18F-labelled fluorodeoxyglucose–positron emission tomography (FDG–PET) heterogeneity of response is prognostic in dabrafenib treated BRAF mutant metastatic melanoma

BackgroundLittle is known about the prevalence and clinical significance of heterogeneity of positron emission tomography with ¹⁸F-labelled fluorodeoxyglucose–positron emission tomography (FDG–PET) response. We aim to determine the prevalence, and clinicopathologic correlates of intra-patient heterogeneity of FDG–PET response in metastatic melanoma treated with dabrafenib, and to determine whether heterogeneity predicts clinical outcome.MethodsPatients with BRAF mutant metastatic melanoma and ?2 FDG avid lesions treated on the Phase I trial of dabrafenib at a single institution (n = 23) were included. FDG–PET response was assessed by comparing baseline PET scans with scans at day 15. A heterogeneous response was defined as responding and new or metabolically progressing lesion(s) in a patient, or >10% of lesions with a stable metabolic response and responding lesions in a patient.ResultsSix (26%) patients had a heterogeneous PET response. The median time to progression (TTP) was 7.4 months (95% confidence interval (CI): 6.5–8.3) for PET homogeneous responders and 3.0 months (95% CI: 0.6–5.4) for PET heterogeneous responders. There were no homogeneous non-responders. Age, BRAF mutation genotype, dose, and lactate dehydrogenase, did not predict for heterogeneity of PET response. Heterogeneity did not correlate with tumour response. Lung metastases were more likely to respond than other visceral metastatic sites.ConclusionsHeterogeneous FDG–PET responses are common in metastatic melanoma treated with dabrafenib, and heterogeneity is associated with a shorter TTP. FDG–PET heterogeneity may predict molecular heterogeneity, and FDG–PET directed biopsies may facilitate investigation into mechanisms of resistance to signal pathway inhibitors.     

18-fluorodeoxy-glucose positron emission computed tomography as predictive of response after chemoradiation in oesophageal cancer patients

IntroductionThe purpose of this study was to evaluate if a baseline, an interim or a post-chemoradiation (CTRT) 18-fluorodeoxy-glucose positron emission computed tomography (18F-FDG PET/CT) studies could provide information on pathologic response to CTRT and overall survival (OS).Materials and methodsThirty-one patients with histologically proven adenocarcinoma or squamous cell carcinoma of the oesophagus, fit for trimodality therapy were prospectively enrolled. Most were men (93.5%), and had a stage III cancer (74.2%). Chemotherapy consisted of oxaliplatin/5-fluorouracil (45.2%) and taxane/5-fluorouracil (54.8%). All patients underwent a baseline, an interim (performed 12 ± 2 days after the onset of CTRT) and a post-CTRT 18F-FDG PET/CT study. The 18F-FDG PET/CT variables evaluated were at baseline, interim and post-CTRT studies maximum standardised uptake value (SUVmax) and total lesion glycolysis (TLG). Clinical and 18F-FDG PET/CT parameters were correlated with pathologic complete response (pathCR) and OS.ResultsAmong the 31 patients studied, 61.3% achieved a clinical complete response (cCR) and 87.1% had surgery. The median OS was 35.1 months (95% confidence interval (CI): 19.9–NA). PathCR rate was 22.2%. There was only a marginal association between cCR and pathCR (p = 0.06). None of the other variables was predictive of pathCR. There was association between OS and baseline TLG (p = 0.03) at the optimal cutoff TLG value of 75.15. Additionally, TLG and ΔTLG post-CTRT were also associated with OS (p = 0.01 and 0.03, respectively).ConclusionNone of the PET parameters is predictive of pathCR but TLG at baseline and post-CTRT are prognostic of OS.     

