Publications by authors named "Serigne N Lo"

26 Publications

  • Page 1 of 1

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

Re-induction ipilimumab following acquired resistance to combination ipilimumab and anti-PD-1 therapy.

Eur J Cancer 2021 Aug 29;153:213-222. Epub 2021 Jun 29.

Melanoma Institute Australia, The University of Sydney, NSW, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, Australia; Royal North Shore and Mater Hospitals, NSW, Australia. Electronic address:

Purpose: Combination immunotherapy with nivolumab and ipilimumab has a high initial response rate in advanced melanoma; however, up to 55% of patients later progress. The efficacy and safety of ipilimumab re-induction in the setting of acquired resistance (AR) to combination immunotherapy is unknown.

Methods: Patients with advanced melanoma who initially achieved a complete response, partial response or sustained stable disease to induction combination immunotherapy then progressed and were reinduced with ipilimumab (alone or in combination with anti-PD-1) and were analysed retrospectively. Demographics, disease characteristics, efficacy and toxicity were examined.

Results: Forty-seven patients were identified from 12 centres. The response rate to reinduction therapy was 12/47 (26%), and disease control rate was 21/47 (45%). Responses appeared more frequent in patients who developed AR after ceasing induction immunotherapy (30% vs. 18%, P = 0.655). Time to AR was 11 months (95% confidence interval [CI], 8-15 months). After a median follow-up of 16 months (95% CI, 10-25 months), responders to reinduction had a median progression-free survival of 14 months (95% CI, 13, NR months), and in the whole cohort, the median overall survival from reinduction was 17 months (95% CI, 12-NR months). Twenty-seven (58%) immune-related adverse events (irAEs) were reported; 18 (38%) were grade 3/4, and in 11 of 27 (40%), the same irAE observed during induction therapy recurred.

Conclusions: Reinduction with ipilimumab ± anti-PD-1 has modest clinical activity. Clinicians should be attentive to the risk of irAEs, including recurrence of irAEs that occurred during induction therapy. Future studies are necessary to determine best management after resistance to combination immunotherapy.
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http://dx.doi.org/10.1016/j.ejca.2021.04.021DOI Listing
August 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.
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http://dx.doi.org/10.1016/j.ejca.2021.04.037DOI Listing
August 2021

Ipilimumab alone or ipilimumab plus anti-PD-1 therapy in patients with metastatic melanoma resistant to anti-PD-(L)1 monotherapy: a multicentre, retrospective, cohort study.

Lancet Oncol 2021 06 11;22(6):836-847. Epub 2021 May 11.

Melanoma Institute Australia, University of Sydney, Sydney, NSW, Australia; Royal North Shore Hospital, Sydney, NSW, Australia; Mater Hospital, Sydney, NSW, Australia. Electronic address:

Background: Anti-PD-1 therapy (hereafter referred to as anti-PD-1) induces long-term disease control in approximately 30% of patients with metastatic melanoma; however, two-thirds of patients are resistant and will require further treatment. We aimed to determine the efficacy and safety of ipilimumab plus anti-PD-1 (pembrolizumab or nivolumab) compared with ipilimumab monotherapy in patients who are resistant to anti-PD-(L)1 therapy (hereafter referred to as anti-PD-[L]1).

Methods: This multicentre, retrospective, cohort study, was done at 15 melanoma centres in Australia, Europe, and the USA. We included adult patients (aged ≥18 years) with metastatic melanoma (unresectable stage III and IV), who were resistant to anti-PD-(L)1 (innate or acquired resistance) and who then received either ipilimumab monotherapy or ipilimumab plus anti-PD-1 (pembrolizumab or nivolumab), based on availability of therapies or clinical factors determined by the physician, or both. Tumour response was assessed as per standard of care (CT or PET-CT scans every 3 months). The study endpoints were objective response rate, progression-free survival, overall survival, and safety of ipilimumab compared with ipilimumab plus anti-PD-1.

Findings: We included 355 patients with metastatic melanoma, resistant to anti-PD-(L)1 (nivolumab, pembrolizumab, or atezolizumab), who had been treated with ipilimumab monotherapy (n=162 [46%]) or ipilimumab plus anti-PD-1 (n=193 [54%]) between Feb 1, 2011, and Feb 6, 2020. At a median follow-up of 22·1 months (IQR 9·5-30·9), the objective response rate was higher with ipilimumab plus anti-PD-1 (60 [31%] of 193 patients) than with ipilimumab monotherapy (21 [13%] of 162 patients; p<0·0001). Overall survival was longer in the ipilimumab plus anti-PD-1 group (median overall survival 20·4 months [95% CI 12·7-34·8]) than with ipilimumab monotherapy (8·8 months [6·1-11·3]; hazard ratio [HR] 0·50, 95% CI 0·38-0·66; p<0·0001). Progression-free survival was also longer with ipilimumab plus anti-PD-1 (median 3·0 months [95% CI 2·6-3·6]) than with ipilimumab (2·6 months [2·4-2·9]; HR 0·69, 95% CI 0·55-0·87; p=0·0019). Similar proportions of patients reported grade 3-5 adverse events in both groups (59 [31%] of 193 patients in the ipilimumab plus anti-PD-1 group vs 54 [33%] of 162 patients in the ipilimumab group). The most common grade 3-5 adverse events were diarrhoea or colitis (23 [12%] of 193 patients in the ipilimumab plus anti-PD-1 group vs 33 [20%] of 162 patients in the ipilimumab group) and increased alanine aminotransferase or aspartate aminotransferase (24 [12%] vs 15 [9%]). One death occurred with ipilimumab 26 days after the last treatment: a colon perforation due to immune-related pancolitis.

