Publications by authors named "Omgo E Nieweg"

145 Publications

Histological regression in melanoma: impact on sentinel lymph node status and survival.

Mod Pathol 2021 Jul 10. Epub 2021 Jul 10.

Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia.

Regression in melanoma is an immunological phenomenon that results in partial or complete replacement of the tumor with variably vascular fibrous tissue, often accompanied by pigment-laden macrophages and chronic inflammation. In some cases, tumor-infiltrating lymphocytes (TILs) may represent the earliest phase of this process. The prognostic significance of regression has long been a matter of debate, with inconsistent findings reported in the literature to date. This study sought to determine whether regression in primary cutaneous melanomas predicted sentinel lymph node (SLN) status and survival outcomes in a large cohort of patients managed at a single centre. Clinical and pathological parameters for 8,693 consecutive cases were retrieved. Associations between regression and SLN status, overall survival (OS), melanoma-specific survival (MSS) and recurrence-free survival (RFS) were investigated using logistic and Cox regression. Histological evidence of regression was present in 1958 cases (22.5%). Regression was significantly associated with lower Breslow thickness, lower mitotic rate, and absence of ulceration (p < 0.0001). Multivariable analysis showed that regression in combination with TILs independently predicted a negative SLN biopsy (OR 0.33; 95% C.I. 0.20-0.52; p < 0.0001). Patients whose tumors showed both regression and TILs had the highest 10-year OS (65%, 95% C.I. 59-71%), MSS (85%, 95% C.I. 81-89%), and RFS (60%, 95% C.I. 54-66%). On multivariable analyses, the concurrent presence of regression and TILs independently predicted the lowest risk of death from melanoma (HR 0.69; 95% C.I. 0.51-0.94; p = 0.0003) as well as the lowest rate of disease recurrence (HR 0.71; 95% C.I. 0.58-0.85; p < 0.0001). However, in contrast, in the subgroup analysis of Stage III patients, the presence of regression predicted the lowest OS and RFS, with MSS showing a similar trend. Overall, these findings indicate a prognostically favorable role of regression in primary cutaneous melanoma. However, in Stage III melanoma patients, regression may be a marker of more aggressive disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41379-021-00870-2DOI Listing
July 2021

Re-defining the role of surgery in the management of patients with oligometastatic stage IV melanoma in the era of effective systemic therapies.

Eur J Cancer 2021 Aug 12;153:8-15. Epub 2021 Jun 12.

Melanoma Institute Australia, The University of Sydney, North Sydney, New South Wales, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia; Mater Hospital, North Sydney, New South Wales, Australia; Royal North Shore Hospital, St Leonards, New South Wales, Australia.

Although previously the mainstay of treatment, the role of surgery in the management of patients with oligometastatic stage IV melanoma has changed with the advent of effective systemic therapies (most notably immunotherapy). Contemporary treatment options for patients with asymptomatic solitary or oligo-metastases include upfront surgery followed by adjuvant immunotherapy or upfront immunotherapy with salvage surgery as required. For suspected solitary or oligo-metastases, surgery serves both diagnostic and therapeutic purposes. Advances in radiological technology allow metastases to be detected earlier and surgery to be less morbid. Surgical morbidities are generally more tolerable than serious immune-related adverse effects, but surgery may be less effective. Upfront immunotherapy ensures that futile surgery is not offered for rapidly progressive disease. It also provides an opportunity to assess response to treatment, which predicts outcome, and may obviate the need for surgery. However, it is important not to miss a window of opportunity for surgical intervention, whereby if disease progresses on immunotherapy it becomes unresectable. In situations where local therapy is recommended but surgery is not desired, stereotactic radiosurgery may be an effective alternative. The decision-making process regarding upfront surgery versus immunotherapy needs to take place within a specialist melanoma multidisciplinary setting and be customised to individual patient and tumour factors. Ultimately, high-level clinical trial evidence is required to resolve uncertainties in the management of patients with oligometastatic stage IV melanoma but the complexity of the varying presentations may make trial design challenging.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejca.2021.04.037DOI Listing
August 2021

Technological (R)Evolution Leads to Detection of More Sentinel Nodes in Patients with Melanoma in the Head and Neck Region.

J Nucl Med 2021 Feb 26. Epub 2021 Feb 26.

Antoni van Leeuwenhoek, Netherlands.

Sentinel lymph node (SN) biopsy (SLNB) has proven to be a valuable tool for staging melanoma patients. Since its introduction in the early 1990s, this procedure has undergone several technological refinements, including the introduction of single photon emission computed tomography combined with computed tomography (SPECT/CT) as well as radio- and fluorescence-guidance. The purpose of the current study was to evaluate the effect of this technological evolution on SLNB in the head and neck region. Primary endpoint was the false-negative (FN) rate. Secondary endpoints were number of harvested SNs, overall operation time, operation time per harvested SN and postoperative complications. A retrospective database was queried for cutaneous head and neck melanoma patients who underwent SLNB at The Netherlands Cancer Institute between 1993 and 2016. The implementation of new detection techniques was divided in 4 groups: (1) 1993-2005, with preoperative lymphoscintigraphy and intraoperative use of both a gamma ray detection probe and patent blue ( = 30); (2) 2006-2007, with addition of preoperative roadmaps based on SPECT/CT ( = 15); (3) 2008-2009, with intraoperative use of a portable gamma camera ( = 40); and (4) 2010-2016, with the addition of near-infrared fluorescence guidance ( = 192). A total of 277 patients were included. At least one SN was identified in all patients. A tumor-positive SN was found in 59 patients (21.3%), 10 in group 1 (33.3%), 3 in group 2 (20.0%), 6 in group 3 (15.0%) and 40 in group 4 (20.8%). Regional recurrences of patients with tumor-negative SNs resulted in an overall FN rate of 11.9% (FN groups 1: 16.7%; 2: 0%; 3: 14.3%; 4: 11.1%). The number of harvested nodes increased with advancing technologies ( = 0.003) whereas Breslow thickness and operation time per harvested SN decreased ( = 0.003 and = 0.017, respectively). There was no significant difference in percentage of tumor-positive SNs, overall operation time and complication rate between the different groups. The use of advanced detection technologies led to a higher number of identified SNs without increase in overall operation time, which may indicate an improved surgical efficiency. Operation time per harvested SN decreased, the average FN rate remained 11.9% and unchanged over 23 years. There was no significant change in postoperative complication rate.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2967/jnumed.120.246819DOI Listing
February 2021

Performance of Long-Term CT and PET/CT Surveillance for Detection of Distant Recurrence in Patients with Resected Stage IIIA-D Melanoma.

Ann Surg Oncol 2021 Aug 3;28(8):4561-4569. Epub 2021 Jan 3.

NHMRC Clinical Trials Centre, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, Australia.