The Registration of Diagnostic versus Planning Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography in Radiotherapy Planning for Non-small Cell Lung Cancer

AimsRadiotherapy for non-small cell lung cancer (NSCLC) increasingly utilises fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) fusion. However, it is unknown whether a PET/CT scan conducted in the treatment position results in more accurate registration to the radiotherapy planning CT (rCT) than a diagnostic PET/CT scan. The aim of this study was to compare the accuracy of registration of the CT components of the planning PET/CT scan (pCT) and diagnostic PET/CT scan (dCT) scan with the rCT.Materials and methodsTen patients with stage I–III NSCLC underwent an rCT immediately followed by a planning PET/CT scan, both carried out with arms placed above the head and immobilisation in the treatment position. All previously underwent a diagnostic FDG PET/CT, which was carried out with the arms above the head, but without custom immobilisation. dCT and pCT were registered to the rCT using a rigid body mutual information algorithm. Four observers identified 12 anatomical points on each scan and differences in their absolute location were analysed.ResultsAt the carina, the mean absolute error (MAE) for pCT–rCT compared with dCT–rCT was 4.37 versus 5.73 mm (P = 0.028). However, there was no significant difference in the root mean squared error (RMSE) for that point. There were no significant differences in MAE or RMSE for all other anatomical points. The MAE for all points was 4.11 versus 4.15 mm (P = NS) and RMSE was 4.40 versus 4.48 mm for pCT–rCT compared with dCT–rCT (P = NS).ConclusionsThere is an average of 4 mm of misregistration when registering the CT components of PET/CT scans to the rCT for NSCLC. Using a rigid registration technique, the registration of a diagnostic PET/CT is as good as the registration of a planning PET/CT.     

Hepatocellular carcinoma surveillance and appropriate treatment options improve survival for patients with liver cirrhosis

Objective/aimHepatocellular carcinoma (HCC) surveillance is a common practice for patients with liver cirrhosis. The aims of the study were to assess impacts of surveillance and therapeutic options on survival of patients with HCC.MethodsA total of 1436 cirrhotic patients with newly diagnosed HCC were enrolled between January 2002 and December 2004. Patients with HCC detected within periodic surveillance were the surveillance group (n = 318, 22.1%). The other patients with HCC incidentally detected were the non-surveillance group (n = 1118, 77.95%). Initial treatment options were recorded and overall survival was analysed.ResultsCompared with patients in the non-surveillance group, larger proportions of patients in the surveillance group possessed small tumours, at an early stage without vascular invasion or metastases, and afforded more curative treatment options including surgical resection, radiofrequency ablation and percutaneous ethanol injection. The overall survival was better for patients in surveillance (3-year survival rate: 59.1% versus 29.3%, p < 0.001), early stages by Barcelona Clinic Liver Cancer (BCLC) staging or curative treatment options. Multivariate analysis demonstrated surveillance, hepatitis aetiology, alpha-fetoprotein, tumour gross type, tumour stage and treatment options were associated factors for patients’ survival. Moreover, surveillance patients in curative BCLC stage following the treatment guideline for HCC proposed by the American association for the study of liver disease (AASLD) had a significantly better 3-year survival rate (77.1% versus 55.2%, p < 0.001).ConclusionsHCC surveillance for cirrhotic patients could detect HCC at early and curative stages. However, appropriate treatment options following AASLD guideline further improve the survival for patients in early stage.     

Early assessment with 18F-fluorodeoxyglucose positron emission tomography/computed tomography can help predict the outcome of neoadjuvant chemotherapy in triple negative breast cancer

BackgroundIn patients with triple-negative breast cancer (TNBC), pathology complete response (pCR) to neoadjuvant chemotherapy (NAC) is associated with improved prognosis. This prospective study was designed and powered to investigate the ability of interim ¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography (¹⁸FDG-PET/CT) to predict pathology outcomes to NAC early during treatment.Patients and methodsConsecutive TNBC women underwent ¹⁸FDG-PET/CT at baseline and after two courses of NAC. Maximum standardised uptake value (SUV_max) in the primary tumour and lymph nodes at each examination and the evolution (ΔSUV_max) between the two scans were measured. NAC was continued irrespective of PET results. Correlations between PET parameters and pathology response, and between PET parameters and event-free survival (EFS), were examined.ResultsFifty patients without distant metastases were enroled. At completion of NAC, surgery showed pCR in 19 patients, while 31 had residual tumour. Mean follow-up was 30.3 months. Thirteen patients, all with residual tumour, experienced relapse. Of all assessed clinical, biological and PET parameters, ΔSUV_max in the primary tumour was the most predictive of pathology results (p < 0.0001; Mann–Whitney-U test) and EFS (p = 0.02; log rank test). A threshold of 42% decrease in SUV was identified because it offered the best accuracy in predicting EFS. There were 32 metabolic responders (⩾42% decrease in SUV_max) and 18 non-responders. Within responders, the pCR rate was 59% and the 3-year EFS 77.5%. In non-responders, the pCR rate was 0% and the 3-year EFS 47.1%.ConclusionInterim ¹⁸FDG can early predict the inefficacy of NAC in TNBC patients. It shows promise as a potential contributory biomarker in these patients.     

