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.     

Analysis of time-to-treatment discontinuation of targeted therapy,immunotherapy, and chemotherapy in clinical trials of patients with non-small-cell lung cancer

BackgroundPragmatic end points, such as time-to-treatment discontinuation (TTD), defined as the date of starting a medication to the date of treatment discontinuation or death has been proposed as a potential efficacy end point for real-world evidence (RWE) trials, where imaging evaluation is less structured and standardized.Patients and methodsWe studied 18 randomized clinical trials of patients with metastatic non-small-cell lung cancer (mNSCLC), initiated after 2007 and submitted to U.S. Food and Drug Administration. TTD was calculated as date of randomization to date of discontinuation or death and compared to progression-free survival (PFS) and overall survival (OS) across all patients, as well as in treatment-defined subgroups [EGFR mutation-positive treated with tyrosine kinase inhibitor (TKI), EGFR wild-type treated with TKI, ALK-positive treated with TKI, immune checkpoint inhibitor (ICI), chemotherapy doublet with maintenance, chemotherapy monotherapy].ResultsOverall across 8947 patients, TTD was more closely associated with PFS (r = 0.87, 95% CI 0.86–0.87) than with OS (0.68, 95% CI 0.67–0.69). Early TTD (PFS—TTD ≥ 3 months) occurred in 7.7% of patients overall, and was more common with chemo monotherapy (15.0%) while late TTD (TTD—PFS ≥ 3 months) occurred in 6.0% of patients overall, and was more common in EGFR-positive and ALK-positive patients (12.4% and 22.9%). In oncogene-targeted subgroups (EGFR positive and ALK positive), median TTDs (13.4 and 14.1 months) exceeded median PFS (11.4 and 11.3 months).ConclusionsAt the patient level, TTD is associated with PFS across therapeutic classes. Median TTD exceeds median PFS for biomarker-selected patients receiving oncogene-targeted therapies. TTD should be prospectively studied further as an end point for pragmatic randomized RWE trials only for continuously administered therapies.     

Long term survival with cytotoxic T lymphocyte-associated antigen 4 blockade using tremelimumab

PurposeOne of the hallmarks of cancer immunotherapy is the long duration of responses, evident with cytokines like interleukin-2 or a variety of cancer vaccines. However, there is limited information available on very long term outcomes of patients treated with anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) antibodies. Tremelimumab is an anti-CTLA-4 antibody of immunoglobulin G2 (IgG2) isotype initially tested in patients with advanced melanoma over 12 years ago.MethodsWe reviewed the outcomes of patients with advanced melanoma enrolled in four phase 1 and 2 tremelimumab trials at two sites to determine response rates and long-term survival.ResultsA total of 143 patients were enrolled at two institutions from 2002 to 2008. Tremelimumab administration varied between a single dose of 0.01 mg/kg and 15 mg/kg every 3 months. Median overall survival was 13 months (95% confidence interval (CI), 10–16.6), ranging from less than a month to 12+ years. An objective response rate of 15.6% was observed, with median duration of response of 6.5 years, range of 3–136+ months. The Kaplan–Meier estimated 5 year survival rate was 20% (95% CI, 13–26%), with 10 and 12.5 year survival rates of 16% (95% CI, 9–23%).ConclusionsCTLA-4 blockade with tremelimumab can lead to very long duration of objective anti-tumour responses beyond 12 years.     

