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Glioblastoma is a highly vascularised tumour and there are few treatment options after disease recurrence. Regorafenib is an oral multikinase inhibitor of angiogenic, stromal, and oncogenic receptor tyrosine kinases. We aimed to assess the efficacy and safety of regorafenib in the treatment of recurrent glioblastoma. REGOMA is a randomised, multicentre, open-label phase 2 trial done in ten centres in Italy. Eligible patients (aged ≥18 years) with histologically confirmed glioblastoma, Eastern Cooperative Oncology Group performance status 0 or 1, and documented disease progression after surgery followed by radiotherapy and temozolomide chemoradiotherapy were randomly assigned (1:1) by a web-based system, stratified by centre and surgery at recurrence (yes vs no), to receive regorafenib 160 mg once daily for the first 3 weeks of each 4-week cycle or lomustine 110 mg/m2 once every 6 weeks until disease progression, death, unacceptable toxicity, or consent withdrawal. The primary endpoint was overall survival in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02926222, and is currently in follow-up. Between Nov 27, 2015, and Feb 23, 2017, 124 patients were screened and 119 eligible patients were randomly assigned to receive regorafenib (n=59) or lomustine (n=60). Median follow-up was 15·4 months (IQR 13·8–18·1). At the analysis cutoff date, 99 (83%) of 119 patients had died: 42 (71%) of 59 in the regorafenib group and 57 (95%) of 60 in the lomustine group. Overall survival was significantly improved in the regorafenib group compared with the lomustine group, with a median overall survival of 7·4 months (95% CI 5·8–12·0) in the regorafenib group and 5·6 months (4·7–7·3) in the lomustine group (hazard ratio 0·50, 95% CI 0·33–0·75; log-rank p=0·0009). Grade 3–4 treatment-related adverse events occurred in 33 (56%) of 59 patients treated with regorafenib and 24 (40%) of 60 with lomustine. The most frequent grade 3 or 4 adverse events related to regorafenib were hand–foot skin reaction, increased lipase, and blood bilirubin increased (in six [10%] of 59 patients each). In the lomustine group, the most common grade 3 or 4 adverse events were decreased platelet count (eight [13%] of 60 patients), decreased lymphocyte count (eight [13%]), and neutropenia (seven [12%]). No death was considered by the investigators to be drug related. REGOMA showed an encouraging overall survival benefit of regorafenib in recurrent glioblastoma. This drug might be a new potential treatment for these patients and should be investigated in an adequately powered phase 3 study. Veneto Institute of Oncology and Bayer Italy.

Objective Although adjuvant trastuzumab improves survival in patients with HER2-positive early breast cancer, there is growing concern about the long-term effect of trastuzumab-induced cardiotoxicity (TIC). We retrospectively assessed the incidence of TIC and heart failure (HF) to identify possible risk and protective factors. Design Retrospective study. Setting Institute for Cancer Research and Treatment, Medical Oncology Department. Patients Consecutive patients who started adjuvant trastuzumab between 2007 and 2010. Main outcome Measures TIC was defined as an absolute left ventricular ejection fraction (LVEF) decrease ≥15 points from baseline or a LVEF<50%. Logistic regression was used to estimate OR and their 95% CI in order to evaluate the risk of TIC, considering potential cardiac risk factors (hypertension, hypercholesterolaemia, diabetes mellitus, smoke, cardiac ischaemia and previous chest radiotherapy) and protective factors (β-blockers, ACE inhibitors and/or angiotensin receptor blockers). Results Among 179 patients, 78 cases of TIC (44%, 95% CI 37% to 51%) and four cases of HF (2%, 95% CI 0% to 4%) were reported. 14 patients stopped trastuzumab as a result of TIC. None of the cardiac risk factors or concomitant cardiovascular medications altered the risk of TIC. A previous cumulative dose >240 mg/m2 of doxorubicin or >500 mg/m2 of epirubicin increased the risk of TIC compared with lower doses (OR 3.07; 95% CI 1.29 to 7.27, p=0.0011). Conclusions TIC is a frequent, albeit generally mild, adverse event in clinical practice. Further studies are warranted to better define the risk of and protective factors for TIC.

Li-Fraumeni syndrome (LFS) is an autosomal dominant disorder occurring at a young age that predisposes individuals to multiple forms of cancer and to a heterogeneous spectrum of malignancies. We describe the clinical history of a patient who had 5 primary malignant cancers and a familiar history consistent with LFS. We analyzed the genomic DNA of the proband and her relatives by next-generation sequencing (NGS) technology using an enrichment protocol for the simultaneous sequencing of 94 genes involved in hereditary cancers. Genetic analysis of the proband revealed a TP53 germline mutation in exon 5 determining a nucleotide alteration at codon 175 (R175H), a hot spot mutation site related to LFS and a reported pathogenic mutation. The proband daughter's and brother's DNA did not carry the TP53 mutation but they had some rare variants in common with the proband, in addition to other variants with a still unclear role. In conclusion, we identified a TP53 mutation in a patient with multiple primary tumors and a family history characterized by a severe susceptibility to cancer. The genetic analysis by targeted NGS led to the identification of the genetic background and to the exclusion of a cancer risk for the family members. Targeted NGS represents an efficient approach for the identification of mutations in families with a heterogeneous phenotype.