Background: Follow-up for patients with resected stage IIIA-D melanoma may include computed tomography (CT) or positron emission tomography (PET)/CT imaging to identify distant metastases. The aim of this study was to evaluate the test performance over follow-up time, of structured 6- and 12-monthly follow-up imaging schedules in these patients.

Methods: We conducted a retrospective analysis of consecutive resected stage IIIA-D melanoma patients from Melanoma Institute Australia (2000-2017). Patients were followed until a confirmed diagnosis of distant metastasis, end of follow-up schedule, or death. Test accuracy was evaluated by cross-classifying the results of the test against a composite reference standard of histopathology, cytology, radiologic imaging, and/or clinical follow-up, and then quantified longitudinally using logistic regression models with random effects.

Results: In total, 1373 imaging tests were performed among 332 patients. Distant metastases were detected in 110 (33%) patients during a median follow-up of 61 months (interquartile range 38-86), and first detected by imaging in 86 (78%) patients. 152 (68%) patients had at least one false-positive result. Sensitivity of the schedule over 5 years was 79% [95% confidence interval (CI) 70-86%] and specificity was 88% (95% CI 86-90%). There was no evidence of a significant difference in test performance over follow-up time or by American Joint Committee on Cancer (AJCC) substage. The positive predictive value ranged between 33 and 48% over follow-up time, reflecting a ratio of 1:2 false-positives per true-positive finding.

Conclusions: Regular 6- or 12-monthly surveillance imaging using CT or PET/CT has reasonable and consistent sensitivity and specificity over 5-year follow-up for resected stage IIIA-D melanoma patients. These data are useful when discussing the risks and benefits of long-term follow-up.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1245/s10434-020-09270-3DOI Listing
August 2021

Cost-effectiveness analysis of PET/CT surveillance imaging to detect systemic recurrence in resected stage III melanoma: study protocol.

BMJ Open 2020 11 5;10(11):e037857. Epub 2020 Nov 5.

NHMRC Clinical Trials Centre, Faculty of Medicine and Health, The University of Sydney, Camperdown, New South Wales, Australia.

Introduction: In the new era of effective systemic therapies for advanced melanoma, early detection of lower volume recurrent disease using surveillance imaging can improve survival. However, intensive imaging follow-up strategies are likely to increase costs to health systems and may pose risks to patients. The objective of this study is to estimate from the Australian health system perspective the cost-effectiveness of four follow-up strategies in resected stage III melanoma over a 5-year period following surgical treatment with curative intent.

Methods And Analysis: A decision-analytic model will be built to estimate the costs and benefits of (1) 12 monthly, (2) 6 monthly, (3) 3-4 monthly positron emission tomography/CT imaging for 5 years, compared with (4) no imaging follow-up. The model will be populated with probabilities of disease recurrence, test performance measures using data from >1000 consecutive resected stage III melanoma patients from Melanoma Institute Australia diagnosed between 2000 and 2017. Healthcare resource use, including surveillance imaging, doctor's visits, subsequent tests and procedures to investigate suspicious findings, will be quantified from detailed patient records and valued using Australian reference pricing. Economic outcomes include cost per new distant melanoma recurrence detected and cost per diagnostic error avoided, for no imaging compared with the other strategies.Deterministic sensitivity analyses will examine the robustness of model results.

Ethics And Dissemination: This study was approved by the Sydney Local Health District, Sydney Local Health District Ethics Review Committee (RPAH Zone), AU/1/830638 and the Australian Institute of Health and Welfare (EO2019-1-454). The results of this study will be published in peer-reviewed medical and health economics journals and will inform melanoma management guidelines.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/bmjopen-2020-037857DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7646332PMC
November 2020

Staging 18F-FDG PET/CT influences the treatment plan in melanoma patients with satellite or in-transit metastases.

Melanoma Res 2020 08;30(4):358-363

Melanoma Institute Australia, Sydney, Australia.

Whole-body positron emission tomography/computed tomography (PET/CT) and brain magnetic resonance imaging (MRI) are commonly used to stage patients with palpable lymph node metastases from melanoma, but their role in patients with satellite and/or in-transit metastasis (S&ITM) is unclear. The aim of this study was to establish the diagnostic value of PET/CT and brain MRI in these patients, and to assess their influence on subsequent management decisions. In this prospective study, 25 melanoma patients with a first presentation of S&ITM who had no clinical evidence of palpable nodal or distant metastasis underwent whole-body F-FDG PET/CT and brain MRI after a tentative pre-scan treatment plan had been made. Sensitivity and specificity of imaging were determined by pathological confirmation, clinical outcome and repeat PET/CT and MRI at 6 months. PET/CT led to a modification of the initial treatment plan in four patients (16%). All four were upstaged (AJCC stage eighth edition). PET/CT was false-positive in one patient, who had a Schwannoma in his trapezius muscle. A thyroid carcinoma was an incidental finding in another patient. The sensitivity of PET/CT was 58% and specificity 83%. In 6 months following the baseline PET/CT, further sites of in-transit or systemic disease were identified in 10 patients (40%). Brain MRI did not alter the treatment plan or change the disease stage in any patient. Whole-body PET/CT improved staging in melanoma patients with S&ITM and changed the originally-contemplated treatment plan in 16%. MRI of the brain appeared not to be useful.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/CMR.0000000000000666DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7331822PMC
August 2020

Improved Risk Prediction Calculator for Sentinel Node Positivity in Patients With Melanoma: The Melanoma Institute Australia Nomogram.

J Clin Oncol 2020 08 12;38(24):2719-2727. Epub 2020 Jun 12.

Melanoma Institute Australia, The University of Sydney, North Sydney, New South Wales, Australia.

Purpose: For patients with primary cutaneous melanoma, the risk of sentinel node (SN) metastasis varies according to several clinicopathologic parameters. Patient selection for SN biopsy can be assisted by National Comprehensive Cancer Network (NCCN) and ASCO/Society of Surgical Oncology (SSO) guidelines and the Memorial Sloan Kettering Cancer Center (MSKCC) online nomogram. We sought to develop an improved online risk calculator using alternative clinicopathologic parameters to more accurately predict SN positivity.

Patients And Methods: Data from 3,477 patients with melanoma who underwent SN biopsy at Melanoma Institute Australia (MIA) were analyzed. A new nomogram was developed by replacing body site and Clark level from the MSKCC model with mitotic rate, melanoma subtype, and lymphovascular invasion. The predictive performance of the new nomogram was externally validated using data from The University of Texas MD Anderson Cancer Center (n = 3,496).

