Outcome improvement with chemotherapy and radiotherapy in primary, localized, radiation-associated angiosarcoma of the breast region: a retrospective case series analysis.

BACKGROUND: We report on a series of consecutive patients with localized radiation-associated angiosarcoma (RAAS) of the breast region (BR) treated at two Italian sarcoma reference centers. MATERIALS AND METHODS: We retrospectively reviewed all cases of primary, localized, resectable RAAS of the BR, treated at one of the two participating institutions from 2000 to 2019. Relapse-free survival (RFS) and overall survival (OS) were calculated. The prognostic role of several variables was investigated. A propensity score matched (PSM) analysis was carried out. RESULTS: Eighty-four patients were retrospectively identified. Nineteen out of 84 patients (22.6%) were pretreated with an anthracycline-based regimen for previous cancer. All patients but one underwent surgery, with 37/84 (44.1%) receiving surgery alone and 46/84 (54.8%) a multimodal approach: 18/84 (21.4%) received radiation therapy (RT) and 46/84 (54.9%) received chemotherapy. An anthracycline-based regimen was used in 10/84 patients (11.9%), while a gemcitabine-based regimen was used in 33/84 (39.3%). With a median follow-up of 51 months (interquartile range: 30-126 months), 36/84 patients (42.9%) relapsed and 35/84 patients (41.7%) died (8/84, 9.5% in the lack of metastatic disease). Five-year OS and 5-year RFS were 57% [95% confidence interval (CI) 43% to 68%] and 52% (95% CI 39% to 63%), respectively. Both (neo)adjuvant RT and chemotherapy were associated with better RFS [hazard ratio (HR) 0.25, 95% CI 0.08-0.83; HR 0.45, 95% CI 0.23-0.89] with a trend towards a better OS (HR 0.51, 95% CI 0.18-1.46; HR 0.60, 95% CI 0.29-1.24). Gemcitabine-based regimens seemed to perform better (HR 4.28, 95% CI 1.29-14.14). PSM analysis retained the above results. CONCLUSIONS: This retrospective study supports the use of (neo)adjuvant RT and chemotherapy, in primary, localized resectable RAAS of the BR. An effort to prospectively validate the role of (neo)adjuvant RT and chemotherapy is warranted.

Sex-based differences in response to anti-PD-1 or PD-L1 treatment in patients with non-small-cell lung cancer expressing high PD-L1 levels. A systematic review and meta-analysis of randomized clinical trials.

BACKGROUND: In our previous works, we demonstrated that patients' sex affects the efficacy of immune checkpoint inhibitors (ICIs) in patients with several advanced solid tumors. Here, we assessed the sex-based heterogeneity of efficacy of anti-programmed cell death protein 1 (anti-PD-1)/anti-programmed death-ligand 1 (anti-PD-L1) given as monotherapy, for advanced non-small-cell lung cancer (NSCLC) expressing high PD-L1 levels, to evaluate if available evidence supports this therapeutic option for both women and men. METHODS: We carried out a systematic review and meta-analysis including all randomized, controlled trials testing anti-PD-1/anti-PD-L1 drugs in monotherapy, as first-line treatment of advanced NSCLC expressing high PD-L1 levels. The primary endpoint was the difference in efficacy of anti-PD-1/anti-PD-L1 drugs versus chemotherapy, between men and women, measured in terms of the difference in overall survival (OS) log [hazard ratio (HR)] reported in male and female study participants. RESULTS: We analyzed four randomized, controlled trials, including 1672 patients, of whom 1224 (73.2%) were men and 448 (26.8%) were women. The pooled OS-HR comparing anti-PD-1/anti-PD-L1 versus chemotherapy was 0.59 [95% confidence interval (CI), 0.50-0.69] for men and only 0.84 (95% CI, 0.64-1.10) for women. The pooled ratio of the OS-HRs reported in men versus women was 0.71 (95% CI, 0.52-0.98; P-heterogeneity: 0.04), indicating a significantly greater effect for men. No heterogeneity among single-study estimates was observed in either male patients (Q = 2.39, P = 0.50, I2 = 0%) or in female patients (Q = 1.13, P = 0.50, I2 = 0%). CONCLUSION: Evidence available indicates anti-PD-1/anti-PD-L1 monotherapy as highly effective in men but not in women, even in NSCLCs expressing high PD-L1 levels. Prospective trials testing sex-based tailored immunotherapy strategies are needed.