Randomized phase III study of docetaxel plus bavituximab in previously treated advanced non-squamous non-small-cell lung cancer

BackgroundBavituximab is a monoclonal antibody that targets phosphatidylserine in the presence of β₂ glycoprotein 1 (β2GP1) to exert an antitumor immune response. This phase III trial determined the efficacy of bavituximab combined with docetaxel in patients with previously treated advanced non-small-cell lung cancer (NSCLC).Patients and methodsKey eligibility criteria included advanced non-squamous NSCLC with disease progression after treatment with platinum-based doublet chemotherapy, evidence of disease control after at least two cycles of first-line therapy, presence of measurable disease, ECOG performance status 0 or 1, adequate bone marrow and organ function, and no recent history of clinically significant bleeding. Eligible patients were randomized 1 : 1 to receive up to six 21-day cycles of docetaxel plus either weekly bavituximab 3 mg/kg or placebo until progression or toxicity. The primary end point was overall survival (OS).ResultsA total of 597 patients were enrolled. Median OS was 10.5 months in the docetaxel + bavituximab arm and was 10.9 months in the docetaxel + placebo arm (HR 1.06; 95% CI 0.88–1.29; P = 0.533). There was no difference in progression-free survival (HR 1.00; 95% CI 0.82–1.22; P = 0.990). Toxicities were manageable and similar between arms. In subset analysis, among patients with high baseline serum β2GP1 levels ≥200 µg/ml, a nonsignificant OS trend favored the bavituximab arm (HR 0.82; 95% CI 0.63–1.06; P = 0.134). Among patients who received post-study immune checkpoint inhibitor therapy, OS favored the bavituximab arm (HR 0.46; 95% CI 0.26–0.81; P = 0.006).ConclusionsThe combination of bavituximab plus docetaxel is not superior to docetaxel in patients with previously treated advanced NSCLC. The addition of bavituximab to docetaxel does not meaningfully increase toxicity. The potential benefit of bavituximab observed in patients with high β2GP1 levels and in patients subsequently treated with immune checkpoint inhibitors requires further investigation.Clinical trial numberNCT01999673.     

Efficacy of targeted therapies after PD-1/PD-L1 blockade in metastatic renal cell carcinoma

BackgroundMonoclonal antibodies that target the programmed death-1 (PD-1)/programmed death-ligand 1(PD-L1) pathway have shown antitumour activity in metastatic renal cell carcinoma (mRCC) and are currently being developed in first-line (in combination) and in previously treated patients. The efficacy targeted therapy (TT) after PD-1/PD-L1 blockade is still unknown.MethodsMedical records of mRCC patients treated with investigational PD-1 or PD-L1 inhibitors at 4 academic institutions were reviewed. Patients who received subsequent treatment with TT were selected to collect outcome measures of subsequent TT.ResultsOf 99 patients who received PD-1/PD-L1 blockade as part of clinical trials, 56 patients have received subsequent therapy: 44 patients received vascular endothelial growth factor (VEGF)/vascular endothelial growth factor receptor (VEGFR) inhibitors and 12 received mammalian target of rapamycin (mTOR) inhibitors as first subsequent TT. Median follow up, from the start of subsequent TT was 16.1 months (range: 0.2, 30.6 months). TT post PD-1/PD-L1 blockade was administered as second-line, third-line or beyond third-line in 9 (16%), 24 (43%) and 23 patients (41%) respectively. Median time to treatment failure on subsequent TT was 6.6 months (range: 0.2+, 23.0). 1-year and 2 year overall survival from the initiation of subsequent TT was 58% (95% confidence interval (CI): 41–72%) and 36% (95% CI: 18–54%), respectively.ConclusionBoth VEGF/VEGFR and mTOR inhibitors demonstrate antitumour activity following PD-1/PD-L1 blockade.     

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.     

Immune checkpoint blockade for unresectable or metastatic uveal melanoma: A systematic review