Results: The MSKCC model receiver operating characteristic curve had a predictive accuracy of 67.7% (95% CI, 65.3% to 70.0%). The MIA model had a predictive accuracy of 73.9% (95% CI, 71.9% to 75.9%), a 9.2% increase in accuracy over the MSKCC model ( < .001). Among the 2,748 SN-negative patients, SN biopsy would not have been offered to 22.1%, 13.4%, and 12.4% based on the MIA model, the MSKCC model, and NCCN or ASCO/SSO criteria, respectively. External validation generated a C-statistic of 75.0% (95% CI, 73.2% to 76.7%).

Conclusion: A robust nomogram was developed that more accurately estimates the risk of SN positivity in patients with melanoma than currently available methods. The model only requires the input of 6 widely available clinicopathologic parameters. Importantly, the number of patients undergoing unnecessary SN biopsy would be significantly reduced compared with use of the MSKCC nomogram or the NCCN or ASCO/SSO guidelines, without losing sensitivity. An online calculator is available at www.melanomarisk.org.au.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.19.02362DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7430218PMC
August 2020

Regional Node Basin Recurrence in Melanoma Patients: More Common After Node Dissection for Macroscopic Rather than Clinically Occult Nodal Disease.

Ann Surg Oncol 2020 Jun 20;27(6):1970-1977. Epub 2019 Dec 20.

Cedars-Sinai Medical Center, The Angeles Clinic and Research Institute, Los Angeles, CA, USA.

Background: Recommended treatment for patients with sentinel lymph node (SLN)-positive melanoma has recently changed. Randomized trials demonstrated equivalent survival with close observation versus completion lymph node dissection (CLND), but increased regional node recurrence. We evaluated factors related to in-basin nodal recurrence after lymphadenectomy (LND) for SLN-positive or macroscopic nodal metastases.

Methods: An institutional database and the first Multicenter Selective Lymphadenectomy Trial (MSLT-I) were analyzed independently. Exclusions were multiple primaries, multi-basin involvement, or in-transit metastases. Patient demographics, primary tumor thickness and ulceration, lymph nodes retrieved, and use of adjuvant radiotherapy were analyzed. Multivariate analyses were performed to determine factors predicting in-basin nodal recurrence (significance p ≤ 0.05).

Results: The retrospective cohort (577 patients) showed an in-basin failure rate of 6.6% after CLND for a positive SLN and 13.1% after LND for palpable disease (p = 0.001). This recurrence risk persisted after adjustment for patient, tumor, and LND factors [hazard ratio (HR) 2.32; p = 0.004]. In the MSLT-I cohort (326 patients), the failure rate after CLND following SLNB was 6.2%, but 10.1% after LND for palpable recurrence in observation patients. After adjustment for other factors, macroscopic disease was associated with an increased risk of recurrence after LND (HR 2.24; p = 0.05).

Conclusion: After LND for melanoma, in-basin recurrence is infrequent, but a clinically significant fraction will fail. Failure is less likely if dissection is performed for clinically occult disease. Further research is warranted to evaluate the long-term regional control and quality of life associated with nodal basin observation, which has now become standard practice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1245/s10434-019-08086-0DOI Listing
June 2020

The prognostic value of tumor mitotic rate in children and adolescents with cutaneous melanoma: A retrospective cohort study.

J Am Acad Dermatol 2020 Apr 2;82(4):910-919. Epub 2019 Nov 2.

Melanoma Institute Australia, Sydney, New South Wales, Australia; Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia; Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia. Electronic address:

Background: Mitotic rate is a strong predictor of outcome in adult patients with primary cutaneous melanoma, but for children and adolescent patients this is unknown.

Objective: We sought to assess the prognostic value of primary tumor mitotic rate in children and adolescents with primary melanoma.

Methods: This was a cohort study of 156 patients who were <20 years of age and who had clinically localized cutaneous melanoma. Patients <12 years of age were classified as children and those 12 to 19 years of age as adolescents. Clinicopathologic and outcome data were collected. Recurrence-free and melanoma-specific survival were calculated. Univariable and multivariable analyses were performed using Cox proportional hazard models.

Results: Thirteen of 156 patients (8%) were children. The mitotic rate was ≥1/mm in 104 patients (67%) and correlated with increasing Breslow thickness. A positive sentinel node was found in 23 of 61 patients (38%) in whom a sentinel lymph node biopsy specimen was obtained. The median follow-up was 61 months. Five-year melanoma-specific and recurrence-free survival rates were 91% and 84%, respectively. Mitotic rate was a stronger predictor of outcome than tumor thickness and was the only factor independently associated with recurrence-free survival.

Limitations: This research was conducted at a single institution and the sample size was small.

Conclusion: Mitotic rate is an independent predictor of recurrence-free survival in children and adolescents with clinically localized melanoma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jaad.2019.10.065DOI Listing
April 2020

Current management of patients with melanoma who are found to be sentinel node-positive.

ANZ J Surg 2020 04 30;90(4):491-496. Epub 2019 Oct 30.

Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia.

Background: The results of the DeCOG-SLT and MSLT-II studies, published in 2016 and mid-2017, indicated no survival benefit from completion lymph node dissection (CLND) in melanoma patients with positive sentinel nodes (SNs). Subsequently, several studies have been published reporting a benefit of adjuvant systemic therapy in patients with stage III melanoma. The current study assessed how these findings influenced management of SN-positive patients in a dedicated melanoma treatment centre.

Methods: SN-positive patients treated at Melanoma Institute Australia between July 2017 and December 2018 were prospectively identified. Surgeons completed a questionnaire documenting the management of each patient. Information on patients, primary tumours, SNs, further treatment and follow-up was collected from patient files, the institutional research database and pathology reports.

Results: During the 18-month study period, 483 patients underwent SN biopsy. A positive SN was found in 61 (13%). Two patients (3%) requested CLND because of anxiety about observation in view of unfavourable primary tumour and SN characteristics. The other 59 patients (97%) were followed with a four-monthly ultrasound examination of the relevant lymph node field(s). Two of them (3%) developed an isolated nodal recurrence after 4 and 11 months of follow-up. Fifty-seven patients (93%) were seen following the publication of the first two adjuvant systemic therapy studies in November 2017; 46 (81%) were referred to a medical oncologist to discuss adjuvant systemic therapy, which 32 (70%) chose to receive.

Conclusion: At Melanoma Institute Australia most patients with an involved SN are now managed without CLND. The majority are referred to a medical oncologist and receive adjuvant systemic therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ans.15491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7216885PMC
April 2020

ASO Author Reflections: Melanoma Patients with a Local Recurrence or In-Transit Metastasis: Sentinel Node Biopsy to Identify Those at Highest Risk of Metastases and Death.

Ann Surg Oncol 2020 Feb 30;27(2):569-570. Epub 2019 Oct 30.

Melanoma Institute Australia, The University of Sydney, Sydney, Australia.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1245/s10434-019-08031-1DOI Listing
February 2020

Sentinel Node Biopsy for Melanoma Patients with a Local Recurrence or In-Transit Metastasis.