Efficacy and safety of ipilimumab 3 mg/kg in patients with pretreated,metastatic, mucosal melanoma

BackgroundMucosal melanoma is an extremely rare and aggressive malignancy that often remains undetected until it reaches an advanced stage, when effective treatment options are limited. The activity and safety of ipilimumab were assessed in an Expanded Access Programme (EAP) that included patients with metastatic, mucosal melanoma.MethodsIpilimumab was available upon physician request for patients aged ⩾16 years with stage III (unresectable) or IV skin, ocular or mucosal melanoma, who had failed or did not tolerate previous treatments and had no other therapeutic option available. Patients received ipilimumab 3 mg/kg every 3 weeks for four doses. Patients with stable disease or an objective response to ipilimumab were eligible for retreatment upon disease progression. Tumour assessments were conducted at baseline and week 12 using immune-related response criteria. Patients were monitored for adverse events (AEs), including immune-related AEs, within 3 to 4 days of each scheduled visit.ResultsOf 855 patients participating in the EAP in Italy, 71 (8%) had metastatic, mucosal melanoma. With a median follow-up of 21.8 months, the response rate was 12% and the immune-related disease control rate was 36%. Median progression-free survival and overall survival were 4.3 and 6.4 months, respectively. In total, 34% of patients reported treatment-related AEs of any grade, which were grade 3 or 4 in 9% of patients. AEs were generally manageable as per protocol-specific guidelines.Conclusion/interpretationIpilimumab may be a feasible treatment option in pretreated patients with metastatic mucosal melanoma, and warrants further investigation in prospective clinical trials.     

Neuronal autoantibodies associated with cognitive impairment in melanoma patients

BackgroundCancer-related cognitive impairment is an important complication in cancer patients, yet the underlying mechanisms remain unknown. Over the last decade, the field of paraneoplastic neurological syndromes has been dramatically changed by the discovery of new neuronal autoantibodies, some of them associated with cognitive impairment. We aimed to assess the prevalence of neuronal autoantibodies in melanoma patients and their association with neurological and cognitive dysfunction.Patients and methodsA total of 157 consecutive melanoma patients with a median age of 63 years were recruited at the Department of Dermatology, Charité—Universitätsmedizin Berlin and tested for neuronal autoantibodies. A comprehensive neuropsychological assessment was carried out in a selected subgroup of 84 patients after exclusion of patients with confounding factors for a cognitive dysfunction, including brain metastases, relevant medication, and neurological disorders.ResultsNeuronal autoantibodies were found in 22.3% of melanoma patients. The most frequent antibodies were IgA/IgM anti-NMDAR antibodies. Applying the International Cognition and Cancer Task Force criteria, 36.9% had cognitive impairment, however, with a threefold higher odds in antibody-positive compared with antibody-negative patients (57.1% versus 30.2%, OR = 3.1, 95% CI: 1.1 to 8.6; P = 0.037). In patients with anti-NMDAR antibodies, this impairment increased with higher antibody titers (P = 0.007). Antibody-positive patients had a significantly impaired overall cognitive performance (z-value: −0.38 ± 0.69 versus 0.00 ± 0.56; P = 0.014) as well as significant impairments in tests of memory, attention, and executive function. In a multiple linear regression analysis, autoantibodies were an independent risk factor for cognitive impairment (B = −0.282; 95% CI: −0.492 to −0.071; P = 0.009). Autoantibody seropositivity was associated with immune checkpoint inhibitor treatment and a history of autoimmune diseases.ConclusionsA large number of melanoma patients harbor neuronal autoantibodies that are associated with significant cognitive impairment affecting memory, attention, and executive function. Neuronal autoantibodies might represent a pathophysiological factor and possible biomarker in the development of cancer-related cognitive impairment.     