BackgroundThe use of immune checkpoint blockade (ICB) for uveal melanoma (UM) is little established. The aim of this review was to provide a comprehensive overview on the efficacy, safety, and tolerability of ICB in patients with UM.MethodsWe performed a systematic literature research covering MEDLINE, Embase and CENTRAL. Abstracts of pertinent conferences and trial registers were handsearched for relevant studies.ResultsOut of 1327 records initially identified, 12 eligible studies were included in the qualitative synthesis. They comprised 7 expanded access or named patient programs (n = 162), 4 phase II trials (n = 171), and 1 phase Ib trial (sample size unknown), while no randomized controlled trial was found. Ipilimumab monotherapy was assessed at 3 mg/kg in 5 trials (n = 186) with a response rate of 0 to 5%. Two reports investigated ipilimumab at 10 mg/kg (n = 45) with radiological responses observed in 0 to 6.5%. The median progression-free survival (PFS) was below 3 months and the median overall survival was 5.2–9.8 months for ipilimumab monotherapy. Severe immune-related adverse events occurred at a frequency comparable to cutaneous melanoma (6 to 36%). Two studies investigated pembrolizumab (2 mg/kg) and nivolumab (3 mg/kg) with overall response rates of 30% and 6%, respectively. Data on combined ipilimumab and programmed cell death protein 1 inhibition were available from one expanded access program, but no response was observed with a median PFS of 2.9 months.ConclusionsUM is little responsive to ipilimumab regardless of dosage schemes. Sound randomized clinical trials are needed to evaluate the efficacy of combined ICB in patients with UM.     

Toxicity and time lapse between immunotherapy and stereotactic radiotherapy of brain metastases

PurposeStereotactic radiotherapy (SRT) is the standard treatment for brain metastases of non-small-cell lung cancer (NSCLC) and melanoma, mostly in combination with immunotherapy. The objective was to retrospectively evaluate the influence of the time-lapse between immunotherapy and stereotactic radiotherapy on toxicity.Patients and methodsFrom 2016 to 2019, 59 patients treated with SRT for 103 brain metastases of NSCLC (60%) and melanoma (40%) in combination with concomitant immunotherapy (≤ 30 days) were included. The prescribed dose was 20 Gy/1f or 33 Gy/3f at the isocentre and 14 Gy or 23.1 Gy (70%) respectively at the PTV envelope (PTV = GTV + 2 mm). The mean tumour diameter was 14 mm (4–52 mm). The immunotherapies used were anti-PD1 and anti-PDL1. The 103 metastases were classified into 3 groups according to the time-lapse between instatement of immunotherapy and instatement of SRT for the patient concerned: 7 (7%) in group A (≤ 7 days), 38 (37%) in group B (7 to 14 days) and 58 (56%) in group C (14 to 30 days).ResultsThe mean follow-up was 10.1 months. The median overall survival was 11.5 months for NSCLC and 12.5 months for melanoma. The percentage of local control (LC) at one year was 65.1% (93.6% for NSCLC and 26.5% for melanoma). The time-lapse between immunotherapy and SRT was not a significant predictor of LC (P = 0.86), while the histology was (P < 0.001). The proportion of grade ≥ 3 toxicities was 5.1%, and that of radionecrosis was 9.7% (among these patients, 80% were non-symptomatic): 0%, 13.1% and 8.6% for groups A, B and C respectively. The time-lapse between immunotherapy and SRT was not a significant predictor of toxicity. Only tumour volume was a significant predictive factor (P = 0.03).ConclusionThe time lapse between immunotherapy and SRT does not influence brain toxicity. The tumour volume remains the main factor.     

Early surgery for failure after chemoradiation in operable thoracic oesophageal cancer. Analysis of the non-randomised patients in FFCD 9102 phase III trial: Chemoradiation followed by surgery versus chemoradiation alone