Ann Surg Oncol 2020 Feb 12;27(2):561-568. Epub 2019 Aug 12.

Melanoma Institute Australia, The University of Sydney, Sydney, Australia.

Background: Sentinel node (SN) biopsy (SNB) is not routinely performed for melanoma patients with local recurrence (LR) or in-transit metastasis (ITM). This study aimed to describe the technique, findings, and prognostic value of this procedure, and the outcome for such patients at our institution.

Methods: Prospectively collected data were obtained from the Melanoma Institute Australia database. Patients who had SNB for LR or ITM between 1992 and 2015 were included in the study. Patient and primary tumor characteristics, lymphoscintigrams, SNB results, and follow-up data were analyzed.

Results: Overall, 7999 patients underwent SNB, 128 (1.6%) of whom met the selection criteria. The SNB procedure was performed for 85 of 1516 patients with LR (6%), 17 of 1671 patients with ITM from a known primary tumor (1%), and 26 of 170 patients who presented with ITM from an unknown primary site (15%). The SN identification rate was 100%. Metastatic melanoma was identified in an SN from 16 of the 128 patients (13%). Follow-up data were available for 114 patients. The false-negative rate was 27%. The SN-positive patients had significantly worse overall survival than the SN-negative patients, with respective 5-year survival rates of 54% and 81% (P = 0.01).

Conclusion: The SNB procedure was performed infrequently for LR or ITM. The SNs were positive for 13% of the patients with LR or ITM. Positive SNs were associated with worse overall survival. Despite the false-negative rate of 27%, the procedure yielded information that was relevant for staging and prognosis. The SNB procedure should be considered for patients with LR or ITM.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1245/s10434-019-07699-9DOI Listing
February 2020

Focused Ultrasound Surveillance of Lymph Nodes Following Lymphoscintigraphy Without Sentinel Node Biopsy: A Useful and Safe Strategy in Elderly or Frail Melanoma Patients.

Ann Surg Oncol 2019 Sep 25;26(9):2855-2863. Epub 2019 Jun 25.

Melanoma Institute Australia, Wollstonecraft, North Sydney, NSW, Australia.

Background: Sentinel node (SN) biopsy (SNB) has become standard of care in clinically localized melanoma patients. Although it is minimally invasive, advanced age and/or comorbidities may render SNB inadvisable in some patients. Focused ultrasound follow-up of SNs identified by preoperative lymphoscintigraphy may be an alternative in these patients. This study examines the outcomes in patients managed in this way at a major melanoma treatment center.

Methods: All patients with clinically localized cutaneous melanoma who underwent lymphoscintigraphy and in whom SNB was intentionally not performed due to advanced age and/or comorbidities were included.

Results: Between 2000 and 2009, 160 patients (5.2% of the total) underwent lymphoscintigraphy without SNB because of advanced age and/or comorbidities. Compared with the 2945 patients who had a SNB, the 160 patients were older, had thicker melanomas that were more often located in the head and neck region, and had more SNs in more nodal regions. Of the 160 patients, 150 (94%) were followed with ultrasound examination of their SNs at each follow-up visit; this identified 33% of the nodal recurrences before they became clinically apparent. Compared with SN-positive patients who were treated by completion lymph node dissection, observed patients who developed nodal recurrence had more involved nodes when a delayed lymphadenectomy was performed. Melanoma-specific survival, recurrence-free survival, and distant recurrence-free survival rates were similar, while regional lymph node-free survival was worse.

Conclusions: Lymphoscintigraphy with focused ultrasound follow-up of SNs is a reasonable management alternative to SNB in patients who are elderly and/or have substantial comorbidities.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1245/s10434-019-07505-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6682569PMC
September 2019

Neoadjuvant dabrafenib combined with trametinib for resectable, stage IIIB-C, BRAF mutation-positive melanoma (NeoCombi): a single-arm, open-label, single-centre, phase 2 trial.

Lancet Oncol 2019 07 3;20(7):961-971. Epub 2019 Jun 3.

Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia; Royal North Shore Hospital, St Leonards, Sydney, NSW, Australia.

Background: Adjuvant dabrafenib plus trametinib therapy improves relapse-free survival in patients with resected stage III melanoma. We aimed to ascertain the proportion of patients who would have a pathological response and a response according to Response Evaluation Criteria in Solid Tumors (RECIST) after neoadjuvant dabrafenib plus trametinib therapy for resectable clinical stage III melanoma.

Methods: NeoCombi was a single-arm, open-label, single-centre, phase 2 study done at Melanoma Institute Australia (Sydney, NSW, Australia). Eligible patients were adults (aged ≥18 years) with histologically confirmed, resectable, RECIST-measurable, clinical stage IIIB-C (American Joint Committee on Cancer [AJCC] 7th edition), BRAF-mutant melanoma, and had an Eastern Cooperative Oncology Group performance status of 1 or lower. Patients received 150 mg dabrafenib orally, twice daily, plus 2 mg trametinib orally, once daily, for 52 weeks (12 weeks of neoadjuvant therapy before complete resection of the pre-therapy tumour bed, and 40 weeks of adjuvant therapy thereafter). CT and PET scans were done at baseline and before resection. The primary outcomes were the proportion of patients achieving a complete pathological response and the proportion of patients achieving a response according to RECIST at week 12, analysed as per protocol. This trial is registered with ClinicalTrials.gov, NCT01972347, and follow-up of patients is ongoing.

Findings: Between Aug 20, 2014, and April 19, 2017, 40 patients were screened, of whom 35 eligible patients were enrolled, received neoadjuvant dabrafenib plus trametinib, and underwent resection. At the data cutoff (Sept 24, 2018), median follow-up was 27 months (IQR 21-36). At resection, 30 (86%) patients achieved a RECIST response; 16 (46%; 95% CI 29-63) had a complete response and 14 (40%; 24-58) had a partial response. Five patients (14%; 95% CI 5-30) had stable disease, and no patients progressed. After resection and pathological evaluation, all 35 patients achieved a pathological response, of whom 17 (49%; 95% CI 31-66) patients had a complete pathological response and 18 (51%; 95% CI 34-69) had a non-complete pathological response. Treatment-related serious adverse events occurred in six (17%) of 35 patients and grade 3-4 adverse events occurred in ten (29%) patients. No treatment-related deaths were reported.

Interpretation: Neoadjuvant dabrafenib plus trametinib therapy could be considered in the management of RECIST-measurable resectable stage III melanoma as it led to a high proportion of patients achieving a complete response according to RECIST and a high proportion of patients achieving a complete pathological response, with no progression during neoadjuvant therapy.