Interpretation: In patients who are resistant to anti-PD-(L)1, ipilimumab plus anti-PD-1 seemed to yield higher efficacy than ipilimumab with a higher objective response rate, longer progression-free, and longer overall survival, with a similar rate of grade 3-5 toxicity. Ipilimumab plus anti-PD-1 should be favoured over ipilimumab alone as a second-line immunotherapy for these patients with advanced melanoma.

Funding: None.
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http://dx.doi.org/10.1016/S1470-2045(21)00097-8DOI Listing
June 2021

Thyroid immune-related adverse events following immune checkpoint inhibitor treatment.

J Clin Endocrinol Metab 2021 Apr 20. Epub 2021 Apr 20.

Faculty of Medicine and Health, The University of Sydney, Sydney, Australia.

Background: Thyroid dysfunction occurs commonly following immune checkpoint inhibition. The etiology of thyroid immune-related adverse events (irAEs) remains unclear and clinical presentation can be variable. This study sought to define thyroid irAEs following immune checkpoint inhibitor (ICI) treatment and describe their clinical and biochemical associations.

Methods: We performed a retrospective cohort study of thyroid dysfunction in patients with melanoma undergoing CTLA-4 and/or PD-1 based ICI treatment from Nov 1, 2009 to Dec 31, 2019. Thyroid function was measured at baseline and at regular intervals following the start of ICI-treatment. Clinical and biochemical features were evaluated for associations with ICI-associated thyroid irAEs. The prevalence of thyroid autoantibodies and the effect of thyroid irAEs on survival were analysed.

Results: A total of 1246 patients were included with a median follow-up of 11.3 months. 518 (42%) patients developed an ICI-associated thyroid irAE. Subclinical thyrotoxicosis (n=234) was the most common thyroid irAE, followed by overt thyrotoxicosis (n=154), subclinical hypothyroidism (n=61), and overt hypothyroidism (n=39). Onset of overt thyrotoxicosis occurred a median of 5 weeks (IQR 2-8) after receipt of first dose of ICI. Combination immunotherapy was strongly associated with development of overt thyrotoxicosis (OR 10.8, 95% CI 4.51-25.6 vs. CTLA-4 monotherapy; p<0.001), as was female sex (OR 2.02, 95% CI 1.37-2.95; p<0.001) and younger age (OR 0.83 per 10-years, 95% CI 0.72-0.95; p=0.007). By comparison, median onset of overt hypothyroidism was 14 weeks (IQR 8-25). The frequency of overt hypothyroidism did not differ between different ICI-types. The strongest associations for hypothyroidism were higher baseline TSH (OR 2.33 per mIU/L, 95% CI 1.61-3.33; p<0.001) and female sex (OR 3.31, 95% CI 1.67-6.56; p=0.01). Overt thyrotoxicosis was associated with longer progression free survival (HR 0.68, 95% CI 0.49-0.94; p=0.02) and overall survival (HR 0.57, 95% CI 0.39-0.84; p=0.005). There was no association between hypothyroidism and cancer outcomes.

Conclusions: Thyroid irAEs are common and there are multiple distinct phenotypes. Different thyroid irAE subtypes have unique clinical and biochemical associations, suggesting potentially distinct etiologies for thyrotoxicosis and hypothyroidism arising in this context.
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http://dx.doi.org/10.1210/clinem/dgab263DOI Listing
April 2021

Treatment of in-transit melanoma metastases using intralesional PV-10.

Melanoma Res 2021 06;31(3):232-241

Melanoma Institute Australia.

Melanoma in-transit metastases (ITMs) can sometimes be difficult to manage by surgical excision due to their number, size or location. Treatment by intralesional injection of PV-10, a 10% solution of rose bengal, has been reported to be a simple, safe and effective alternative, but more outcome data are required to confirm its value in the management of ITMs. Two hundred and twenty-six melanoma ITMs in 48 patients were treated with intralesional PV-10 supplied under a special-access scheme. By 8 weeks a complete response in all injected ITMs was achieved in 22 patients (46%) and a partial response in 19 patients (40%). Of 19 patients who had uninjected metastases, 3 (16%) had a response in these. The most common adverse event was transient localised pain in injected tumours. New ITMs developed in 25 patients within 8 weeks, and later in another 8 patients. Repeat injection cycles were given to 21 patients: 13 of these received repeat injection into partially responding or nonresponding tumours, 5 had new ITMs, as well as partially-responding lesions injected, and 3 received injection into new ITMs only. Twenty-two patients received subsequent systemic therapy. At 1 year 37 of the 48 patients were alive, 28 with melanoma, and at 2 years 27 were alive, and 19 with melanoma. Injection of PV-10 was simple and safe and resulted in tumour involution in most patients and sometimes in noninjected tumours. However, many patients developed new lesions; these were treated by further PV-10 injections or with alternative therapies.
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http://dx.doi.org/10.1097/CMR.0000000000000729DOI Listing
June 2021

Surgical excision margins in primary cutaneous melanoma: A systematic review and meta-analysis.