BackgroundTwo randomised trials concerning thoracic oesophageal cancer concluded that for squamous cell carcinoma, chemoradiation alone leads to the same overall survival (OS) as chemoradiation followed by surgery. One of these trials, FFCD 9102, randomised only fit, compliant and operable responders to induction chemoradiation between continuation of chemoradiation and surgery. In the present analysis, the outcome in the patients not eligible for randomisation was calculated to determine if attempt of surgery should be recommended.MethodsEligible patients had operable T3-N0/N1-M0 thoracic oesophageal cancer. After initial chemoradiation, patients with no clinical response, or with contraindication to follow any attributed treatment, were not randomised. OS was studied first in the whole population of not randomised patients, and then specifically in clinical non-responders. The impact of surgery on OS was studied in these two populations.FindingsOf the 451 registered patients in the trial, 192 were not randomised. Among them, 111 were clinical non-responders. Median OS was significantly shorter for non-randomised patients (11.5 months) than for randomised patients (18.9 months; p = 0.0024). However, for the 112 non-randomised patients who underwent surgery, median OS was not different from that in randomised patients: 17.3 versus 18.9 months (p = 0.58).Concerning clinical non-responders, median OS was longer for those who underwent surgery compared to non-operated patients: 17.0 versus 5.5 months (hazard ratio (HR) = 0.39 [0.25–0.61]; p < 0.0001), and again was not different from that in responding, randomised patients (p = 0.40).InterpretationIn patients with locally advanced thoracic oesophageal cancer, overall survival did not differ between responders to induction chemoradiation and patients having surgery after clinical failure of chemoradiation. Surgery should therefore be considered in those patients who are still operable.     

Progression-free survival at 24 months (PFS24) and subsequent outcome for patients with diffuse large B-cell lymphoma (DLBCL) enrolled on randomized clinical trials

BackgroundPatients with diffuse large B-cell lymphoma treated with first-line anthracycline-based immunochemotherapy and remaining in remission at 2 years have excellent outcomes. This study assessed overall survival (OS) stratified by progression-free survival (PFS) at 24 months (PFS24) using individual patient data from patients with DLBCL enrolled in multi-center, international randomized clinical trials as part of the Surrogate Endpoint for Aggressive Lymphoma (SEAL) Collaboration.Patients and methodsPFS24 was defined as being alive and PFS24 after study entry. OS from PFS24 was defined as time from identified PFS24 status until death due to any cause. OS was compared with each patient’s age-, sex-, and country-matched general population using expected survival and standardized mortality ratios (SMRs).ResultsA total of 5853 patients enrolled in trials in the SEAL database received rituximab as part of induction therapy and were included in this analysis. The median age was 62 years (range 18–92), and 56% were greater than 60 years of age. At a median follow-up of 4.4 years, 1337 patients (23%) had disease progression, 1489 (25%) had died, and 5101 had sufficient follow-up to evaluate PFS24. A total of 1423 assessable patients failed to achieve PFS24 with a median OS of 7.2 months (95% CI 6.8–8.1) after progression; 5-year OS after progression was 19% and SMR was 32.1 (95% CI 30.0–34.4). A total of 3678 patients achieved PFS24; SMR after achieving PFS24 was 1.22 (95% CI 1.09–1.37). The observed OS versus expected OS at 3, 5, and 7 years after achieving PFS24 was 93.1% versus 94.4%, 87.6% versus 89.5%, and 80.0% versus 83.7%, respectively.ConclusionPatients treated with rituximab containing anthracycline-based immunochemotherapy on clinical trials who are alive without progression at 24 months from the onset of initial therapy have excellent outcomes with survival that is marginally lower but clinically indistinguishable from the age-, sex-, and country-matched background population for 7 years after achieving PFS24.     

Long-term outcome in BRAFV600E melanoma patients treated with vemurafenib: Patterns of disease progression and clinical management of limited progression