Despite advances in the treatment of glioblastoma (GBM), median survival is 12–15 months. O 6-methylguanine-DNA methyltransferase (MGMT) gene promoter methylation status is acknowledged as a predictive marker for temozolomide (TMZ) treatment. When MGMT promoter values fall into a “methylated” range, a better response to chemotherapy is expected. However, a cutoff that discriminates between “methylated” and “unmethylated” status has yet to be defined. We aimed to identify the best cutoff value and to find out whether variability in methylation profiles influences the predictive capacity of MGMT promoter methylation. Data from 105 GBM patients treated between 2008 and 2013 were analyzed. MGMT promoter methylation status was determined by analyzing 10 CpG islands by pyrosequencing. Patients were treated with radiotherapy followed by TMZ. MGMT promoter methylation status was classified into unmethylated 0–9 %, methylated 10–29 % and methylated 30–100 %. Statistical analysis showed that an assumed methylation cutoff of 9 % led to an overestimation of responders. All patients in the 10–29 % methylation group relapsed before the 18-month evaluation. Patients with a methylation status ≥30 % showed a median overall survival of 25.2 months compared to 15.2 months in all other patients, confirming this value as the best methylation cutoff. Despite wide variability among individual profiles, single CpG island analysis did not reveal any correlation between single CpG island methylation values and relapse or death. Specific CpG island methylation status did not influence the predictive value of MGMT. The predictive role of MGMT promoter methylation was maintained only with a cutoff value ≥30 %.

Introduction The optimal management of high risk WHO grade II gliomas after surgery is debated including the role of initial temozolomide to delay radiotherapy and risk of cognitive defects. Methods A post-hoc analysis of a phase II multicenter study on high risk WHO grade II gliomas, receiving initial temozolomide alone, has re-evaluated the long-term results within the molecular subgroups of WHO 2016. The primary endpoint of the study was response according to RANO, being seizure response, PFS and OS secondary endpoints. Results Response rate among oligodendrogliomas IDH-mutant and 1p/19q codeleted (76%) was significantly higher than that among diffuse astrocytomas either mutant (55%) or wild-type (36%). A reduction of seizure frequency > 50% was observed in 87% of patients and a seizure freedom in 72%. The probability of seizure reduction > 50% was significantly associated with the presence of an IDH mutation. Median PFS, PFS at 5 and 10 years, median OS and OS at 5 and 10 years were significantly longer in oligodendrogliomas IDH-mutant and 1p/19q codeleted. Sixty-seven percent of patients with oligodendroglioma IDH mutant and 1p/19q codeleted did not recur with a median follow up of 9.3 years, while 59% did not receive radiotherapy at recurrence with a median follow up of 8.2 years. Conclusions The beneficial effects of initial temozolomide prevail in oligodendrogliomas IDH-mutant and 1p/19q codeleted: thus, these tumors, when incompletely resected or progressive after surgery alone, or with intractable seizures, should receive temozolomide as initial treatment with salvage radiotherapy and/o reoperation and/or second-line chemotherapy at recurrence.

Purpose Hydroxyurea (HU) is among the most widely used salvage therapies in progressive meningiomas. Platelet-derived growth factor receptors are expressed in virtually all meningiomas. Imatinib sensitizes transformed cells to the cytotoxic effects of chemotherapeutic agents that interfere with DNA metabolism. The combination of HU with imatinib yielded intriguing results in recurrent malignant glioma. The current trial addressed the activity of this association against meningioma. Methods Patients with recurrent or progressive WHO grade I–III meningioma, without therapeutic indication for surgery, radiotherapy, or stereotactic radiosurgery, aged 18–75 years, ECOG performance status 0–2, and not on enzyme-inducing anti-epileptic drugs were randomized to receive HU 500 mg BID ± imatinib 400 mg QD until progression, unacceptable toxicity, or patient’s refusal. The primary endpoint was progression-free survival rate at 9 months (PFS-9). Results Between September 2009 and February 2012, 15 patients were randomized to receive HU + imatinib ( N  = 7; Arm A) or HU alone ( N  = 8; Arm B). Afterward the trial was prematurely closed due to slow enrollment rate. PFS-9 (A/B) was 0/75 %, and median PFS was 4/19.5 months. Median and 2-year overall survival (A/B) rates were: 6/27.5 months; 28.5/75 %, respectively. Main G3-4 toxicities were: G3 neutropenia in 1/0, G4 headache in 1/1, and G3 vomiting in 1/0. Conclusion The conduction of a study in recurrent or progressive meningioma remains a challenge. Given the limited number of patients enrolled, no firm conclusions can be drawn about the combination of imatinib and HU. The optimal systemic therapy for meningioma failing surgery and radiation has yet to be identified.