Funding: GlaxoSmithKline; Novartis; National Health and Medical Research Council, Australia; and Melanoma Institute Australia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S1470-2045(19)30331-6DOI Listing
July 2019

Identification of the optimal combination dosing schedule of neoadjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma (OpACIN-neo): a multicentre, phase 2, randomised, controlled trial.

Lancet Oncol 2019 07 31;20(7):948-960. Epub 2019 May 31.

Melanoma Institute of Australia, The University of Sydney, Sydney, NSW, Australia; Royal North Shore and Mater Hospitals, Sydney, NSW, Australia; Royal Prince Alfred Hospital, Sydney, NSW, Australia.

Background: The outcome of patients with macroscopic stage III melanoma is poor. Neoadjuvant treatment with ipilimumab plus nivolumab at the standard dosing schedule induced pathological responses in a high proportion of patients in two small independent early-phase trials, and no patients with a pathological response have relapsed after a median follow up of 32 months. However, toxicity of the standard ipilimumab plus nivolumab dosing schedule was high, preventing its broader clinical use. The aim of the OpACIN-neo trial was to identify a dosing schedule of ipilimumab plus nivolumab that is less toxic but equally effective.

Methods: OpACIN-neo is a multicentre, open-label, phase 2, randomised, controlled trial. Eligible patients were aged at least 18 years, had a WHO performance status of 0-1, had resectable stage III melanoma involving lymph nodes only, and measurable disease according to the Response Evaluation Criteria in Solid Tumors version 1.1. Patients were enrolled from three medical centres in Australia, Sweden, and the Netherlands, and were randomly assigned (1:1:1), stratified by site, to one of three neoadjuvant dosing schedules: group A, two cycles of ipilimumab 3 mg/kg plus nivolumab 1 mg/kg once every 3 weeks intravenously; group B, two cycles of ipilimumab 1 mg/kg plus nivolumab 3 mg/kg once every 3 weeks intravenously; or group C, two cycles of ipilimumab 3 mg/kg once every 3 weeks directly followed by two cycles of nivolumab 3 mg/kg once every 2 weeks intravenously. The investigators, site staff, and patients were aware of the treatment assignment during the study participation. Pathologists were masked to treatment allocation and all other data. The primary endpoints were the proportion of patients with grade 3-4 immune-related toxicity within the first 12 weeks and the proportion of patients achieving a radiological objective response and pathological response at 6 weeks. Analyses were done in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT02977052, and is ongoing with an additional extension cohort and to complete survival analysis.

Findings: Between Nov 24, 2016 and June 28, 2018, 105 patients were screened for eligibility, of whom 89 (85%) eligible patients were enrolled and randomly assigned to one of the three groups. Three patients were excluded after randomisation because they were found to be ineligible, and 86 received at least one dose of study drug; 30 patients in group A, 30 in group B, and 26 in group C (accrual to this group was closed early upon advice of the Data Safety Monitoring Board on June 4, 2018 because of severe adverse events). Within the first 12 weeks, grade 3-4 immune-related adverse events were observed in 12 (40%) of 30 patients in group A, six (20%) of 30 in group B, and 13 (50%) of 26 in group C. The difference in grade 3-4 toxicity between group B and A was -20% (95% CI -46 to 6; p=0·158) and between group C and group A was 10% (-20 to 40; p=0·591). The most common grade 3-4 adverse events were elevated liver enzymes in group A (six [20%)]) and colitis in group C (five [19%]); in group B, none of the grade 3-4 adverse events were seen in more than one patient. One patient (in group A) died 9·5 months after the start of treatment due to the consequences of late-onset immune-related encephalitis, which was possibly treatment-related. 19 (63% [95% CI 44-80]) of 30 patients in group A, 17 (57% [37-75]) of 30 in group B, and nine (35% [17-56]) of 26 in group C achieved a radiological objective response, while pathological responses occurred in 24 (80% [61-92]) patients in group A, 23 (77% [58-90]) in group B, and 17 (65% [44-83]) in group C.

Interpretation: OpACIN-neo identified a tolerable neoadjuvant dosing schedule (group B: two cycles of ipilimumab 1 mg/kg plus nivolumab 3 mg/kg) that induces a pathological response in a high proportion of patients and might be suitable for broader clinical use. When more mature data confirm these early observations, this schedule should be tested in randomised phase 3 studies versus adjuvant therapies, which are the current standard-of-care systemic therapy for patients with stage III melanoma.

Funding: Bristol-Myers Squibb.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S1470-2045(19)30151-2DOI Listing
July 2019

Clinical importance and surgical management of sentinel lymph nodes in the popliteal fossa of melanoma patients.

Eur J Surg Oncol 2019 Sep 23;45(9):1706-1711. Epub 2019 Mar 23.

Melanoma Institute Australia, The University of Sydney, Sydney, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, Australia; Department of Melanoma and Surgical Oncology, Royal Prince Alfred Hospital, Sydney, Australia.

Background And Purpose: Patients with a primary melanoma below the knee may have lymphatic drainage to a sentinel node (SN) in the popliteal fossa. The purpose of this study was to analyze lymphatic drainage to this site and to describe clinical features and surgical management of SNs in the popliteal fossa.

Methods: Patients with a primary melanoma below the knee presenting to Melanoma Institute Australia between 1992 and 2013 were analyzed. Those found to have a popliteal SN were evaluated. Data on imaging, SN biopsy, completion lymph node dissection, morbidity and follow-up were analyzed.

Results: Lymphoscintigraphy showed drainage to a popliteal SN in 176 of 3902 cases of melanoma below the knee (4.5%). In 96 of these patients (55%) a popliteal SN biopsy was attempted. The procedure failed to identify the node(s) in seventeen of them (18%). Thirteen of the 79 patients (17%) had a positive popliteal SN and in eight (10%) this was the only positive node. The tumor stage of ten patients (13%) changed as a result of the popliteal node biopsy. A positive popliteal node was associated with an increased risk of recurrence and diminished overall survival. Popliteal SN biopsy did not improve regional control or survival.

Conclusion: Melanomas below the knee infrequently drain to lymph nodes in the popliteal fossa. Although popliteal SN biopsy can be challenging, it is worthwhile, providing improved staging and guiding subsequent management.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejso.2019.03.026DOI Listing
September 2019

False-Positive Results and Incidental Findings with Annual CT or PET/CT Surveillance in Asymptomatic Patients with Resected Stage III Melanoma.

Ann Surg Oncol 2019 Jun 25;26(6):1860-1868. Epub 2019 Mar 25.

Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia.

Objective: The aim of this study was to quantify false-positive and incidental findings from annual surveillance imaging in asymptomatic, American Joint Committee on Cancer stage III melanoma patients.