IntroductionVemurafenib induces tumour regression in most patients with BRAF^V600E-mutant melanoma; eventually, most experience progressive disease (PD). Long-term follow-up of patients with BRAF^V600E melanoma treated in the phase 1 vemurafenib trial is reported.MethodsPatients received vemurafenib 240–1120 mg (dose escalation cohort) or 960 mg (extension cohort) orally twice daily. Clinical response was evaluated every 8 weeks by Response Evaluation Criteria In Solid Tumors (RECIST). Patients with PD amenable to local therapy (surgery or radiotherapy) were allowed to continue vemurafenib after progression. Overall survival (OS) from time of treatment initiation and from PD was estimated. Sites of PD were recorded.ResultsForty-eight patients (escalation cohort, n = 16; extension cohort, n = 32) received therapeutic doses of vemurafenib (⩾240 mg twice daily). Forty-four patients had PD by the time of this analysis and four remained progression free (follow-up time, 1.2–56.1 months). Median OS was 14 months (range, 1.2–56.1); 3- and 4-year melanoma-specific survival rate in the extension cohort was 26% and 19%, respectively. Median OS was 26.0 months (range, 7.7–56.1) among 20 patients who continued vemurafenib after local therapy. Median treatment duration beyond initial PD was 3.8 months (range, 1.1–26.6). In the extension cohort, six and five patients were alive after 3 and 4 years, respectively, on vemurafenib monotherapy.ConclusionsSome patients with melanoma achieved long-term survival with vemurafenib monotherapy. Continuation of vemurafenib after PD might be beneficial in some patients because remaining disease might continue to respond to BRAF inhibition.     

Clinical outcomes in patients receiving three lines of targeted therapy for metastatic renal cell carcinoma: Results from a large patient cohort

AimA number of targeted therapies (TTs) are effective in metastatic renal cell carcinoma (mRCC) but clinical outcomes with the sequential use of three TTs have been poorly investigated, this study evaluates their outcome.MethodsPatients with clear cells mRCC treated with three TTs were retrospectively studied. Therapies were classified as vascular endothelial growth factor (VEGF)/vascular endothelial growth factor receptor (VEGFR) or mammalian target of rapamycin inhibitors (mTORi). Progression free survival (PFS), overall survival (OS) and total PFS (tPFS) – defined as the time from start of first-line to progression on third-line treatment – were estimated using the Kaplan–Meier method and curves were compared with log-rank test.ResultsA total of 2065 patients with mRCC were consecutively treated with first-line TT in 23 centres in Italy. Overall 281/2065 patients (13%) were treated with three TTs. Median OS and tPFS were 44.7 and 34.1 months, respectively and were longer in patients receiving the sequence vascular endothelial growth factor inhibitors (VEGFi)–VEGFi–mTORi compared with those receiving VEGFi–mTORi–VEGFi with a statistical difference in OS (50.7 versus 37.8 months, p = 0.004; 36.5 versus 29.3 months, p = 0.059, respectively).ConclusionsFew patients received three lines of TTs. The sequence VEGFi–VEGFi–mTORi was associated with improved survival with respect to VEGFi–mTORi–VEGFi and primary resistance to first-line was a negative predictive and prognostic factor.     

Sorafenib and sunitinib for elderly patients with renal cell carcinoma

BackgroundSunitinib and sorafenib are small-molecule tyrosine kinase inhibitors with known antitumor activity in advanced renal cell carcinoma.Materials and MethodsWe retrospectively assess the response and tolerance of elderly patients with renal cell carcinoma to these two agents. Data of patients aged ≥ 70 years receiving sorafenib or sunitinib at the Centre Léon Bérard were analyzed. Forty-eight patients received sorafenib or sunitinib as a first line treatment, 8 received sorafenib followed by sunitinib and 4 received the reverse sequence. Objective responses (ORs), stable disease (SD), toxicity, overall survival (OS) and progression-free survival (PFS) were reported.ResultsSorafenib and sunitinib achieved similar OR + SD rates (79% vs. 71% respectively). Median PFS was 6 months in first-line sorafenib treated patients and 5 months in the sunitinib group. Median OS was 16 months in first-line sorafenib-treated patients and 15 months in the sunitinib group. In patients receiving sorafenib followed by sunitinib, median PFS was 11.5 months, and median OS was 13.1 months. With the reverse sequence, median PFS was 8.1 months and median OS was 15 months. Treatment modifications were more frequent in sunitinib-treated patients, in first or second line (75% vs. 50%). Limitations are the retrospective design of the study and the small number of patients.ConclusionFirst-line sunitinib and sorafenib seem equally efficient in elderly patients treated for advanced renal carcinomas, but sunitinib is less well tolerated. Sequential treatment with sorafenib followed by sunitinib seems to be better tolerated. These results should be confirmed in a larger prospective study.     