Indoleamine 2,3-dioxygenase, a new prognostic marker in sentinel lymph nodes of melanoma patients

BackgroundIndoleamine 2,3-dioxygenase (IDO), an enzyme with immunosuppressive properties is considered as a factor that impairs the antitumour immune response in melanoma. In this study, we investigated the expression of IDO in sentinel nodes of melanoma patients to determine its prognostic relevance.Patients and methodsOne hundred and sixteen melanoma patients were enrolled in this study with a median follow-up time after diagnosis of 71 months. The expression of IDO and forkhead box P3 (Foxp3) in the sentinel lymph nodes was determined by immunohistochemistry and correlated with progression-free survival and overall survival. In 42 patients, regulatory T cells were investigated by flow cytometry.ResultsCox regression survival analysis showed a significant negative effect of IDO expression on progression-free survival (p = 0.015) and overall survival (p = 0.010). High IDO expression was correlated with a significant higher frequency of Foxp3-positive cells in uninvaded lymph nodes (p = 0.016). The presence of IDO expression in the sentinel nodes was not associated with an increased frequency of circulating regulatory T cells (Tregs) but was significantly correlated with an increased mean fluorescence intensity of Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) in Tregs (p = 0.019). After CD3CD28 stimulation, peripheral blood mononuclear cells of patients with high IDO expression showed a lower production of interferon-gamma (IFN-γ) (p = 0.025).ConclusionsThis study points to an independent predictive role of IDO on survival, especially in melanoma patients with uninvolved sentinel nodes. Investigating IDO expression in the sentinel nodes of melanoma patients may be a useful marker to pre-identify patients with a less favourable prognosis in stage I and II disease.     

BRAF mutation status is an independent prognostic factor for resected stage IIIB and IIIC melanoma: Implications for melanoma staging and adjuvant therapy

Background5-year survival for melanoma metastasis to regional lymph nodes (American Joint Committee on Cancer stage III) is <50%. Knowledge of outcomes following therapeutic lymphadenectomy for stage III melanoma related to BRAF status may guide adjuvant use of BRAF/MEK inhibitors along with established and future therapies.AimsTo determine patterns of melanoma recurrence and survival following therapeutic lymph node dissection (TLND) associated with oncogenic mutations.MethodsDNA was obtained from patients who underwent TLND and had ⩾2 positive nodes, largest node >3 cm or extracapsular invasion. Mutations were detected using an extended Sequenom MelaCARTA panel.ResultsMutations were most commonly detected in BRAF (57/124 [46%] patients) and NRAS (26/124 [21%] patients). Patients with BRAF mutations had higher 3-year recurrence rate (77%) versus 54% for BRAF wild-type patients (hazard ratio (HR) 1.8, p = 0.008). The only prognostically significant mutations occurred in BRAF: median recurrence-free (RFS) and disease-specific survival (DSS) for BRAF mutation patients was 7 months and 16 months, versus 19 months and not reached for BRAF wild-type patients, respectively. Multivariate analysis identified BRAF mutant status and number of positive lymph nodes as the only independent prognostic factors for RFS and DSS.ConclusionsPatients with BRAF mutations experienced rapid progression of metastatic disease with locoregional recurrence rarely seen in isolation, supporting incorporation of BRAF status into melanoma staging and use of BRAF/MEK inhibitors post-TLND.     