Methods: This was a cohort study of patients treated at Melanoma Institute Australia (2000-2015) with baseline computed tomography (CT) or positron emission tomography (PET)/CT imaging and at least two annual surveillance scans. False-positives were defined as findings suspicious for melanoma recurrence that were not melanoma, confirmed by histopathology, subsequent imaging, or clinical follow-up, while incidental findings were defined as non-melanoma-related findings requiring further action. Outcomes of incidental findings were classified as 'benign' if they resolved spontaneously or were not seriously harmful; 'malignant' if a second malignancy was identified; or 'other' if potentially harmful.

Results: Among 154 patients, 1022 scans were performed (154 baseline staging, 868 surveillance) during a median follow-up of 85 months (interquartile range 56-112); 57 patients (37%) developed a recurrence. For baseline and surveillance imaging, 124 false-positive results and incidental findings were identified in 81 patients (53%). The frequency of these findings was 5-14% per year, and an additional 181 tests, procedures, and referrals were initiated to investigate these findings. The diagnosis was benign in 109 findings of 124 findings (88%). Fifteen patients with a benign finding underwent an unnecessary invasive procedure. Surveillance imaging identified distant metastases in 20 patients (13%).

Conclusion: False-positive results and incidental findings occur in at least half of all patients undergoing annual surveillance imaging, and the additional healthcare use is substantial. These findings persist over time. Clinicians need to be aware of these risks and discuss them with patients, alongside the expected benefits of surveillance imaging.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1245/s10434-019-07311-0DOI Listing
June 2019

Correlation Between Surgical and Histologic Margins in Melanoma Wide Excision Specimens.

Ann Surg Oncol 2019 Jan 16;26(1):25-32. Epub 2018 Oct 16.

Melanoma Institute Australia, The University of Sydney, North Sydney, NSW, Australia.

Introduction: Wide surgical excision is the standard treatment for localized primary cutaneous melanomas, with a narrow histologic margin associated with an increased risk of local recurrence. The correlation between surgical and histologic margins is poorly documented in the literature.

Methods: An audit was performed to (1) document the shrinkage of formalin-fixed specimens, and (2) use a precisely measured surgical margin in vivo to predict the histologic margin. For patients presenting for wide excision of melanomas and other malignant skin tumors, measured surgical margin, in vivo and ex vivo specimen width, and histologic margins after formalin fixation were recorded. The effects of clinicopathologic characteristics, including age, sex, body mass index (BMI), tumor type, anatomic site, and presence of visible tumor in predicting specimen shrinkage and histologic margin were assessed.

Results: In total, 252 specimens were evaluated. When compared with measured width in vivo, the formalin-fixed specimens showed a mean shrinkage of 14% (R = 0.98), regardless of patient age, sex, BMI, or site of the lesion. The measured surgical margin was not a strong predictor of the histologic margin, with a high degree of variability (R = 0.55) not explained by patient factors, tumor subtype, or presence of visible tumor at the time of excision (p > 0.05).

Conclusions: A consistent 14% shrinkage rate of wide excision specimens was found across all patients and excision sites, and we propose a clinically useful 15% correction factor that will account for fixation and shrinkage of cutaneous excision specimens. Excision margins measured by the surgeon were a poor predictor of the histologic margins.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1245/s10434-018-6858-yDOI Listing
January 2019

Sentinel lymph node biopsy in patients with thin melanomas: Frequency and predictors of metastasis based on analysis of two large international cohorts.

J Surg Oncol 2018 Sep 9;118(4):599-605. Epub 2018 Sep 9.

Department of Clinical Sciences Lund, Surgery, Lund University, Skåne University Hospital, Lund, Sweden.

Background: Sentinel lymph node (SLN) metastasis in patients with thin melanomas (≤1 mm) is uncommon but adverse prognostic factors may indicate an increased risk. We sought to determine how often SLN biopsy (SLNB) was performed in patients with thin melanomas, establish the frequency of SLN metastasis and evaluate the predictive value of ulceration, tumor mitotic rate, and thickness for SLN involvement.

Methods: Melanoma patients with a Breslow thickness greater than or equal to 0.5 to less than or equal to 1 mm, diagnosed 2009-2016, were identified in the Swedish Melanoma Register (SMR) and the Melanoma Institute Australia (MIA) Database.

Results: In total 8165 patients were included from the SMR and 1603 from MIA. SLNB was performed in 9.5% and 16.2% of patients, respectively. Corresponding figures for T1b (American Joint Committee on Cancer [AJCC] 7th Edition) were 19.5% and 24.6%. The SLN positivity rate were 4.4% (Sweden) and 5.8% (MIA). SLN metastasis was more frequent in tumors with ulceration, mitoses, and Breslow thickness greater than or equal to 0.9 mm but none were statistically significant. Younger age was identified as a significant risk factor for SLN positivity at MIA.

Conclusions: A minority of patients with thin melanomas had SLNB performed and the SLN positivity rate was low. This study did not confirm tumor ulceration, mitoses, or thickness as statistically significant predictors for SLN metastasis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jso.25208DOI Listing
September 2018

The role of sentinel lymph node biopsy as a staging procedure in patients with melanoma - A critical appraisal.

Australas J Dermatol 2018 08 11;59(3):235-236. Epub 2018 May 11.

Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ajd.12839DOI Listing
August 2018

Anti-Melanoma immunity and local regression of cutaneous metastases in melanoma patients treated with monobenzone and imiquimod; a phase 2 a trial.

Oncoimmunology 2018;7(4):e1419113. Epub 2018 Jan 15.

Dept. of Dermatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

Vitiligo development in melanoma patients during immunotherapy is a favorable prognostic sign and indicates breakage of tolerance against melanocytic/melanoma antigens. We investigated a novel immunotherapeutic approach of the skin-depigmenting compound monobenzone synergizing with imiquimod in inducing antimelanoma immunity and melanoma regression. Stage III-IV melanoma patients with non-resectable cutaneous melanoma metastases were treated with monobenzone and imiquimod (MI) therapy applied locally to cutaneous metastases and adjacent skin during 12 weeks, or longer. Twenty-one of 25 enrolled patients were evaluable for clinical assessment at 12 weeks. MI therapy was well-tolerated. Partial regression of cutaneous metastases was observed in 8 patients and stable disease in 1 patient, reaching the statistical endpoint of treatment efficacy. Continued treatment induced clinical response in 11 patients, including complete responses in three patients. Seven patients developed vitiligo-like depigmentation on areas of skin that were not treated with MI therapy, indicating a systemic effect of MI therapy. Melanoma-specific antibody responses were induced in 7 of 17 patients tested and melanoma-specific CD8+T-cell responses in 11 of 15 patients tested. These systemic immune responses were significantly increased during therapy as compared to baseline in responding patients. This study shows that MI therapy induces local and systemic anti-melanoma immunity and local regression of cutaneous metastases in 38% of patients, or 52% during prolonged therapy. This study provides proof-of-concept of MI therapy, a low-cost, broadly applicable and well-tolerated treatment for cutaneous melanoma metastases, attractive for further clinical investigation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/2162402X.2017.1419113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5889200PMC
January 2018

Updated evidence-based clinical practice guidelines for the diagnosis and management of melanoma: definitive excision margins for primary cutaneous melanoma.