Thymic carcinoma with Lynch syndrome or microsatellite instability, a rare entity responsive to immunotherapy.

IMPORTANCE: Thymic carcinoma (TC) is a rare aggressive tumour occurring in adults characterised by one of the lowest tumor mutational burdens (TMB). Microsatellite instability (MSI) is a mutational signature, caused by defects in the DNA MisMatch Repair (MMR) system, that predicts benefit from immunotherapy and causes high TMB. Fragmentary and unstructured evidence of these conditions co-occurring are reported in literature. OBJECTIVE: Review available data on the co-occurrence of these two conditions and determine its frequency in our institute case series. DESIGN: We performed a systematic analysis of literature and a retrospective evaluation of all the cases of TET treated at our institution from 2000 to 2020, selecting patients with a medical history of multiple tumours to enhance a priori probability of identifying cases with underlying predisposition. RESULTS: Literature yielded 3 cases of patients with MSI TC, for which MMR gene alteration was reported. None of them received immunotherapy. Of 366 patients with TETs treated in our institute, 32 had a medical history of multiple tumours and 25 of 32 (19 thymomas and 6 TCs) had available tissue for MMR analysis. One patient with TC showed a high TMB, and MSI due to MLH1 mutation and was treated in a phase II study with avelumab and axitinib combination obtaining a long-lasting partial response. MLH1 alterations are shared across MSI TC cases. CONCLUSIONS AND RELEVANCE: This analysis highlights the usefulness of MSI testing in patients with TC. The observation of cases of TC occurring in patients with Lynch syndrome and the unexpected homogeneity of gene alterations support further investigation.

Clinical management of patients with thymic epithelial tumors: the recommendations endorsed by the Italian Association of Medical Oncology (AIOM).

The Italian Association of Medical Oncology recommendations on thymic epithelial tumors, which have been drawn up for the first time in 2020 through an evidence-based approach, report indications on all the main aspects of clinical management of this group of rare diseases, from diagnosis and staging, to new available systemic treatments, such as targeted therapies and immunotherapies. A summary of key recommendations is presented here and complete recommendations are reported as Supplementary Materials, available at https://doi.org/10.1016/j.esmoop.2021.100188.

Adjuvant radiotherapy treatment for soft tissue sarcoma of extremities and trunk. A retrospective mono-institutional analysis.

Soft tissue sarcomas (STS) are uncommon, heterogeneous malignant tumors of mesodermal origin. Other than conservative surgery (CS), neoadjuvant or adjuvant radiotherapy (RT) is recommended when the risk of local recurrence is high. The aim of this study is to present our Institutional experience in adjuvant RT for treatment of STS of extremities and trunk (with either brachytherapy (BRT), external beam RT (EBRT), or both) and to provide an insight of toxicity and oncological outcomes for each RT modality. According to the RT treatment approach, patients were divided into three categories: 1) BRT alone; 2) EBRT alone; 3) combined BRT+EBRT. Differences among the three groups were assessed by the Chi-squared test. Patients' follow-up was performed every 6 months for the first two years after the end of RT and then once a year. Data from 90 patients were analyzed. The overall 3-year distant relapse-free survival (DRFS), progression-free survival (PFS), and overall survival (OS) were 84%, 80%, and 97%, respectively. Acute erythema was the most frequent side effect, although severe grade 3 toxicity was present in 5 patients. Chronic toxicity of any grade was reported in 14 patients. The incidence of chronic toxicity did not show any association with treatment modality. Multivariate analysis suggested a significant correlation between acute toxicity and tumor size, RT modality, and RT dose. In conclusion, good local control and toxicity profile were observed, despite negative patients' selection at baseline. Further investigation on wider series is warranted in order to define the optimal combination with systemic therapy.

The sacral chordoma margin.