Conditional survival of malignant melanoma in The Netherlands: 1994–2008

BackgroundCutaneous malignant melanoma causes the majority of skin cancer related deaths and features increasing incidence and mortality rates in the Netherlands. Conditional survival analysis is performed on patients who survived the preceding year(s).MethodsPatients with invasive melanoma, as recorded in the population-based Netherlands Cancer Registry, were included. To assess prognosis of melanoma survivors according to gender and Breslow thickness, conditional five-year relative survival was calculated for lymph node negative melanoma patients and conditional one-year relative survival was analysed for melanoma patients with and without nodal involvement.FindingsBetween 1994 and 2008, 40,050 patients developed a melanoma (stage I–III, of whom 6% with nodal involvement). Six to 8 years after diagnosis, survival of patients with a 1–2 mm (T2) thick melanoma equalised the general population. Conditional five-year relative survival for patients with >4 mm thick (T4) melanomas increased from about 60% at diagnosis to 90% at 7 years after diagnosis. Largest improvements were found in patients with thick melanomas and female patients with nodal involvement.InterpretationThe prognosis for melanoma survivors improved with each additional year of survival after diagnosis, except for patients with a ⩽1 mm thick melanoma, who never had any excess mortality during follow-up. Conditional survival of melanoma was better amongst females, amongst those with lower Breslow thickness and nodal stage.     

Pre-operative ctDNA predicts survival in high-risk stage III cutaneous melanoma patients

BackgroundThe outcomes of patients with stage III cutaneous melanoma who undergo complete surgical resection can be highly variable, and estimation of individual risk of disease recurrence and mortality remains imprecise. With recent demonstrations of effective adjuvant targeted and immune checkpoint inhibitor therapy, more precise stratification of patients for costly and potentially toxic adjuvant therapy is needed. We report the utility of pre-operative circulating tumour DNA (ctDNA) in patients with high-risk stage III melanoma.Patients and methodsctDNA was analysed in blood specimens that were collected pre-operatively from 174 patients with stage III melanoma undergoing complete lymph node (LN) dissection. Cox regression analyses were used to evaluate the prognostic significance of ctDNA for distant metastasis recurrence-free survival and melanoma-specific survival (MSS).ResultsThe detection of ctDNA in the discovery and validation cohort was 34% and 33%, respectively, and was associated with larger nodal melanoma deposit, higher number of melanoma involved LNs, more advanced stage and high lactate dehydrogenase (LDH) levels. Detectable ctDNA was significantly associated with worse MSS in the discovery [hazard ratio (HR) 2.11 P < 0.01] and validation cohort (HR 2.29, P = 0.04) and remained significant in a multivariable analysis (HR 1.85, P = 0.04). ctDNA further sub-stratified patients with AJCC stage III substage, with increasing significance observed in more advanced stage melanoma.ConclusionPre-operative ctDNA predicts MSS in high-risk stage III melanoma patients undergoing complete LN dissection, independent of stage III substage. This biomarker may have an important role in determining prognosis and stratifying patients for adjuvant treatment.     

443 paediatric cases of malignant melanoma registered with the German Central Malignant Melanoma Registry between 1983 and 2011

BackgroundMalignant melanoma is a very rare paediatric tumour. This study was performed in order to understand clinical features and prognosis of malignant melanoma in children and adolescents.Methods443 patients ⩽18 years of age with malignant melanoma were prospectively registered with the German Central Malignant Melanoma Registry between 1983 and 2011. Cases were collected from 58 participating centres. 276 paediatric cases with a follow-up >3 months were evaluated for survival probabilities and prognostic factors by Kaplan–Meier method.ResultsAge of diagnosis ranged from 3 months to 18 years (median age 16 years). The male to female ratio was 0.8 (202 male, 240 female). Most melanoma were located at the trunk (n = 195) and the lower extremity (n = 114). Patients with >3 months of follow-up (median 55 months) showed an overall survival (OS) of 94.8% in 5 years. Survival according to tumour stage was 98.5% for stage I (n = 190), 91.1% for stage II (n = 39) and 53.0% for stage III/IV tumours (n = 11). Worse outcome was seen in patients with nodular melanoma (OS 77.9%, n = 42) compared to superficial spread histotype (OS 100%, n = 138) or other histotype (OS 96.9%, n = 88) (p < 0.0001), in case of thicker tumours (Clark level IV or V, OS 87.1%, n = 84) compared to thinner tumours (Clark level I, II, III, OS 99.1%, n = 164) (p = 0.0008) and in case of ulceration (OS 65.6%, n = 17) compared to no ulceration (OS 99.2%, n = 182).ConclusionPatient and tumour characteristics in paediatric melanoma patients show no evident differences to adult melanoma cases. The same clinical approach as in adults should be used.     