Med J Aust 2018 02;208(3):137-142

Melanoma Institute Australia, Sydney, NSW.

Introduction: Definitive management of primary cutaneous melanoma consists of surgical excision of the melanoma with the aim of curing the patient. The melanoma is widely excised together with a safety margin of surrounding skin and subcutaneous tissue, after the diagnosis and Breslow thickness have been established by histological assessment of the initial excision biopsy specimen. Sentinel lymph node biopsy should be discussed for melanomas ≥ 1 mm thickness (≥ 0.8 mm if other high risk features) in which case lymphoscintigraphy must be performed before wider excision of the primary melanoma site. The 2008 evidence-based clinical practice guidelines for the management of melanoma (http://www.cancer.org.au/content/pdf/HealthProfessionals/ClinicalGuidelines/ClinicalPracticeGuidelines-ManagementofMelanoma.pdf) are currently being revised and updated in a staged process by a multidisciplinary working party established by Cancer Council Australia. The guidelines for definitive excision margins for primary melanomas have been revised as part of this process. Main recommendations: The recommendations for definitive wide local excision of primary cutaneous melanoma are: melanoma in situ: 5-10 mm margins invasive melanoma (pT1) ≤ 1.0 mm thick: 1 cm margins invasive melanoma (pT2) 1.01-2.00 mm thick: 1-2 cm margins invasive melanoma (pT3) 2.01-4.00 mm thick: 1-2 cm margins invasive melanoma (pT4) > 4.0 mm thick: 2 cm margins Changes in management as a result of the guideline: Based on currently available evidence, excision margins for invasive melanoma have been left unchanged compared with the 2008 guidelines. However, melanoma in situ should be excised with 5-10 mm margins, with the aim of achieving complete histological clearance. Minimum clearances from all margins should be assessed and stated. Consideration should be given to further excision if necessary; positive or close histological margins are unacceptable.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.5694/mja17.00278DOI Listing
February 2018

Role of sentinel lymph node biopsy as a staging procedure in patients with melanoma: A critical appraisal.

Australas J Dermatol 2017 Nov 14;58(4):268-273. Epub 2017 Jul 14.

Melanoma Institute Australia, University of Sydney, Sydney, New South Wales, Australia.

Worldwide, sentinel node (SN) biopsy for accurate staging is now part of the standard work-up of patients with melanomas ≥1.0 mm Breslow thickness, as it is for staging patients with breast cancer. Nuclear medicine imaging and surgical techniques have evolved to such a degree that a SN can be identified and removed in virtually every patient. Nevertheless, some opposition to a routine SN biopsy remains, perhaps due to a failure to appreciate the serious implications of incomplete or inaccurate staging. Guided by a critical appraisal of the available evidence, this review elucidates the definition of an SN, discusses the sensitivity and specificity of the information it provides, emphasises that it is a minor staging procedure that can lead to improved survival when followed by appropriate therapy, and explains the necessarily unconventional and complex design of the only randomised trial that addresses this subject. It also describes other benefits and risks of an SN biopsy and outlines its role in current melanoma management.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ajd.12655DOI Listing
November 2017

Impact of Time Between Diagnosis and SLNB on Outcomes in Cutaneous Melanoma.

J Am Coll Surg 2017 Aug 28;225(2):302-311. Epub 2017 Jun 28.

Division of Surgical Oncology, The Angeles Clinic and Research Institute, Los Angeles, CA. Electronic address:

Background: Hypothetically, delay between melanoma diagnosis and SLNB could affect outcomes, either adversely by allowing growth and dissemination of metastases, or beneficially by allowing development of an anti-melanoma immune response. Available data are conflicting about the effect of SLNB delay on patient survival. Our objective was to determine whether delay between initial diagnosis and SLNB affects outcomes in patients with cutaneous melanoma.

Study Design: We performed query and analysis of a large prospectively maintained database of patients with primary cutaneous melanomas undergoing SLNB. An independent dataset from MSLT-1 (Multicenter Selective Lymphadenectomy Trial-1) was used for validation. Primary outcomes included disease-free survival and melanoma-specific survival.

Results: Early and delayed SLNB were defined as less than 30 and 30 or more days from initial diagnosis, respectively. There were 2,483 patients that met inclusion criteria. Positive sentinel lymph nodes were identified in 17.4% (n = 432). Among all patients, 42% had SLNB 30 or more days after diagnosis and 37% of positive sentinel lymph nodes were at 30 or more days. No differences in sex, anatomic site, or histopathologic features were identified between the 2 groups. There was no difference in melanoma-specific survival or disease-free survival between those undergoing early or delayed SLNB. Examination of MSLT-1 trial data similarly demonstrated no difference in survival outcomes.

Conclusions: This, the largest study on this subject to date, found no adverse impact on long-term clinical outcomes of patients due to delay of SLNB beyond 30 days. The MSLT-1 data confirm this result. Patients can be reassured that if the operation is performed 30 or more days after diagnosis, it will not cause harm.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jamcollsurg.2017.05.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5553862PMC
August 2017

Completion Dissection or Observation for Sentinel-Node Metastasis in Melanoma.