Eur J Surg Oncol 2021 Jul 3;47(7):1558-1574. Epub 2021 Mar 3.

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

Background: The main treatment of primary cutaneous melanoma is surgery. This review aims to assess the width of excision margin that minimises the risk of adverse outcome from surgery, locoregional recurrence, distant recurrence, and death.

Methods: PRISMA guidelines were followed. MEDLINE, EMBASE, and four other databases were searched by using the term "melanoma", "margin", and limiting the search to randomised clinical trials (RCTs).

Results: Seven RCTs involving 4579 patients data were analysed. No statistically significant difference was found in locoregional recurrence RR 1.09 (95%CI 0.98-1.22, p = 0.12), local recurrence RR 1.20 (95%CI 0.66-2.21, p = 0.55), in-transit metastasis RR1.30 (95%CI 0.86-1.97, p = 0.21), regional nodal metastasis RR 1.04 (95%CI 0.91-1.18, p = 0.56), distant metastasis RR 0.95 (95%CI 0.72-1.24, p = 0.68), death RR 1.00 (95%CI 0.93-1.07, p = 0.97), death from melanoma RR 1.11 (95%CI 0.96-1.28, p = 0.16), wound infection RR 1.22 (95%CI 0.68-2.17, p = 0.50), and wound dehiscence RR 0.96 (95%CI 0.54-1.71, p = 0.88) when narrow (1-2 cm) versus wide (3-5 cm) excision margins were compared. In contrast, patients with narrow excision margins had a significant reduction in complex surgical reconstruction RR 0.30 (95%CI 0.19-0.49, p < 00001). When studies were excluded because of high risk of bias the only significant difference was death due to melanoma RR 1.25 (95%CI1.01-1.55, P = 0.04).

Conclusions: No significant difference between narrow and wide excision margins in locoregional or distant recurrence, metastasis, death, or death due to melanoma. Wide margins (2-5 cm) increased the need for surgical reconstruction. Further studies are needed to assess optimal excision margins with regards to Breslow thickness and other prognostic factors and are in progress.
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http://dx.doi.org/10.1016/j.ejso.2021.02.025DOI Listing
July 2021

Development and Validation of Nomograms to Predict Local, Regional, and Distant Recurrence in Patients With Thin (T1) Melanomas.

J Clin Oncol 2021 Apr 18;39(11):1243-1252. Epub 2021 Feb 18.

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

Purpose: Although the prognosis of patients with thin primary cutaneous melanomas (T1, ≤ 1.0 mm) is generally excellent, some develop recurrence. We sought to develop and validate a model predicting recurrences in patients with thin melanomas.

Methods: A Dutch population-based cohort (n = 25,930, development set) and a cohort from an Australian melanoma treatment center (n = 2,968, validation set) were analyzed (median follow-up 6.7 and 12.0 years, respectively). Multivariable Cox models were generated for local, regional, and distant recurrence-free survival (RFS). Discrimination was assessed using Harrell's C-statistic for each outcome. Each nomogram performance was evaluated using calibration plots defining low-risk and high-risk groups as the lowest and top 5% of the nomogram risk score, respectively. The nomograms' C-statistics were compared with those of a model including the current American Joint Committee on Cancer staging parameters (T-stage and sentinel node status).

Results: Local, regional, and distant recurrences were found in 209 (0.8%), 503 (1.9%), and 203 (0.8%) Dutch patients, respectively, and 23 (0.8%), 61 (2.1%), and 75 (2.5%) Australian patients, respectively. C-statistics of 0.79 (95% CI, 0.75 to 0.82) for local RFS, 0.77 (95% CI, 0.75 to 0.78) for regional RFS, and 0.80 (95% CI, 0.77 to 0.83) for distant RFS were obtained for the development model. External validation showed C-statistics of 0.80 (95% CI, 0.69 to 0.90), 0.76 (95% CI, 0.70 to 0.82), and 0.74 (95% CI, 0.69 to 0.80), respectively. Calibration plots showed a good match between predicted and observed rates. Using the nomogram, the C-statistic was increased by 9%-12% for the development cohort and by 11%-15% for the validation cohort, compared with a model including only T-stage and sentinel node status.

Conclusion: Most patients with thin melanomas have an excellent prognosis, but some develop recurrence. The presented nomograms can accurately identify a subgroup at high risk. An online calculator is available at www.melanomarisk.org.au.
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http://dx.doi.org/10.1200/JCO.20.02446DOI Listing
April 2021

Association of Histologic Regression With a Favorable Outcome in Patients With Stage 1 and Stage 2 Cutaneous Melanoma.

JAMA Dermatol 2021 Feb;157(2):166-173

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

Importance: Although regression is commonly observed in cutaneous melanoma, it is uncertain whether it is associated with patient prognosis.

Objective: To determine whether histologically confirmed regression was associated with better or worse survival in patients with primary cutaneous melanoma.