Adjuvant bevacizumab for melanoma patients at high risk of recurrence: survival analysis of the AVAST-M trial

BackgroundBevacizumab is a recombinant humanised monoclonal antibody to vascular endothelial growth factor shown to improve survival in advanced solid cancers. We evaluated the role of adjuvant bevacizumab in melanoma patients at high risk of recurrence.Patients and methodsPatients with resected AJCC stage IIB, IIC and III cutaneous melanoma were randomised to receive either adjuvant bevacizumab (7.5 mg/kg i.v. 3 weekly for 1 year) or standard observation. The primary end point was detection of an 8% difference in 5-year overall survival (OS) rate; secondary end points included disease-free interval (DFI) and distant metastasis-free interval (DMFI). Tumour and blood were analysed for prognostic and predictive markers.ResultsPatients (n=1343) recruited between 2007 and 2012 were predominantly stage III (73%), with median age 56 years (range 18–88 years). With 6.4-year median follow-up, 515 (38%) patients had died [254 (38%) bevacizumab; 261 (39%) observation]; 707 (53%) patients had disease recurrence [336 (50%) bevacizumab, 371 (55%) observation]. OS at 5 years was 64% for both groups [hazard ratio (HR) 0.98; 95% confidence interval (CI) 0.82–1.16, P = 0.78). At 5 years, 51% were disease free on bevacizumab versus 45% on observation (HR 0.85; 95% CI 0.74–0.99, P = 0.03), 58% were distant metastasis free on bevacizumab versus 54% on observation (HR 0.91; 95% CI 0.78–1.07, P = 0.25). Forty four percent of 682 melanomas assessed had a BRAF^V600 mutation. In the observation arm, BRAF mutant patients had a trend towards poorer OS compared with BRAF wild-type patients (P = 0.06). BRAF mutation positivity trended towards better OS with bevacizumab (P = 0.21).ConclusionsAdjuvant bevacizumab after resection of high-risk melanoma improves DFI, but not OS. BRAF mutation status may predict for poorer OS untreated and potential benefit from bevacizumab.Clinical Trial InformationISRCTN 81261306; EudraCT Number: 2006-005505-64     

Clinical and histopathological risk factors to predict sentinel lymph node positivity, disease-free and overall survival in clinical stages I–II AJCC skin melanoma: Outcome analysis from a single-institution prospectively collected database

BackgroundTo investigate if the tumour infiltrating lymphocytes (TILs) are able to predict the sentinel lymph node (SLN) positivity, the disease-free survival (DFS) and overall survival (OS) in clinical stages I-II AJCC primary cutaneous melanoma (PCM).MethodsThe study included consecutive patients with PCM, all diagnosed, treated and followed up prospectively. Logistic regression was used to investigate the association between DFS, OS, SLN positivity and Breslow thickness, Clark level, TIL, ulceration, lesion site, gender, regression and age.ResultsFrom November 1998 to October 2008, 1251 consecutive patients with PCM were evaluated. Median age was 51 (range 15–96) with 32.2% (N = 393) of them older than 60; 44.8% of them were males. Of the whole series, a total of 404 patients with primary vertical growth phase (VGP) melanoma and no clinical evidence of metastatic disease underwent SLN biopsy. Of these, 74 (18.8%) had a positive SLN. In a multivariate analysis, primary melanoma on the extremities versus that on the axial locations (truncal and head/neck) (OR 0.49, 95% CI 0.25–0.98, p 0.04) and TILs (TILs versus no TILs) (OR 0.47, 95%CI 0.25–0.90, p 0.02) were predictive for lower probability of SLN involvement, while thickness (>4 mm versus 0–1 mm) (OR 24, 19, 95% CI 4.91–119.13, p < .001) was predictive for higher risk of SLN positivity. A multivariate stepwise analysis confirmed these results. The histological status of the SLN was the most significant predictor of DFS and OS. Patients with a negative SLN had a 5-year DFS of 75.9%, compared with 35.2% in patients with a positive SLN (p < .0001) and a 5-year OS of 88.7% versus 42.9%, respectively (p < .0001).ConclusionsOur study demonstrates that the absence of TILs predicts SLN metastasis, in multivariate analysis the SLN positivity predicts DFS and OS.     

