteins such as flotillin-1 were enriched in both large and small LD EVs, while ADAM10 were exclusively enriched in small LD EVs. In contrast, mitofilin was enriched only in the large EVs. We conclude that enzymatic treatments improve EV isolation from dense fibrotic tissue without any apparent effect on molecular or morphological characteristics. By providing a detailed categorization of several subpopulations of EVs isolated directly from tumour tissues, we might better understand the function of EVs in tumour biology and their possible use in biomarker discovery.
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The effect of preoperative physical activity on recovery and complications after primary breast cancer surgery is unknown. The objective of this trial was to evaluate whether a recommendation of ...non-supervised physical activity improved recovery after breast cancer surgery.
This parallel, unblinded, multicentre interventional trial randomized women in whom breast cancer surgery was planned. The intervention consisted of an individual recommendation of added aerobic physical activity (30 min/day), before and 4 weeks after surgery. The control group did not receive any advice regarding physical activity. The primary outcome was patient-reported physical recovery at 4 weeks after surgery. Secondary outcomes included mental recovery, complications, reoperations, and readmissions.
Between November 2016 and December 2018, 400 patients were randomized, 200 to each group. Some 370 participants (180 intervention, 190 control) remained at 4 weeks, and 368 at 90 days. There was no significant difference in favour of the intervention for the primary outcome physical recovery (risk ratio (RR) 1.03, 95 per cent c.i. 0.95 to 1.13). There was also no difference for mental recovery (RR 1.05, 0.93 to 1.17) nor in mean Comprehensive Complication Index score (4.2 (range 0-57.5) versus 4.7 (0-58.3)) between the intervention and control groups.
An intervention with recommended non-supervised physical activity before and after breast cancer surgery did not improve recovery at 4 weeks after surgery. Registration number: NCT02560662 (http://www.clinicaltrials.gov).
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The European Society for Medical Oncology (ESMO) held a consensus conference on melanoma on 5–7 September 2019 in Amsterdam, The Netherlands. The conference included a multidisciplinary panel of 32 ...leading experts in the management of melanoma. The aim of the conference was to develop recommendations on topics that are not covered in detail in the current ESMO Clinical Practice Guideline and where available evidence is either limited or conflicting. The main topics identified for discussion were: (i) the management of locoregional disease; (ii) targeted versus immunotherapies in the adjuvant setting; (iii) targeted versus immunotherapies for the first-line treatment of metastatic melanoma; (iv) when to stop immunotherapy or targeted therapy in the metastatic setting; and (v) systemic versus local treatment of brain metastases. The expert panel was divided into five working groups in order to each address questions relating to one of the five topics outlined above. Relevant scientific literature was reviewed in advance. Recommendations were developed by the working groups and then presented to the entire panel for further discussion and amendment before voting. This manuscript presents the results relating to the management of locoregional melanoma, including findings from the expert panel discussions, consensus recommendations and a summary of evidence supporting each recommendation. All participants approved the final manuscript.
•A melanoma consensus conference, organised by the ESMO Guidelines Committee, was attended by 32 experts from 14 countries•The experts compiled recommendations (with supporting evidence) on controversial topics in melanoma management•Recommendations for locoregional melanoma in this manuscript include:○indications for sentinel lymph node biopsy and radical lymph node dissection○adjuvant targeted versus immunotherapy○adjuvant therapy in specific situations (after node dissection, stage IIIA, resected stage IV, in-transit metastasis)○adjuvant therapy toxicity management•A separate manuscript presenting results relating to the management of metastaticmelanoma is also available
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background
Sentinel lymph node biopsy (SLNB) is an important staging tool for the management of melanoma. A multicentre study was done to validate previous findings that the timing of ...lymphoscintigraphy influences the accuracy of SLNB and patient outcomes, particularly survival.
Methods
Data were reviewed on patients undergoing SLNB for melanoma at three centres in the UK and Sweden, examining the effect of timing of SLNB after nuclear medicine scanning. Kaplan–Meier survival analysis was used to assess overall (OS), disease‐specific (DSS) and progression‐free (PFS) survival, stratified by timing of lymphoscintigraphy. Independent risk factors for survival were identified by Cox multivariable regression analysis.
Results
A total of 2270 patients were identified. Median follow‐up was 56 months. Univariable analysis showed a 4·2 per cent absolute and 35·5 per cent relative benefit in DSS (hazard ratio 1·36, 95 per cent c.i. 1·05 to 1·74; P = 0·018) for 863 patients whose SLNB was performed up to 12 h after lymphoscintigraphy compared with 1407 patients who had surgery after more than 12 h. There were similar OS and PFS benefits (P = 0·036 and P = 0·022 respectively). Multivariable analysis identified timing of lymphoscintigraphy as an independent predictor of OS (P = 0·017) and DSS (P = 0·030). There was an excess of nodal recurrences as first site of recurrence in the group with delayed surgery (4·5 versus 2·5 per cent; P = 0·008).
Conclusion
Delaying SLNB beyond 12 h after lymphoscintigraphy with 99Tc‐labelled nanocolloid has a significant negative survival impact in patients with melanoma.
Antecedentes
La biopsia de ganglio centinela (sentinel lymph node biopsy, SLNB) es una técnica importante para la estadificación y tratamiento del melanoma. Se realizó un estudio multicéntrico para validar hallazgos previos según los cuales el momento de la linfogammagrafía (lymphoscintigraphy, LS) influye en la precisión de la SLNB y en los resultados de los pacientes, especialmente en la supervivencia.