Design, Setting, And Participants: This cohort study analyzed data from 2 large cohorts of adults (one in the Netherlands and the other in Australia) with histologically proven, stage 1 and 2 primary, invasive cutaneous melanoma with known regression status treated between 2000 and 2014, with median follow-up times of 4.5 and 11.1 years for the Dutch and Australian cohorts, respectively. For the Dutch patients, population-based data from PALGA, the Dutch Pathology Registry, were used, and follow-up data were retrieved from the Netherlands Cancer Registry. For the Australian patients, data from the database of a large, specialized melanoma treatment center were used.

Main Outcomes And Measures: Multivariable Cox proportional hazards analyses were performed per cohort to assess recurrence-free survival (RFS) and overall survival (OS), and subgroup analyses according to Breslow thickness category and melanoma subtype were performed.

Results: A total of 17 271 Dutch patients and 4980 Australian patients were included. In both cohorts, survival outcomes were better for patients with disease regression. For Dutch patients, the hazard ratio (HR) for those with disease regression was 0.55 (95% CI, 0.48-0.63; P < .001) for RFS and 0.87 (95% CI, 0.79-0.96; P = .004) for OS; for the Australian patients, the HR was 0.61 (95% CI, 0.52-0.72; P < .001) for RFS and 0.73 (95% CI, 0.64-0.84; P < .001) for OS. Subgroup analyses showed that the presence of regression improved RFS within thin and intermediate Breslow thickness melanomas in both cohorts. For patients with superficial spreading melanoma (SSM) subtype, regression improved RFS and OS in both cohorts. For Dutch patients with SSM, the HR for those with disease regression was 0.54 (95% CI, 0.46-0.63; P < .001) for RFS and 0.86 (95% CI, 0.76-0.96; P = .009) for OS; for the Australian patients with SSM, the HR was 0.67 (95% CI, 0.52-0.85; P = .001) for RFS and 0.72 (95% CI, 0.59-0.88; P = .001) for OS.

Conclusions And Relevance: In 2 large patient cohorts from 2 different continents, regression was a favorable prognostic factor for patients with stage 1 and 2 melanomas, especially in those with thin and intermediate thickness tumors and those with SSM subtype.
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http://dx.doi.org/10.1001/jamadermatol.2020.5032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7758823PMC
February 2021

Prognostic significance of postsurgery circulating tumor DNA in nonmetastatic colorectal cancer: Individual patient pooled analysis of three cohort studies.

Int J Cancer 2021 02 6;148(4):1014-1026. Epub 2020 Oct 6.

Division of Personalised Oncology, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.

Studies in multiple solid tumor types have demonstrated the prognostic significance of ctDNA analysis after curative intent surgery. A combined analysis of data across completed studies could further our understanding of circulating tumor DNA (ctDNA) as a prognostic marker and inform future trial design. We combined individual patient data from three independent cohort studies of nonmetastatic colorectal cancer (CRC). Plasma samples were collected 4 to 10 weeks after surgery. Mutations in ctDNA were assayed using a massively parallel sequencing technique called SafeSeqS. We analyzed 485 CRC patients (230 Stage II colon, 96 Stage III colon, and 159 locally advanced rectum). ctDNA was detected after surgery in 59 (12%) patients overall (11.0%, 12.5% and 13.8% for samples taken at 4-6, 6-8 and 8-10 weeks; P = .740). ctDNA detection was associated with poorer 5-year recurrence-free (38.6% vs 85.5%; P < .001) and overall survival (64.6% vs 89.4%; P < .001). The predictive accuracy of postsurgery ctDNA for recurrence was higher than that of individual clinicopathologic risk features. Recurrence risk increased exponentially with increasing ctDNA mutant allele frequency (MAF) (hazard ratio, 1.2, 2.5 and 5.8 for MAF of 0.1%, 0.5% and 1%). Postsurgery ctDNA was detected in 3 of 20 (15%) patients with locoregional and 27 of 60 (45%) with distant recurrence (P = .018). This analysis demonstrates a consistent long-term impact of ctDNA as a prognostic marker across nonmetastatic CRC, where ctDNA outperforms other clinicopathologic risk factors and MAF further stratifies recurrence risk. ctDNA is a better predictor of distant vs locoregional recurrence.
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http://dx.doi.org/10.1002/ijc.33312DOI Listing
February 2021

Tumor Mutation Burden and Structural Chromosomal Aberrations Are Not Associated with T-cell Density or Patient Survival in Acral, Mucosal, and Cutaneous Melanomas.

Cancer Immunol Res 2020 11 11;8(11):1346-1353. Epub 2020 Sep 11.