FDG-PET response and outcome from anti-PD-1 therapy in metastatic melanoma

BackgroundImmune checkpoint inhibitor therapy has resulted in impressive and durable clinical activity for many cancers including melanoma; however, there remain few reliable predictors for long-term response. This study investigated whether [¹⁸F]2-fluoro-2-deoxy-D-glucose (FDG-PET) imaging may better predict long-term outcomes compared with standard computed tomography (CT) response criteria.Patients and methodsRetrospective analysis of metastatic melanoma patients treated with anti-PD-1-based immunotherapy with baseline and 1-year FDG-PET and CT imaging at Melanoma Institute Australia. One-year response was determined using RECIST for CT and EORTC criteria for PET, coded as complete response (CR or CMR), partial response (PR or PMR), stable disease (SD or SMD) or progressive disease (PD or PMD). Progression-free survival (PFS) was determined from the 1-year landmark.ResultsPatients (n = 104) were evaluated with median follow-up 30.1 months and 98% remain alive. Most received anti-PD-1 as monotherapy (67%) or combined with ipilimumab (31%). At 1 year, 28% had CR, 66% had PR and 6% had SD on CT, while 75% had CMR, 16% PMR and 9% SMD/PMD on PET. CMR was observed in 68% of patients with PR on CT. RECIST PFS post 1-year landmark was similar in patients with CR versus PR/SD, but improved in patients with CMR versus non-CMR {median not reached [NR] versus 12.8 month; hazard ratio [HR] 0.06 [95% confidence interval (CI) 0.02–0.23]; P < 0.01}. In patients with PR on CT, PFS was improved in patients with PR + CMR versus PR + non-CMR (median NR versus 12.8 months; HR 0.07 [95% CI 0.02–0.27]; P < 0.01). In the 78 CMR patients, 78% had discontinued treatment and 96% had ongoing response.ConclusionsWhilst only a small proportion of patients have a CR at 1 year, most patients with a PR have CMR on PET. Almost all patients with CMR at 1 year have ongoing response to therapy thereafter. PET may have utility in predicting long-term benefit and help guide discontinuation of therapy.     

Comparative study of YKL-40, S-100B and LDH as monitoring tools for Stage IV melanoma

BackgroundSerum markers can be important tools for the prognostic classification and the treatment monitoring in cancer patients. Recently, the potential new serum marker YKL-40 has been introduced for patients with malignant melanoma. The purpose of this study was to assess the prognostic value of YKL-40 in stage IV melanoma patients regarding treatment outcome and survival compared to the established markers LDH and serum S-100B and to evaluate their ability to discriminate between different stages of the disease.MethodsYKL-40, LDH and S-100B were measured in serum samples of 50 patients with stage I/II melanoma and 61 patients with metastatic melanoma before and after treatment. Univariate and multivariate analyses were performed to determine prognostic factors.ResultsYKL-40, S-100B and LDH correlated significantly with the stage of disease. In stage IV melanoma patients, only the baseline serum levels of S-100B were significantly associated with treatment response (p = 0.031), but not those of LDH (p = 0.193) or YKL-40 (p = 0.186). We found a strong correlation between treatment response and unchanged or declining S-100B levels over time (p = 0.003, OR: 9.52, 95%-CI: 1.87–47.62), but no significant correlation between treatment response and serum changes for LDH (p = 0.534) and YKL-40 (p = 0.306), respectively. In the Cox Regression analysis, only the serum levels of S-100B proved to have a significant prognostic impact on survival (p < 0.0001).ConclusionIn melanoma patients, serum levels of YKL-40, S-100B and LDH correlate significantly with the stage of disease. In stage IV melanoma, S100-B significantly correlates with treatment response and survival and is superior to LDH and YKL-40.     