Patterns of care and outcomes in elderly patients with glioblastoma in Sao Paulo,Brazil: A retrospective study

ObjectiveTo analyze how elderly patients with glioblastoma are managed in Brazil.Material and MethodsWe identified 30 patients aged ≥ 65 years treated between 2003 and 2011 at Albert Einstein Hospital in Sao Paulo. We retrospectively reviewed medical records to obtain data on clinical variables, treatment and outcomes. Overall survival (OS) was evaluated using Kaplan–Meier methods and compared using a Wilcoxon log-rank test.ResultsThe median age was 73 years. The majority of patients (73.2%) underwent surgical intervention. Following surgery, 80% received radiotherapy (RT), and of those, 79.2% were treated with concurrent temozolomide (TMZ). The median progression free survival and OS were 5 and 10.6 months, respectively. Patients with a KPS ≥ 70 had a median OS of 16.2 months, compared to 6.4 months for those with a KPS < 70 (p = 0.032). For those patients in whom biopsy only was performed, the median OS was 5.3 months, as compared to 7.8 months for those who underwent partial resection and 18.6 months for those treated with gross total resection (p = 0.021). A longer survival was found among patients who received RT versus those who did not (11 months vs. 1 month, p = 0.003), as well as for those treated with chemoradiation (13.6 months vs. 6.4 months, p < 0.0001).ConclusionsThis study brings new information about the management of elderly patients with glioblastoma in Brazil. Our data may suggest that elderly patients who undergo cytoreductive surgery and adjuvant RT with concurrent TMZ can do better than those with less aggressive treatment.     

Postprogression survival for first-line chemotherapy in patients with advanced gastric cancer

BackgroundWith the increasing availability of active agents, the importance of postprogression survival (PPS) has been recognised for several malignancies. However, little is known of PPS in advanced gastric cancer.Patients and methodsA literature search identified 43 randomised trials in chemotherapy-naive patients with advanced gastric cancer. We partitioned overall survival (OS) into progression-free survival (PFS) and PPS, and then examined the correlation between median OS and either median PFS or median PPS. The correlation between differences in OS (ΔOS) and those in PFS (ΔPFS) between trial arms was also investigated.ResultsThe average median OS was significantly longer in recent (2006 and later) trials than in older (2005 and earlier) trials (10.60 versus 8.64 months, P < 0.001), as was the average median PPS (5.34 versus 3.74 months, P = 0.001). Median PPS was correlated with median OS for all trials (r = 0.732), and this correlation was more pronounced in recent trials (r = 0.850). By contrast, the correlation between median PFS and median OS was less pronounced in recent trials (r = 0.282), as was that between ΔPFS and ΔOS (r = 0.365).ConclusionAn increase in median PPS was found in accordance with an increase in median OS in recent trials compared with older trials for patients with advanced gastric cancer.     

Clinical outcome after CyberKnife® radiosurgery re-irradiation for recurrent brain metastases