OBJECTIVE: Aim of the manuscript is to discuss how to improve margins in sacral chordoma. BACKGROUND: Chordoma is a rare neoplasm, arising in half cases from the sacrum, with reported local failure in >50% after surgery. METHODS: A multidisciplinary meeting of the "Chordoma Global Consensus Group" was held in Milan in 2017, focusing on challenges in defining and achieving optimal margins in chordoma with respect to surgery, definitive particle radiation therapy (RT) and medical therapies. This review aims to report on the outcome of the consensus meeting and to provide a summary of the most recent evidence in this field. Possible new ways forward, including on-going international clinical studies, are discussed. RESULTS: En-bloc tumor-sacrum resection is the cornerstone of treatment of primary sacral chordoma, aiming to achieve negative microscopic margins. Radical definitive particle therapy seems to offer a similar outcome compared to surgery, although confirmation in comparative trials is lacking; besides there is still a certain degree of technical variability across institutions, corresponding to different fields of treatment and different tumor coverage. To address some of these questions, a prospective, randomized international study comparing surgery versus definitive high-dose RT is ongoing. Available data do not support the routine use of any medical therapy as (neo)adjuvant/cytoreductive treatment. CONCLUSION: Given the significant influence of margins status on local control in patients with primary localized sacral chordoma, the clear definition of adequate margins and a standard local approach across institutions for both surgery and particle RT is vital for improving the management of these patients.

EGFR Inhibition in a Pretreated Sacral Chordoma: A Role for Erlotinib? Case Report and a Brief Review of Literature.

We describe the case of a 69-year old male with an EGFR- positive Imatinib refractory sacral chordoma with synchronous lung metastases, treated with erlotinib, a first-generation EGFR inhibitor. After disease progression following first-line Imatinib and a combination therapy with everolimus plus metformin, we made a challenge with an EGFR tyrosine kinase inhibitor (EGFR TKI), erlotinib. Despite a brief clinical benefit, the patient presented a rapid clinical deterioration leading to death, after 8 weeks of treatment.

A phase I, dose-escalation study of volasertib combined with nintedanib in advanced solid tumors.

BACKGROUND: Volasertib is a potent and selective cell-cycle kinase inhibitor that induces mitotic arrest and apoptosis by targeting Polo-like kinases. This study determined the maximum tolerated dose (MTD) and pharmacokinetics of volasertib combined with nintedanib, a potent and orally bioavailable triple angiokinase inhibitor, in patients with advanced solid tumors. PATIENTS AND METHODS: This open-label, dose-escalation trial recruited patients with advanced metastatic solid tumors following failure of conventional treatment (NCT01022853; Study 1230.7). Volasertib was administered by intravenous infusion over 2 h, starting at 100 mg in the first dose cohort. Nintedanib was administered orally at a dose of 200 mg twice daily. The first treatment cycle comprised 28 days (days 1-7 and days 9-28: nintedanib; day 8: volasertib). From cycle 2 onwards, volasertib was administered on day 1 of a 21-day cycle and nintedanib was administered days 2-21. The primary objective was the MTD of volasertib in combination with nintedanib. RESULTS: Thirty patients were treated. The MTD of volasertib plus fixed-dose nintedanib was 300 mg once every 3 weeks, the same as the recommended single-agent dose of volasertib in solid tumors. Two of 12 assessable patients treated with the MTD experienced dose-limiting toxicities [grade 3 increased alanine aminotransferase (ALT); grade 3 ALT increase and grade 3 increased aspartate aminotransferase]. Disease control [stable disease (SD)/partial response (PR)/complete response (CR)] was achieved in 18 patients (60%): 1 CR (breast cancer), 1 PR (nonsmall-cell lung cancer), and 16 patients with SD. Volasertib showed that multiexponential pharmacokinetic behavior and co-administration of nintedanib had no significant effects on its exposure. CONCLUSIONS: Volasertib could be combined with fixed-dose nintedanib at the recommended single-agent dose. At this dose, the combination had a manageable safety profile without unexpected or overlapping adverse events, and showed antitumor activity.

A randomized phase II study of the MEK1/MEK2 inhibitor trametinib (GSK1120212) compared with docetaxel in KRAS-mutant advanced non-small-cell lung cancer (NSCLC)†.