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

Tumor mutation burden (TMB) has been proposed as a key determinant of immunogenicity in several cancers, including melanoma. The evidence presented thus far, however, is often contradictory and based mostly on RNA-sequencing data for the quantification of immune cell phenotypes. Few studies have investigated TMB across acral, mucosal, and cutaneous melanoma subtypes, which are known to have different TMB. It is also unknown whether chromosomal structural mutations [structural variant (SV) mutations] contribute to the immunogenicity in acral and mucosal melanomas where such aberrations are common. We stained 151 cutaneous and 35 acral and mucosal melanoma patient samples using quantitative IHC and correlated immune infiltrate phenotypes with TMB and other genomic profiles. TMB and SVs did not correlate with the densities of CD8 lymphocytes, CD103 tumor-resident T cells (Trm), CD45RO cells, and other innate and adaptive immune cell subsets in cutaneous and acral/mucosal melanoma tumors, respectively, including in analyses restricted to the site of disease and in a validation cohort. In 43 patients with stage III treatment-naïve cutaneous melanoma, we found that the density of immune cells, particularly Trm, was significantly associated with patient survival, but not with TMB. Overall, TMB and chromosomal structural aberrations are not associated with protective antitumor immunity in treatment-naïve melanoma.
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http://dx.doi.org/10.1158/2326-6066.CIR-19-0835DOI Listing
November 2020

The Melanoma Genomics Managing Your Risk Study randomised controlled trial: statistical analysis plan.

Trials 2020 Jun 30;21(1):594. Epub 2020 Jun 30.

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

Background: The Melanoma Genomics Managing Your Risk Study is a randomised controlled trial that aims to evaluate the efficacy of providing information on personal genomic risk of melanoma in reducing ultraviolet radiation (UV) exposure, stratified by traditional risk group (low or high phenotypic risk) in the general population. The primary outcome is objectively measured total daily Standard Erythemal Doses at 12 months. Secondary outcomes include UV exposure at specific time periods, self-reported sun protection and skin-examination behaviours, psychosocial outcomes, and ethical considerations surrounding offering genomic testing at a population level. A within-trial and modelled economic evaluation will be undertaken from an Australian health system perspective to assess the cost-effectiveness of the intervention.

Objective: To publish the pre-determined statistical analysis plan (SAP) before database lock and the start of analysis.

Methods: This SAP describes the data synthesis, analysis principles and statistical procedures for analysing the outcomes from this trial. The SAP was approved after closure of recruitment and before completion of patient follow-up. It outlines the planned primary analyses and a range of subgroup and sensitivity analyses. Health economic outcomes are not included in this plan but will be analysed separately. The SAP will be adhered to for the final data analysis of this trial to avoid potential analysis bias that may arise from knowledge of the outcome data.

Results: This SAP is consistent with best practice and should enable transparent reporting.

Conclusion: This SAP has been developed for the Melanoma Genomics Managing Your Risk Study and will be followed to ensure high-quality standards of internal validity and to minimise analysis bias.

Trial Registration: Prospectively registered with the Australian New Zealand Clinical Trials Registry, ID: ACTR N12617000691347 . Registered on 15 May 2017.
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http://dx.doi.org/10.1186/s13063-020-04351-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7329549PMC
June 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.
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http://dx.doi.org/10.1200/JCO.19.02362DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7430218PMC
August 2020

The prognostic significance of microsatellites in cutaneous melanoma.

Mod Pathol 2020 07 13;33(7):1369-1379. Epub 2020 Feb 13.

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

Microscopic satellite metastases are an adverse prognostic feature in primary cutaneous melanoma patients. The prognostic significance of microsatellites, including their number, size and distance from the primary melanoma, using the 8th edition American Joint Committee on Cancer definition, has not previously been evaluated. This study sought to determine the prognostic significance of microsatellites in histopathologically reviewed cases. Eighty-seven cases of primary cutaneous melanoma with the presence of microsatellites documented in the original pathology report and all histopathology slides available were reviewed and the findings were correlated with clinical outcome. Matched control cases were selected for all confirmed microsatellites cases. The presence of microsatellites was confirmed in 69 cases. The microsatellite group had significantly worse prognosis, with 21% 5-year disease-free survival compared with 56% in the control group (p < 0.001). The 5-year melanoma-specific survival was 53% in the microsatellites group and 73% in the control group (p = 0.004). Increasing distance (mm) of the microsatellite from the primary melanoma was found to adversely influence disease-free survival (HR = 1.24, 95% CI: 1.13-1.36, p < 0.001), overall survival (HR = 1.26 95%CI: 1.13-1.40, p < 0.001), and melanoma-specific survival (HR = 1.27 95% CI: 1.11-1.45, p < 0.001). Number and size of microsatellites were not significant prognostic factors. The presence of microsatellites was the only factor that proved to be an independent predictor of sentinel node positivity in multivariate analysis (OR 4.64; 95% CI 1.66-12.95; p = 0.003). Microsatellites were significantly associated with more loco-regional recurrences (p < 0.001) but not distant metastases (p = 0.821). Melanomas with microsatellites as defined by the 8th edition American Joint Committee on Cancer staging system are thus aggressive tumors, associated with significantly worse disease-free survival, overall survival and melanoma-specific survival. The presence of microsatellites is also associated with sentinel node-positivity and local and in-transit recurrence. Increasing distance of the microsatellite from the primary tumor is an independent adverse prognostic factor that warrants further evaluation.
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http://dx.doi.org/10.1038/s41379-020-0500-9DOI Listing
July 2020

Cumulative Incidence and Predictors of CNS Metastasis for Patients With American Joint Committee on Cancer 8th Edition Stage III Melanoma.

J Clin Oncol 2020 05 28;38(13):1429-1441. Epub 2020 Jan 28.

Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX.