PurposeThe objective of this study was to elucidate the impact on clinical outcomes resulting from re-irradiation for locally recurrent (LR) brain metastases (BM) using CyberKnife® stereotactic radiosurgery (SRS).Materials and methodsSeventy-seven patients with 254 LR BM lesions treated using SRS re-irradiation between January 2014 and December 2018 were analysed in this retrospective study. The local control (LC), overall survival (OS) rates, and adverse events were assessed. The adverse events were classified according to the Common terminology for adverse event (CTCAE) v5.0.ResultsThe median follow-up duration was 8.9 months. The median age of the patients was 55 years (IQR: 47–62). The 3, 6, and 9-month LC and OS rates were 92.2%, 73.4%, and 73.4% and 79.2%, 61.0%, and 48.1%, respectively. On multivariate analysis the gender (male vs. female; HR, 1.79; 95% CI, 1.06–3.01; P = 0.028), type of first brain radiation (WBI vs. SRS) followed by re-irradiation using SRS (HR, 9.32; 95% CI, 2.77–15.27; P < 0.001) tumour volume (> 12cc vs. ≤ 12cc; HR, 1.84; 95% CI, 1.10–3.11; P = 0.02), and recursive partitioning analysis (RPA) (I vs. II & III; HR, 0.38; 95% CI, 0.19–0.70; P = 0.001) were independent predictive factor for OS. Radionecrosis was reported in 3 patients.ConclusionWith acceptable toxicity, SRS re-irradiation for LR BM showed a favourable rate for LC and OS and reported better OS for the female gender, a patient undergoing first brain radiation with SRS, tumour volume ≤ 12cc, and RPA-I. This result needs to be further evaluated in future clinical studies.     

First-line anthracycline-based chemotherapy for angiosarcoma and other soft tissue sarcoma subtypes: Pooled analysis of eleven European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group trials

BackgroundAngiosarcoma is a rare subtype of soft tissue sarcoma (STS). Doxorubicin is the standard first-line chemotherapy for advanced STS. It is not known whether angiosarcoma response to anthracycline-based chemotherapy is different to other STS subtypes.MethodsPooled data were analysed from 11 prospective randomised and non-randomised European Organisation for Research and Treatment of Cancer (EORTC) clinical trials of first-line anthracycline-based chemotherapy for advanced STS. Baseline patient characteristics, chemotherapy response, progression free survival (PFS) and overall survival (OS) of angiosarcoma patients were compared with other STS patients. Analysis was performed to identify factors prognostic for angiosarcoma response to chemotherapy, PFS and OS.ResultsWith a median follow-up of 4.2 years, data from 108 locally advanced and metastatic angiosarcoma patients and 2557 patients with other STS histologies were analysed. 25% of angiosarcoma patients had a complete or partial response to chemotherapy compared to 21% for other STS histotypes. The median PFS was 4.9 months and OS 9.9 months, which were not significantly different from other STS histotypes. In univariate analysis, bone metastases were an adverse prognostic factor for OS (hazard ratio (HR) 1.66, 95% confidence interval (CI) 1.03–2.67; p = 0.036). Tumour grade was as an adverse prognostic factor for PFS (HR 1.72, 95% CI 1.01–2.92; p = 0.044) and OS (HR 2.03; 95% CI 1.16–3.56; p = 0.011). Compared to single agent anthracyclines, doxorubicin + ifosfamide was associated with improved PFS (HR 0.53, 95% CI 0.33–0.86; p = 0.010) and OS (HR 0.53, 95% CI 0.32–0.90; p = 0.018).ConclusionsAngiosarcoma response and survival following first-line anthracycline-based chemotherapy was similar to other STS histotypes. Our analysis provides a useful measure of angiosarcoma response to chemotherapy for comparison with future clinical trials.     

High subcutaneous adipose tissue predicts the prognosis in metastatic castration-resistant prostate cancer patients in post chemotherapy setting