A phase 2 study of vatalanib in metastatic melanoma patients

BackgroundA phase 2 study of vatalanib (PTK787/ZK222584) an oral tyrosine kinase inhibitor of VEGFR 1, 2 and 3 was undertaken in patients with metastatic melanoma.MethodsAdults with pathologically confirmed metastatic melanoma, WHO Performance status 0–2, and adequate haematological, hepatic and renal function, were treated with vatalanib until disease progression. The trial used Fleming’s single stage design.ResultsTumour control rate (CR + PR + SD) was 35% at 16 weeks, with objective response seen in only 1 patient. Median progression-free survival was 1.8 months (95% CI 1.8–3.7 months) and median overall survival was 6.5 months (95% CI 3.9–10.2 months).ConclusionVatalanib stabilised disease in a proportion of patients, although overall survival was disappointing.     

Clinical,pathological, and demographic factors associated with development of recurrences after surgical resection in elderly patients with neuroendocrine tumors

BackgroundIncidence of locoregional neuroendocrine tumors (NETs) is rising. However, after curative resection, the patterns and risk factors associated with recurrence remain unknown. Consensus guidelines recommend surveillance every 6–12 months for up to 10 years after surgery for resected, well-differentiated NETs irrespective of patient demographics, site, grade or stage of tumor with few exceptions.Patients and methodsFrom the Surveillance, Epidemiology, and End Results (SEER)-Medicare database, we identified localized and regional stage NET patients who underwent surgical resection between January 2002 and December 2011. Development of recurrence was identified by capturing at least two claims indicative of metastatic disease until 31 December 2013.ResultsOf the 2366 identified patients (median age 73 years), 369 (16%) developed metastatic disease within 5 years and only an additional 1% developed metastases between years 5 and 10 with the majority dying due to unrelated causes. The 5-year risk of developing metastases (hazard ratio, HR) varied significantly (log-rank P < 0.001) by grade: 9.9% versus 25.9% (2.2) versus 48.1% (4.4) for grades 1, 2, and  ≥ 3, respectively; stage: 10.3% versus 31.1% (2.8) for localized versus regional; primary tumor size: 7.6% versus 15% (1.3) versus 26.6% (1.5) for <1, 1–2, and > 2 cm, respectively; and site: ranging from 11.3% for colon to 23.9% for pancreas.ConclusionsContrary to current guidelines, our study suggests that surveillance recommendations should be tailored according to patient and tumor characteristics. Surveillance past 5 years may be avoided in elderly patients with competing morbidities or low risk of recurrence. Pancreatic, lung, higher grade, and regional NETs have a higher risk of recurrence and may be considered for future adjuvant trials.     

Long duration of immunotherapy before radiosurgery might improve intracranial control of melanoma brain metastases

PurposeDespite significant advances that have been made in management of metastatic melanoma with immune checkpoint therapy, optimal timing of combination immune checkpoint therapy and stereotactic radiosurgery is unknown. We have reported toxicity and efficiency outcomes of patients treated with concurrent immune checkpoint therapy and stereotactic radiosurgery.Patients and methodsFrom January 2014 to December 2016, we analyzed 62 consecutive patients presenting 296 melanoma brain metastases, treated with gamma-knife and receiving concurrent immune checkpoint therapy with anti-CTLA4 or anti-PD1 within the 12 weeks of SRS procedure. Median follow-up time was 18 months (mo) (13–22). Minimal median dose delivered was 18 gray (Gy), with a median volume per lesion of 0.219 cm³.ResultsThe 1-year control rate per irradiated lesion was 89% (CI 95%: 80.41–98.97). Twenty-seven patients (43.5%) developed distant brain metastases after a median time of 7.6 months (CI 95% 1.8–13.3) after gamma-knife. In multivariate analysis, positive predictive factors for intracranial tumor control were: delay since the initiation of immunotherapy exceeding 2 months before gamma-knife procedure (P = 0.003) and use of anti-PD1 (P = 0.006). Median overall survival (OS) was 14 months (CI 95%: 11–NR). Total irradiated tumor volume < 2.1 cm³ was a positive predictive factor for overall survival (P = 0.003). Ten patients (16.13%) had adverse events following irradiation, with four grade ≥ 3. Predictive factors of all grade toxicity were: female gender (P = 0.001) and previous treatment with MAPK (P = 0.05).ConclusionA long duration of immune checkpoint therapy before stereotactic radiosurgery might improve intracranial tumor control, but this relationship and its ideal timing need to be assessed in prospective trials.