Purpose: Improved understanding of the incidence, risk factors, and timing of CNS metastasis is needed to inform surveillance strategies for patients with melanoma.

Patients And Methods: Clinical data were extracted from the databases of 2 major melanoma centers in the United States and Australia for 1,918 patients with American Joint Committee on Cancer (AJCC) 8th edition stage III melanoma, diagnosed from 1998-2014, who had (negative) baseline CNS imaging within 4 months of diagnosis. The cumulative incidence of CNS metastasis was calculated in the presence of the competing risk of death, from stage III presentation and at benchmark time points 1, 2, and 5 years postdiagnosis.

Results: At a median follow-up of 70.2 months, distant recurrence occurred in 711 patients (37.1%). The first site of distant metastasis was CNS only for 3.9% of patients, CNS and extracranial (EC) for 1.8%, and EC only for 31.4%. Overall, 16.7% of patients were diagnosed with CNS metastasis during follow-up. The cumulative incidence of CNS metastasis was 3.6% (95% CI, 2.9% to 4.6%) at 1 year, 9.6% (95% CI, 8.3% to 11.0%) at 2 years, and 15.8% (95% CI, 14.1% to 17.6%) at 5 years. The risk of CNS metastasis was significantly influenced by patient sex, age, AJCC stage, primary tumor site, and primary tumor mitotic rate in multivariable and conditional analyses. High primary tumor mitotic rate was significantly associated with increased risk of CNS metastasis at diagnosis and all subsequent time points examined.

Conclusion: Similar rates of CNS metastasis were observed in 2 large, geographically distinct cohorts of patients with stage III melanoma. The results highlight the importance of primary tumor mitotic rate. Furthermore, they provide a framework for developing evidence-based surveillance strategies and evaluating the impact of contemporary adjuvant therapies on the risk of CNS metastasis development.
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http://dx.doi.org/10.1200/JCO.19.01508DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7193747PMC
May 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.
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http://dx.doi.org/10.1016/j.jaad.2019.10.065DOI Listing
April 2020

Adjuvant Whole-Brain Radiation Therapy Compared With Observation After Local Treatment of Melanoma Brain Metastases: A Multicenter, Randomized Phase III Trial.

J Clin Oncol 2019 11 25;37(33):3132-3141. Epub 2019 Sep 25.

The University of Sydney, Sydney, NSW, Australia.

Purpose: The brain is a common site of metastasis for patients with high-risk melanoma. Although surgery or stereotactic radiosurgery are highly effective local treatments for a small number of metastases, there is a high risk of developing additional brain metastases. The role of adjuvant whole-brain radiotherapy (WBRT) in reducing new metastases is controversial, with a lack of high-level evidence specifically for melanoma.

Methods: In this randomized phase III trial, patients who had local treatment of one to three melanoma brain metastases were randomly assigned to WBRT or observation. The primary end point was distant intracranial failure within 12 months, and secondary end points included time to intracranial failure, survival, and time to deterioration in performance status.

Results: Between April 2009 and September 2017, 215 patients were randomly assigned from 24 centers. Median follow-up was 48.1 months (range, 39.6 to 68 months). Forty-two percent of patients in the WBRT group and 50.5% of those in the observation developed distant intracranial failure within 12 months (odds ratio, 0.71; 95% CI, 0.41 to 1.23; = .22) and the rates over the entire follow-up period were 52.0% and 57.9%, respectively (odds ratio, 0.79; 95% CI, 0.45 to 1.36; = .39). Local failure rate was lower after WBRT (20.0% 33.6%; = .03). At 12 months, 41.5% of patients in the WBRT group and 51.4% of patients in the observation group had died ( = .28), with no difference in the rate of neurologic death. Median time to deterioration in performance status was 3.8 months after WBRT and 4.4 months with observation ( = .32). WBRT was associated with more grade 1 to 2 acute toxicity.

Conclusion: After local treatment of one to three melanoma brain metastases, adjuvant WBRT does not provide clinical benefit in terms of distant intracranial control, survival, or preservation of performance status.
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http://dx.doi.org/10.1200/JCO.19.01414DOI Listing
November 2019

Whole brain radiotherapy (WBRT) after local treatment of brain metastases in melanoma patients: Statistical Analysis Plan.

Trials 2019 Aug 5;20(1):477. Epub 2019 Aug 5.

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

Background: The WBRTMel trial is a multinational, open-label, phase III randomised controlled trial comparing whole brain radiotherapy (WBRT) to observation following local treatment of one to three melanoma brain metastases with surgery and/or stereotactic irradiation. The primary trial endpoint was to determine the effect of adding WBRT to local treatment on distant intracranial control, and the secondary endpoints were neurocognitive function, quality of life (QoL), performance status, overall survival, death from intracranial causes, death from melanoma and cost-effectiveness.

Objective: The objective of this update is to outline and publish the pre-determined statistical analysis plan (SAP) before the database lock and the start of analysis.

Methods: The SAP describes basic analysis principles, methods for dealing with a range of commonly encountered data analysis issues and the specific statistical procedures for analysing efficacy and safety outcomes. The SAP was approved after closure of recruitment and before completion of patient follow-up. It outlines the planned primary analyses and a range of subgroup and sensitivity analyses regarding the clinical and QoL outcomes. Health economic outcomes are not included in this plan but will be analysed separately. The SAP will be adhered to for the final data analysis of this trial to avoid analysis bias arising from knowledge of the data.