BACKGROUND: KRAS mutations are detected in 25% of non-small-cell lung cancer (NSCLC) and no targeted therapies are approved for this subset population. Trametinib, a selective allosteric inhibitor of MEK1/MEK2, demonstrated preclinical and clinical activity in KRAS-mutant NSCLC. We report a phase II trial comparing trametinib with docetaxel in patients with advanced KRAS-mutant NSCLC. PATIENTS AND METHODS: Eligible patients with histologically confirmed KRAS-mutant NSCLC previously treated with one prior platinum-based chemotherapy were randomly assigned in a ratio of 2 : 1 to trametinib (2 mg orally once daily) or docetaxel (75 mg/m(2) i.v. every 3 weeks). Crossover to the other arm after disease progression was allowed. Primary end point was progression-free survival (PFS). The study was prematurely terminated after the interim analysis of 92 PFS events, which showed the comparison of trametinib versus docetaxel for PFS crossed the futility boundary. RESULTS: One hundred and twenty-nine patients with KRAS-mutant NSCLC were randomized; of which, 86 patients received trametinib and 43 received docetaxel. Median PFS was 12 weeks in the trametinib arm and 11 weeks in the docetaxel arm (hazard ratio [HR] 1.14; 95% CI 0.75-1.75; P = 0.5197). Median overall survival, while the data are immature, was 8 months in the trametinib arm and was not reached in the docetaxel arm (HR 0.97; 95% CI 0.52-1.83; P = 0.934). There were 10 (12%) partial responses (PRs) in the trametinib arm and 5 (12%) PRs in the docetaxel arm (P = 1.0000). The most frequent adverse events (AEs) in ≥20% of trametinib patients were rash, diarrhea, nausea, vomiting, and fatigue. The most frequent grade 3 treatment-related AEs in the trametinib arm were hypertension, rash, diarrhea, and asthenia. CONCLUSION: Trametinib showed similar PFS and a response rate as docetaxel in patients with previously treated KRAS-mutant-positive NSCLC. CLINICALTRIALSGOV REGISTRATION NUMBER: NCT01362296.

Gene expression profiling reveals GC and CEACAM1 as new tools in the diagnosis of lung carcinoids.

BACKGROUND: Classification of lung carcinoids into typical and atypical is a diagnostic challenge since no immunohistochemical tools are available to support pathologists in distinguishing between the two subtypes. A differential diagnosis is essential for clinicians to correctly discuss therapy, prognosis and follow-up with patients. Indeed, the distinction between the two typical and atypical subtypes on biopsies/cytological specimens is still unfeasible and sometimes limited also after radical surgeries. By comparing the gene expression profile of typical (TC) and atypical carcinoids (AC), we intended to find genes specifically expressed in one of the two subtypes that could be used as diagnostic markers. METHODS: Expression profiling, with Affymetrix arrays, was performed on six typical and seven atypical samples. Data were validated on an independent cohort of 29 tumours, by means of quantitative PCR and immunohistochemistry (IHC). RESULTS: High-throughput gene expression profiling was successfully used to identify a gene signature specific for atypical lung carcinoids. Among the 273 upregulated genes in the atypical vs typical subtype, GC (vitamin D-binding protein) and CEACAM1 (carcinoembryonic antigen family member) emerged as potent diagnostic markers. Quantitative PCR and IHC on a validation set of 17 ACs and 12 TCs confirmed their reproducibility and feasibility. CONCLUSIONS: GC and CEACAM1 can distinguish between TC and AC, defining an IHC assay potentially useful for routine cytological and histochemical diagnostic procedures. The high sensitivity and reproducibility of this new diagnostic algorithm strongly support a further validation on a wider sample size.

The choice of whether to participate in a phase I clinical trial: increasing the awareness of patients with cancer. An exploratory study.