The third and fourth authors' affiliation was incorrectly specified in the original publication. It is correctly shown here.The third and fourth authors' affiliation was incorrectly specified in the original publication. It is correctly shown here.

The efficacy of temozolomide (TMZ) plus radiation therapy (RT) in elderly patients with glioblastoma is unclear. We performed a large multicenter retrospective study to analyze prognostic factors and clinical outcome in these patients. Inclusion criteria were age ≥65 years, newly histologically confirmed glioblastoma, ECOG PS 0-2, adjuvant treatment with RT plus TMZ. We enrolled 237 patients; the average age was 71 and ECOG PS was 0-1 in 196 patients; gross total resection was performed in 174 cases. MGMT was analyzed in 151 persons and was methylated in 56 %. IDH1 was assessed in 100 patients and was mutated in 6 %. Seventy-one patients were treated with RT 40 Gy and 166 with RT 60 Gy. Progression-free survival and overall survival (OS) were 11.3 and 17.3 months, respectively. Overall survival was 19.4 vs 13.8 months for patients treated with RT 60 Gy and 40 Gy (p = 0.02); OS was 17.7 versus 16.1 months for patients treated with gross total resection vs partial surgery (p = 0.02); OS was 21.2 versus 13.6 months for methylated and unmethylated MGMT (p < 0.001). On multivariate analysis, gross total resection, RT 60 Gy, methylated MGMT and ECOG PS 0-1 were independent predictors of longer survival. Twenty-five patients (10 %) had grade 3-4 haematological toxicity during the concomitant treatment. We showed that, in elderly patients in good clinical condition treated with concomitant treatment, standard-course irradiation might be more effective than short-course irradiation. Methylated MGMT remains the most important prognostic factor.

Purpose Combination of anthracyclines with trastuzumab is hampered by cardiotoxicity. Pegylated liposomal doxorubicin and lapatinib could represent a safer alternative to combination therapy. Methods In this phase Ib study with 3 + 3 dose escalation design, patients with HER2-positive advanced breast cancer received pegylated liposomal doxorubicin 30 mg/m 2 intravenously on day 1 plus lapatinib 1250 (level 1) or 1500 (level 2) mg/day orally on days 1–21 of each 21-day cycle. The aims were to establish the maximum tolerated dose at first cycle, and the activity and safety of multiple cycles. Results Nine patients out of 11 enrolled were evaluable: 3 at level 1 and 6 at level 2. No dose-limiting toxicities occurred at dose level 1, while 1 (grade 3 diarrhea) occurred at dose level 2, leading to the expansion of this cohort to 6 patients, with no further dose-limiting toxicities. Main grade 1–2 toxicities at first cycle were leucopenia, diarrhea, elevated transaminases, mucositis. Three patients had grade 3 toxicities at subsequent cycles, including colitis, anorexia, stomatitis plus hand-foot syndrome. One partial response, 5 disease stabilizations, and 3 disease progressions were reported. Conclusions Combination of pegylated liposomal doxorubicin and lapatinib is feasible and potentially active in pretreated HER2-positive advanced breast cancer patients. Trial registration NCT02131506 (ClinicalTrials.gov identifier).

There are no validated predictors of benefit from anthracyclines. We compared cyclophosphamide, methotrexate, 5-fluorouracil (CMF), and epirubicin in different sequences with CMF alone in a phase III trial on operable breast cancers. Outcomes were analyzed in relation to tumor biological profiles to identify potential predictors of the efficacy of different treatments/drug combinations. Patients with N− or 1–3N+ tumors, were randomized to receive (a) epirubicin (4 cycles) followed by CMF (4 cycles); (b) CMF (4 cycles) followed by epirubicin (4 cycles), or (c) CMF (6 cycles) alone. Immunohistochemical assessments of estrogen (ER) and progesterone (PgR) receptors, HER2 and Ki67 were available for 705 patients (arm A/B/C: 276/269/160). Prognostic and predictive relevance was analyzed by log-rank tests and Cox models. Ki67 > 20 % and absent/low expression of ER and PgR were associated with worsen disease-free (DFS) and overall survival (OS). In patients with triple negative tumors (ER−, PgR−, HER2−), epirubicin-containing regimens yielded better DFS (HR 0.33, 95 % CI 0.17–0.62, P  = 0.0007) and OS (HR 0.24, 95 % CI 0.10–0.57, P  = 0.001) compared with CMF alone, whereas no differences were found in patients with HER2-positive (HER2+, ER−, PgR−) subtype. Treatment by subtype interaction (HER2-positive vs. others) was significant for DFS ( χ 2  = 6.72, P  = 0.009). In triple unfavorable (ER−, PgR−, Ki67 > 20 %) tumors, the use of epirubicin yielded better DFS (HR 0.45,95 % CI 0.26–0.78, P  = 0.005) and OS (HR 0.30, 95 % CI 0.15–0.63, P  = 0.001). Epirubicin-containing regimens seem to be superior to CMF alone in patients with highly proliferating, triple negative or triple unfavorable tumors .