BackgroundCancer studies have shown that body mass index (BMI), skeletal muscle mass (SMM) and adipose tissue indexes are linked to overall survival (OS) and progression-free survival (PFS). New treatments (abiraterone acetate, enzalutamide cabazitaxel, radium-223, sipuleucel-T) have improved patient outcomes in metastatic castration-resistant prostate cancer (mCRPC). Our objective was to analyse whether body composition parameters exert a prognostic role in mCRPC patients treated with next generation of androgen receptor (AR) axis inhibitors (abiraterone and enzalutamide).MethodsAll mCRPC patients from our institution who were enrolled in two prospective trials, assessing the efficacy of abiraterone acetate and the efficacy of enzalutamide, were selected. SMM, visceral and subcutaneous adipose tissue (SAT) indexes were assessed with computed tomography imaging by measuring cross-sectional areas of the tissues.ResultsIn the 120 patients with available data, median OS and PFS were respectively: 16 months (95% confidence interval [CI] = 12–19) and 4 months (95% [CI] = 3–6). OS was associated with the SAT index: median survival was 15 months (95% [CI] 9–18) for patients with a SAT index < median value and 18 months (95% [CI] 13–30) for patients with a SAT index above (P = 0.008). In multivariate analyses, only the occurrence of visceral metastasis (P = 0.004), pain (P = 0.015) and SAT index (P = 0.036) were statistically significant predictors of OS. From baseline to 3 months, the SMM index loss was 2.49 ± 0.44 cm²/m² (P < 0.001) corresponding to nearly 3.4 kg of muscle loss.ConclusionsHigh volume of SAT is independently associated with overall survival in mCRPC patients treated with next generation AR axis inhibitors.     

Treatment patterns and outcomes among patients diagnosed with unresectable stage III or IV melanoma in Europe: A retrospective,longitudinal survey (MELODY study)

BackgroundMELanoma treatment patterns and Outcomes among patients with unresectable stage III or stage IV Disease: a retrospective longitudinal surveY (MELODY), the first multicountry, observational survey in patients with advanced melanoma, aimed to quantify the impact of existing treatment strategies by capturing information on treatment patterns and clinical outcomes.Patients and methodsPatients attending a participating site between 1st July 2005 and 30th June 2006 with ⩾2 months follow-up were eligible. Data were retrieved retrospectively from advanced melanoma diagnosis until 1st May 2008. Treatment data were collected by line of therapy and response and progression-free survival data by line of systemic treatment. Overall survival (OS) was evaluated for all treated patients.ResultsAmong all patients screened, 776 were eligible for this analysis. Median OS from the date of advanced disease diagnosis was 16.4 months. After excluding patients diagnosed prior to 1st July 2005 to account for any bias resulting from patient selection, the 12-month survival rate and median OS from the start date of second-line treatment was 28.8% and 6.8 months, respectively. Survival was lower in patients with brain metastases, elevated lactate dehydrogenase levels and more advanced disease. Rates of complete/partial tumour response were 15% and 7% in patients treated with first- and second-line systemic therapy, respectively.ConclusionsDespite receiving first- and second-line treatment, most patients with advanced melanoma have short survival times and poor prognoses, reinforcing the need for new treatments.     

Response to chemotherapy is predictive in relation to longer overall survival in an individual patient combined-analysis with pleural mesothelioma

BackgroundThere is currently no early predictive marker of survival for patients receiving chemotherapy for malignant pleural mesothelioma (MPM). Tumour response may be predictive for overall survival (OS), though this has not been explored. We have thus undertaken a combined-analysis of OS, from a 42 day landmark, of 526 patients receiving systemic therapy for MPM. We also validate published progression-free survival rates (PFSRs) and a progression-free survival (PFS) prognostic-index model.MethodsAnalyses included nine MPM clinical trials incorporating six European Organisation for Research and Treatment of Cancer (EORTC) studies. Analysis of OS from landmark (from day 42 post-treatment) was considered regarding tumour response. PFSR analysis data included six non-EORTC MPM clinical trials. Prognostic index validation was performed on one non-EORTC data-set, with available survival data.ResultsMedian OS, from landmark, of patients with partial response (PR) was 12·8 months, stable disease (SD), 9·4 months and progressive disease (PD), 3·4 months. Both PR and SD were associated with longer OS from landmark compared with disease progression (both p < 0·0001). PFSRs for platinum-based combination therapies were consistent with published significant clinical activity ranges. Effective separation between PFS and OS curves provided a validation of the EORTC prognostic model, based on histology, stage and performance status.ConclusionResponse to chemotherapy is associated with significantly longer OS from landmark in patients with MPM.