Métodos
Se revisaron los datos de los pacientes a los que se realizó una SLNB por melanoma en 3 centros en el Reino Unido y Suecia, con especial atención al efecto del período entre la inyección el material radioactivo y la SLNB. Se realizó un análisis de supervivencia mediante el método de Kaplan‐Meier para la supervivencia específica de la enfermedad (disease‐specific survival, DSS), supervivencia global (overall survival, OS) y supervivencia libre de progresión (progression‐free survival, PFS), todas ellas estratificadas por el momento de la LS. Los factores de riesgo independientes para la supervivencia se determinaron mediante un análisis de regresión multivariable de Cox.
Resultados
Se incluyeron 2.270 pacientes. La mediana de seguimiento fue de 49 meses. El análisis univariado mostró un beneficio absoluto del 4,2% y relativo del 35,5% (cociente de riesgos instantáneos, hazard ratio, HR: 1,36 (i.c. del 95% 1,05‐1,74, P = 0.02)) en la DDS para los pacientes a los que la SLNB se realizó < 12 horas después de la LS (n = 863) en comparación con aquellos realizados > 12 horas (n = 1407). Se detectaron beneficios similares para la OS y la PFS (P = 0,04 y P = 0,02, respectivamente). El análisis multivariable identificó el tiempo entre la LS y la SLNB como un factor independiente de OS (P = 0,017) y DSS (P = 0,03). Hubo un aumento en las recidivas ganglionares como primer sitio de recidiva en el grupo de > 12 horas (2,5% versus 4,5%; P = 0,008).
Conclusión
Estos datos validan nuestra investigación previa y tienen implicaciones significativas para las unidades de melanoma, en el sentido de que retrasar la SLNB más allá de las 12 horas después de realizar la LS con nanocoloides marcados con Tc99 tiene un impacto negativo significativo en la supervivencia de los pacientes y debe evitarse. Se presenta la hipótesis de que la causa subyacente es la migración temporal del trazador que determina una SLNB incorrecta.
This international multicentre study with 2270 patients investigated the timing of sentinel lymph node biopsy for melanoma. The data suggest that delaying surgery beyond 12 h after nuclear medicine imaging that uses a 99Tc‐labelled nanocolloid has a significant negative survival impact and should be avoided. Temporal tracer migration, leading to inaccurate sentinel lymph node biopsy, is suspected to be the underlying cause.
Should be less than 12 hours
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We aimed to develop a European Organization for Research and Treatment of Cancer (EORTC) Quality of Life (QoL) module tailored for patients with advanced (resectable or unresectable stage III/IV) ...melanoma receiving immune checkpoint inhibitors or targeted therapy.
Following the EORTC QoL Group module development guidelines, we conducted phases 1 and 2 of the development process. In phase 1, we generated a list of health-related (HR)QoL issues through a systematic literature review and semi-structured interviews with healthcare professionals (HCPs) and patients with advanced melanoma. In phase 2, these issues were converted into questionnaire items to create the preliminary module.
Phase 1: we retrieved 8006 articles for the literature review, of which 35 were deemed relevant, resulting in 84 HRQoL issues being extracted to create the initial issue list. Semi-structured interviews with 18 HCPs and 28 patients with advanced melanoma resulted in 28 issues being added to the initial issue list. Following EORTC module development criteria, 26 issues were removed, and two issues were added after review by patient advocates.
Phase 2: To ensure uniformity and avoid duplication, 16 issues were consolidated into eight items. Additionally, an independent expert contributed one new item, resulting in a preliminary module comprising 80 HRQoL items.
We identified a range of HRQoL issues (dry skin, xerostomia, and arthralgia) relevant to patients with stage III/IV melanoma. Future module development phases will refine the questionnaire. Once completed, this module will enable standardized assessment of HRQoL in patients with (locally) advanced melanoma.
•We aimed to create a HRQoL module tailored for patients with advanced melanoma.•We identified the most important symptomatic HRQoL issues associated with ICI and TT.•Our study highlights the benefit of using a disease-specific instrument to measure HRQoL.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
In patients with cutaneous melanoma, sentinel lymph node biopsy (SLNB) serves as an important technique to asses disease stage and to guide adjuvant systemic therapy. A model using clinicopathologic ...and gene expression variables (CP-GEP; Merlin Assay) has recently been introduced to identify patients that may safely forgo SLNB. Herein we present data from an independent validation cohort of the CP-GEP model in Swedish patients.
Archival histological material (primary melanoma tissue) from a prospectively collected cohort of 421 consecutive patients with pT1-T4 melanoma undergoing SLNB between 2006 and 2014 was analyzed using the CP-GEP model. CP-GEP combines Breslow thickness and patient age with the expression levels of eight genes from the primary melanoma. Stratification is based on their risk for nodal metastasis: CP-GEP Low Risk or CP-GEP High Risk.
The SLNB positivity rate was 13%. Of 421 primary melanomas, the CP-GEP model identified 86 patients as having a low risk for nodal metastasis. In patients with pT1-2 melanomas, the SLNB reduction rate was 35.4% (95% CI: 29.4–41.8) with a negative predictive value (NPV) of 96.5% (95% CI: 90.0–99.3). Among patients with pT1-3 melanomas, CP-GEP suggested a SLNB reduction rate of 24.0% (95% CI: 19.7–28.8) and a NPV of 96.5% (95% CI: 90.1–99.3). Only one of 118 pT3 tumors was classified as CP-GEP Low Risk, and all pT4 tumors were classified as being high risk for nodal metastasis.
This study demonstrates that CP-GEP can identify patients with a low risk for nodal metastasis. Patients with pT1-2 melanomas have the highest clinical benefit from using the test, where 35% of the patients could forgo a SLNB procedure.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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