N Engl J Med 2017 06;376(23):2211-2222

From the John Wayne Cancer Institute at Saint John's Health Center, Santa Monica (M.B.F., D.S.B.H.), and the Departments of Pathology (A.J.C.), Biomathematics (H.-J.W., D.A.E., R.M.E.), and Medicine (D.A.E.), University of California, Los Angeles - both in California; Melanoma Institute Australia and the University of Sydney, Sydney (J.F.T., O.E.N.), Peter MacCallum Cancer Centre, Melbourne, VIC (M.H.), Princess Alexandra Hospital, Brisbane, QLD (B.M.S.), and Newcastle Melanoma Unit, Waratah, NSW (P.H.) - all in Australia; Huntsman Cancer Institute, Salt Lake City (R.H.A., R.D.N.), and Intermountain Healthcare Cancer Services-Intermountain Medical Center, Murray (T.L.B.) - both in Utah; Istituto Nazionale dei Tumori Napoli, Naples (N.M.), Istituto Europeo di Oncologia, Milan (A.T.), and Istituto Oncologico Veneto-University of Padua, Padua (C.R.R.) - all in Italy; H. Lee Moffitt Cancer Center, Tampa, FL (J.S.Z.); Helsinki University Hospital, Helsinki (T.J.); Dallas Surgical Group, Dallas (P.D.B.); Universitair Medisch Centrum Groningen, Groningen (H.J.H.), and Netherlands Cancer Institute, Amsterdam (M.W.J.M.W.) - both in the Netherlands; Norfolk and Norwich University Hospital, Norwich (M. Moncrieff), and Guy's and St. Thomas' NHS Foundation Trust, London (A.M.-R.) - both in the United Kingdom; Swedish Melanoma Study Group-University Hospital Lund, Lund, Sweden (C.I.); University of Michigan, Ann Arbor (M.S.S.); Wake Forest University, Winston-Salem (E.A.L.), and Duke University, Durham (R.S.) - both in North Carolina; Ohio State University, Columbus (D.A.); University of Zurich, Zurich (R.D.), and Centre Hospitalier Universitaire Vaudois, Lausanne (M. Matter) - both in Switzerland; Penn State Hershey Cancer Institute, Hershey (R.I.N.), Thomas Jefferson University (A.C.B.) and Fox Chase Cancer Center (J.M.F.), Philadelphia, and St. Luke's University Health Network, Bethlehem (D.C.D.) - all in Pennsylvania; Greenville Health System Cancer Center, Greenville, SC (S.D.T.); Sunnybrook Research Institute, Toronto (F.W.), and Tom Baker Cancer Centre, Calgary, AB (G.M.) - both in Canada; University of Washington, Seattle (D.R.B.); Saint Louis University, St. Louis (E.H.); Vanderbilt University (D.B.J., M.C.K.), Nashville, and University of Tennessee, Knoxville (J.M.L.) - both in Tennessee; University Hospital Schleswig-Holstein-Campus Lübeck, Lübeck (P.T.), University Hospital of Würzburg, Würzburg (A.G.), and City Hospital of Nürnberg, Nuremberg (E.S.) - all in Germany; SUNY at Stony Brook Hospital Medical Center, Stony Brook (T.L.H.), Memorial Sloan Kettering Cancer Center, New York (C.E.A.), and Roswell Park Cancer Institute, Buffalo (J.M.K.) - all in New York; Northwestern University Feinberg School of Medicine (J.D.W.) and Rush University Medical Center (S.D.B.), Chicago; University of Wisconsin, Madison (H.B.N.); Tel Aviv Sourasky Medical Center, Tel Aviv, Israel (S.S.); M.D. Anderson Medical Center, Houston (J.E.G.); Johns Hopkins University School of Medicine, Baltimore (L.J.); University of Louisville, Louisville, KY (K.M.M.); Dartmouth-Hitchcock Medical Center, Lebanon, NH (R.J.B.); Hospital Clinic Barcelona, Barcelona (S.V.-S.); and Sentara CarePlex Hospital, Hampton, VA (R.A.H.).

Background: Sentinel-lymph-node biopsy is associated with increased melanoma-specific survival (i.e., survival until death from melanoma) among patients with node-positive intermediate-thickness melanomas (1.2 to 3.5 mm). The value of completion lymph-node dissection for patients with sentinel-node metastases is not clear.

Methods: In an international trial, we randomly assigned patients with sentinel-node metastases detected by means of standard pathological assessment or a multimarker molecular assay to immediate completion lymph-node dissection (dissection group) or nodal observation with ultrasonography (observation group). The primary end point was melanoma-specific survival. Secondary end points included disease-free survival and the cumulative rate of nonsentinel-node metastasis.

Results: Immediate completion lymph-node dissection was not associated with increased melanoma-specific survival among 1934 patients with data that could be evaluated in an intention-to-treat analysis or among 1755 patients in the per-protocol analysis. In the per-protocol analysis, the mean (±SE) 3-year rate of melanoma-specific survival was similar in the dissection group and the observation group (86±1.3% and 86±1.2%, respectively; P=0.42 by the log-rank test) at a median follow-up of 43 months. The rate of disease-free survival was slightly higher in the dissection group than in the observation group (68±1.7% and 63±1.7%, respectively; P=0.05 by the log-rank test) at 3 years, based on an increased rate of disease control in the regional nodes at 3 years (92±1.0% vs. 77±1.5%; P<0.001 by the log-rank test); these results must be interpreted with caution. Nonsentinel-node metastases, identified in 11.5% of the patients in the dissection group, were a strong, independent prognostic factor for recurrence (hazard ratio, 1.78; P=0.005). Lymphedema was observed in 24.1% of the patients in the dissection group and in 6.3% of those in the observation group.

Conclusions: Immediate completion lymph-node dissection increased the rate of regional disease control and provided prognostic information but did not increase melanoma-specific survival among patients with melanoma and sentinel-node metastases. (Funded by the National Cancer Institute and others; MSLT-II ClinicalTrials.gov number, NCT00297895 .).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1056/NEJMoa1613210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5548388PMC
June 2017

Futility of imaging to stage melanoma patients with a positive sentinel lymph node.

Melanoma Res 2017 10;27(5):457-462

aMelanoma Institute Australia, North Sydney bDepartment of Nuclear Medicine and PET, St Vincent's Hospital cSt Vincent's Clinical School, University of New South Wales dSydney Medical School, The University of Sydney eDepartment of Melanoma and Surgical Oncology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia fDepartment of Surgical Oncology, University of Groningen, University Medical Center Groningen, The Netherlands.

The use of staging imaging in melanoma patients with a positive sentinel lymph node (SLN) has been reported to be of limited value. Improved accuracy resulting from the development of time-of-flight positron emission tomography (PET) and ongoing image quality improvement of computed tomography (CT) may challenge this statement. Our retrospective study assessed the clinical value of routine staging CT and PET/CT imaging in a recent cohort of asymptomatic SLN-positive patients. Between January 2011 and April 2014, 143 patients with a positive SLN were routinely staged using CT of various parts of the body or whole-body PET/CT. Scores were assigned for level of certainty for regional or distant metastases and incidental second primary malignancies. Diagnostic test performance was assessed, as well as the number and nature of ensuing additional diagnostic actions. CT was performed in 102 of 143 (71%) patients and PET/CT in 41 (29%) patients. The use of PET/CT increased over the study period. Metastases were found in two of the 143 patients (true-positive yield 1.4%). Sensitivity, specificity and positive predictive value were 11, 73 and 4% for CT and 17, 57 and 6%, respectively, for PET/CT. None of the 143 patients had a change in AJCC stage. Two other primary malignancies were found. Twenty-one (15%) patients were subjected to 37 additional investigations, referrals or procedures. Routine staging imaging with CT or PET/CT in SLN-positive patients is not useful. The yield is low and the results are often false positive, leading to unnecessary additional tests, most of which are costly and some potentially morbid.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/CMR.0000000000000362DOI Listing
October 2017
-->