OBJECTIVE: In a previous study, we found that patients who were offered the possibility of participation in a clinical trial had unexpressed concerns and fears that prevented them from making free or fully knowledgeable choices about their trial participation. In a selected population of patients who were offered participation in a phase I trial, we prospectively investigated whether a face-to-face discussion about their unexpressed fears might lead to a more conscious decision about whether to accept/refuse participation in the trial. METHODS: After the presentation of the trial, a questionnaire was administered to assess the presence of specific fears. Before the patients decided whether to participate in the trial, they discussed any fears that they had; finally, the impact of the discussion on the patients' choice to participate was evaluated. RESULTS: The majority (86%) of the patients thought that physicians conduct clinical trials for scientific interest, 13% felt exploited as 'guinea pigs' and 20% believed they were offered participation because they had no further hope for improvement. These existing fears were not elicited during the trial interview because the patients were themselves unaware of having them (28%) and because of fear of the doctors (3%). The possibility of discussing these fears was felt as an opportunity and made patients feel more conscious (92%) and freer (97%) when making their choice. CONCLUSIONS: Recognising and discussing misconceptions and fears, often unexpressed, make patients freer and more aware when facing the choice of whether or not \to participate in a phase I clinical trial.

Grading the neuroendocrine tumors of the lung: an evidence-based proposal.

Lung neuroendocrine tumors are catalogued in four categories by the World Health Organization (WHO 2004) classification. Its reproducibility and prognostic efficacy was disputed. The WHO 2010 classification of digestive neuroendocrine neoplasms is based on Ki67 proliferation assessment and proved prognostically effective. This study aims at comparing these two classifications and at defining a prognostic grading system for lung neuroendocrine tumors. The study included 399 patients who underwent surgery and with at least 1 year follow-up between 1989 and 2011. Data on 21 variables were collected, and performance of grading systems and their components was compared by Cox regression and multivariable analyses. All statistical tests were two-sided. At Cox analysis, WHO 2004 stratified patients into three major groups with statistically significant survival difference (typical carcinoid vs atypical carcinoid (AC), P=0.021; AC vs large-cell/small-cell lung neuroendocrine carcinomas, P<0.001). Optimal discrimination in three groups was observed by Ki67% (Ki67% cutoffs: G1 <4, G2 4-<25, G3 ≥25; G1 vs G2, P=0.021; and G2 vs G3, P≤0.001), mitotic count (G1 ≤2, G2 >2-47, G3 >47; G1 vs G2, P≤0.001; and G2 vs G3, P≤0.001), and presence of necrosis (G1 absent, G2 <10% of sample, G3 >10% of sample; G1 vs G2, P≤0.001; and G2 vs G3, P≤0.001) at uni and multivariable analyses. The combination of these three variables resulted in a simple and effective grading system. A three-tiers grading system based on Ki67 index, mitotic count, and necrosis with cutoffs specifically generated for lung neuroendocrine tumors is prognostically effective and accurate.

Phase I/II study of the tumour-targeting human monoclonal antibody-cytokine fusion protein L19-TNF in patients with advanced solid tumours.

PURPOSE: L19-TNF is an armed antibody that selectively targets human TNF to extra domain B-fibronectin on tumour blood vessels. We performed a phase I/II first-in-man trial with L19-TNF monotherapy in metastatic solid cancer patients to study safety and signs of clinical activity. METHODS: Six cohorts of patients were treated with increasing (1.3-13 µg/kg) doses of intravenous L19-TNF on day 1, 3, and 5 of repeated 3-weekly cycles, and 12 colorectal cancer patients were treated at 13 µg/kg. PK, antibody formation, changes in lymphocyte subsets, 5-HIAA plasma levels as well as safety and clinical activity were analysed. RESULTS: Thirty-four patients received at least one L19-TNF dose. The serum half-life of L19-TNF at 13 µg/kg was 33.6 min, and maximum peak serum concentration was 73.14 µg/L. Mild chills, nausea and vomiting but no haemato- or unexpected toxicity were observed. Grade 3 lumbar pain in bone metastasis was the only dose-limiting toxicity found in one patient. Objective tumour responses were not detected. Transient stable disease occurred in 19 of 31 evaluable patients. CONCLUSIONS: Intravenous L19-TNF on day 1, 3, and 5 of a 3-weekly schedule was safe up to 13 µg/kg, but did not result in objective tumour responses. The maximally tolerated dose (MTD) was not reached, allowing for further dose escalation of L19-TNF possibly in combination with chemotherapy.