Results: The resulting SAP is consistent with best practice and will allow open and transparent reporting.

Conclusion: We have developed a SAP for the WBRTMel trial which will be followed to ensure high-quality standards of internal validity to minimise analysis bias.

Trial Registration: ANZ Clinical Trials Registry, ACTRN12607000512426 . Registered on 9 October 2007. ClinicalTrials.gov, NCT01503827 . Registered on 4 January 2012. Trial group reference numbers ANZMTG 01.07, TROG 08.05.
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http://dx.doi.org/10.1186/s13063-019-3555-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6683544PMC
August 2019

Primary anorectal melanoma: clinical, immunohistology and DNA analysis of 43 cases.

Pathology 2019 Jan 26;51(1):39-45. Epub 2018 Nov 26.

Melanoma Institute Australia, The University of Sydney, Sydney, Australia; Royal Prince Alfred Hospital, Sydney, Australia; Sydney Medical School, The University of Sydney, Sydney, Australia. Electronic address:

Primary melanoma involving the anorectal region is rare, accounting for <1% of all melanomas in most Western countries. It characteristically presents at an advanced clinical stage and is associated with poor clinical outcomes. Preliminary reports suggest that response rates to immunotherapies in patients with advanced stage mucosal melanoma are much lower than in cutaneous (or acral) melanoma patients but reasons for this are unclear. Comprehensive characterisation of the immune microenvironment in anorectal melanoma has not previously been performed. A single-institution cohort of 43 primary anorectal melanoma patients was examined to describe clinicopathological features and characterise the immune microenvironment to provide insights into the behaviour of this rare melanoma subtype. The tumours displayed multiple adverse prognostic attributes including deep thickness (median 11.5 mm), ulceration (81%) and high mitotic rate (median 12/mm). The median overall survival was 24 months and the median recurrence-free survival was 9 months. Tumour-infiltrating lymphocytes (TILs) were absent or mild in most tumours (75%); PD-L1 positive staining (>1% of tumour cells) was present in 44% of cases, however in 86% of positive tumours the percentage of positive cells was ≤10%. Four tumours underwent whole genome sequencing; no ultraviolet signature was identified, and there was a lower mutational load but higher structural chromosomal variant load compared with cutaneous melanomas. Poor responses of anorectal melanomas to immunotherapy may be caused by lower immunogenicity of these tumours as characterised by low mutation burden (and therefore low neoantigenicity), low TILs infiltrates and low PD-L1 expression. Further investigation is required to determine whether TILs and PD-L1 expression predict response to immunotherapy in patients with mucosal melanoma.
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http://dx.doi.org/10.1016/j.pathol.2018.09.060DOI Listing
January 2019

ASO Author Reflections: Long-Term Survival of Patients with Thin (T1) Cutaneous Melanomas.

Ann Surg Oncol 2018 12 9;25(Suppl 3):918-919. Epub 2018 Nov 9.

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

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http://dx.doi.org/10.1245/s10434-018-7014-4DOI Listing
December 2018

Comment on "Prognostic value of sentinel lymph node biopsy according to Breslow thickness for cutaneous melanoma".

J Am Acad Dermatol 2019 01 15;80(1):e21-e22. Epub 2018 Sep 15.

Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia; Sydney Medical School, The University of Sydney, Sydney, NSW, Australia; Royal Prince Alfred Hospital, Camperdown, NSW, Australia. Electronic address:

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http://dx.doi.org/10.1016/j.jaad.2018.07.068DOI Listing
January 2019

Reply to M. Horiguchi et al.

J Clin Oncol 2018 03 16;36(7):722-723. Epub 2018 Jan 16.

Serigne N. Lo, Melanoma Institute Australia and the University of Sydney, Sydney, New South Wales, Australia; and Shahneen Sandhu, Peter MacCallum Cancer Centre and University of Melbourne, Melbourne, Victoria, Australia.

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http://dx.doi.org/10.1200/JCO.2017.76.5347DOI Listing
March 2018

Long-Term Survival of Patients with Thin (T1) Cutaneous Melanomas: A Breslow Thickness Cut Point of 0.8 mm Separates Higher-Risk and Lower-Risk Tumors.

Ann Surg Oncol 2018 Apr 12;25(4):894-902. Epub 2018 Jan 12.

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

Background: Counterintuitively, more deaths from melanoma occur among patients with thin (T1) primary melanomas (≤ 1 mm) than among those with thick primary melanoma because the great majority present with T1 tumors. Therefore, it is important to stratify their risk as accurately as possible to guide their management and follow-up. This study sought to explore the relationship between tumor thickness and prognosis for patients with thin primary melanomas.

Methods: A retrospective, single-institution study investigated 6263 patients with cutaneous melanoma (including 2117 T1 cases) who had a minimum follow-up period of 10 years.

Results: For the entire patient cohort, the 10-year melanoma-specific survival (MSS) rate ranged between 92% for the patients with primary melanomas up to 0.3 mm thick and 32% for those with melanomas thicker than 8 mm. When divided into 25-quantile-thickness groups there was a significant difference in 10-year MSS between the two consecutive groups 0.8 and 0.9 mm; the differences in survival were not significantly different for any other consecutive cut points within the less than or equal to 1 mm thickness range, indicating a biologically-relevant difference in outcome above and below 0.8 mm. For the patients treated initially at the authors' institution, the 10- and 20-year MSS rates for those with tumors up to 0.8 mm thick were respectively 93.4 and 85.7%, and for tumors 0.9 to 1.0 mm, the rates were respectively 81.1 and 71.4%. Only 29.3% of the T1 patients who died of melanoma were deceased within 5 years.

Conclusions: A naturally occurring thickness cut point of 0.8 mm predicts higher or lower risk for patients with thin primary cutaneous melanomas. Long-term follow-up assessment of patients with T1 melanoma is important because late mortality due to melanoma is more common than early mortality.
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http://dx.doi.org/10.1245/s10434-017-6325-1DOI Listing
April 2018

Accurate p-values for adaptive designs with binary endpoints.

Stat Med 2017 Jul 3;36(17):2643-2655. Epub 2017 May 3.

Melanoma Institute Australia, North Sydney, NSW, Australia.

Adaptive designs encompass all trials allowing various types of design modifications over the course of the trial. A key requirement for confirmatory adaptive designs to be accepted by regulators is the strong control of the family-wise error rate. This can be achieved by combining the p-values for each arm and stage to account for adaptations (including but not limited to treatment selection), sample size adaptation and multiple stages. While the theory for this is novel and well-established, in practice, these methods can perform poorly, especially for unbalanced designs and for small to moderate sample sizes. The problem is that standard stagewise tests have inflated type I error rate, especially but not only when the baseline success rate is close to the boundary and this is carried over to the adaptive tests, seriously inflating the family-wise error rate. We propose to fix this problem by feeding the adaptive test with second-order accurate p-values, in particular bootstrap p-values. Secondly, an adjusted version of the Simes procedure for testing intersection hypotheses that reduces the built-in conservatism is suggested. Numerical work and simulations show that unlike their standard counterparts the new approach preserves the overall error rate, at or below the nominal level across the board, irrespective of the baseline rate, stagewise sample sizes or allocation ratio. Copyright © 2017 John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/sim.7324DOI Listing
July 2017

Semiparametric methods for multistate survival models in randomised trials.

Stat Med 2014 May 13;33(10):1621-45. Epub 2013 Dec 13.

NHMRC Clinical Trials Centre, University of Sydney, New South Wales 2006, Australia; The George Institute, University of Sydney, New South Wales 2050, Australia; Department of Statistics, Macquarie University, North Ryde, New South Wales 2109, Australia.

Transform methods have proved effective for networks describing a progression of events. In semi-Markov networks, we calculated the transform of time to a terminating event from corresponding transforms of intermediate steps. Saddlepoint inversion then provided survival and hazard functions, which integrated, and fully utilised, the network data. However, the presence of censored data introduces significant difficulties for these methods. Many participants in controlled trials commonly remain event-free at study completion, a consequence of the limited period of follow-up specified in the trial design. Transforms are not estimable using nonparametric methods in states with survival truncated by end-of-study censoring. We propose the use of parametric models specifying residual survival to next event. As a simple approach to extrapolation with competing alternative states, we imposed a proportional incidence (constant relative hazard) assumption beyond the range of study data. No proportional hazards assumptions are necessary for inferences concerning time to endpoint; indeed, estimation of survival and hazard functions can proceed in a single study arm. We demonstrate feasibility and efficiency of transform inversion in a large randomised controlled trial of cholesterol-lowering therapy, the Long-Term Intervention with Pravastatin in Ischaemic Disease study. Transform inversion integrates information available in components of multistate models: estimates of transition probabilities and empirical survival distributions. As a by-product, it provides some ability to forecast survival and hazard functions forward, beyond the time horizon of available follow-up. Functionals of survival and hazard functions provide inference, which proves sharper than that of log-rank and related methods for survival comparisons ignoring intermediate events.
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http://dx.doi.org/10.1002/sim.6060DOI Listing
May 2014

An adaptive confirmatory trial with interim treatment selection: practical experiences and unbalanced randomization.

Stat Med 2011 Jun 22;30(13):1541-54. Epub 2011 Mar 22.

The George Institute, Sydney, Australia.

This article has been motivated by an ongoing international adaptive confirmatory trial. At the interim analysis of this two-stage trial, none, one or two active treatment regimens are selected for further study in the second stage. A combination test approach is used in this practical setting with an extension of the theory to unbalanced randomization. We show that a combination test with suitable weights can still preserve the overall Type I error rate provided that the test statistic is chosen appropriately and the unpooled Z-test for proportions is not used. The accuracy of stagewise p-values is also discussed in a more general framework. Monte Carlo simulations confirm the validity of the approach retained and evaluate the necessary sample size. Additional issues addressed during the design of the trial are also examined such as multiplicity due to testing hypotheses on key secondary endpoints, a non-inferiority comparison to an active treatment and covariate adjusted analyses for various types of outcome.
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http://dx.doi.org/10.1002/sim.4179DOI Listing
June 2011
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