Optimizing clinical care in patients with advanced soft tissue sarcoma: a phase II study of a new schedule of high-dose continuous infusion ifosfamide and doxorubicin combination.

BACKGROUND: Ifosfamide and doxorubicin combination is an active regimen for patients with advanced soft tissue sarcomas (STS) but is burdened by high toxicity. A phase II trial was designed to assess the activity of continuous infusion ifosfamide and doxorubicin combination. PATIENTS AND METHODS: Thirty-four chemotherapy-naive patients with advanced STS were treated with ifosfamide (13 g/m(2)/12 days as continuous infusion) and doxorubicin (75 mg/m(2) on day 8) every 28 days with granulocyte colony-stimulating factor. RESULTS: The major toxicity was hematological: grade 3/4 neutropenia, anemia and thrombocytopenia occurred in 63, 30 and 12% of patients, respectively. The disease control rate was 68% and the median time to progression was 7.1 months. Among leiomyosarcomas, 2 partial responses and 4 stable diseases were observed. CONCLUSIONS: Our study confirms that the ifosfamide and doxorubicin combination has a very low non-hematological toxicity profile. This regimen attained a high disease control rate with moderate activity. Further investigation into leiomyosarcoma is warranted.

Vatalanib for metastatic gastrointestinal stromal tumour (GIST) resistant to imatinib: final results of a phase II study.

BACKGROUND: Vatalanib (PTK787/ZK 222584) inhibits a few tyrosine kinases including KIT, platelet-derived growth factor receptors (PDGFRs) and vascular endothelial growth factor receptors (VEGFRs). We report efficacy and safety results of vatalanib in advanced gastrointestinal stromal tumour (GIST) resistant to imatinib or both imatinib and sunitinib. PATIENTS AND METHODS: Forty-five patients whose metastatic GIST had progressed on imatinib were enrolled. Nineteen (42.2%) patients had received also prior sunitinib. Vatalanib 1250 mg was administered orally daily. RESULTS: Eighteen patients (40.0%; 95% confidence interval (CI), 25.7-54.3%) had clinical benefit including 2 (4.4%) confirmed partial remissions (PR; duration, 9.6 and 39.4 months) and 16 (35.6%) stabilised diseases (SDs; median duration, 12.5 months; range, 6.0-35.6+ months). Twelve (46.2%) out of the 26 patients who had received prior imatinib only achieved either PR or SD compared with 6 (31.6%, all SDs) out of the 19 patients who had received prior imatinib and sunitinib (P=0.324). The median time to progression was 5.8 months (95% CI, 2.9-9.5 months) in the subset without prior sunitinib and 3.2 (95% CI, 2.1-6.0) months among those with prior imatinib and sunitinib (P=0.992). Vatalanib was generally well tolerated. CONCLUSION: Vatalanib is active despite its narrow kinome interaction spectrum in patients diagnosed with imatinib-resistant GIST or with imatinib and sunitinib-resistant GIST.

Expression of gemcitabine- and cisplatin-related genes in non-small-cell lung cancer.

The aim of this study was to investigate the influence of histology and site of analysis (primary tumor versus lymph node) on the expression of genes involved in gemcitabine and cisplatin activity in non-small-cell lung cancer (NSCLC). Excision repair cross-complementing-1 (ERCC1), human equilibrative nucleoside transporter-1 (hENT1), deoxycytidine kinase (dCK), 5'-nucleotidase (5'-NT), cytidine deaminase (CDA) and ribonucleotide-reductase regulatory subunits (RRM1 and RRM2) were analyzed by quantitative-reverse transcription-PCR in 88 microdissected samples from 69 chemonaive patients. The results showed different patterns of expression for all studied genes, suggesting a possible stratification of the patients. No difference was observed between primary tumor and lymph node metastasis, as well as in adenocarcinoma and squamous-cell carcinoma specimens, while we found a correlation between the CDA-A79C polymorphism and gene expression levels. These data suggest a similar genetic susceptibility to gemcitabine-cisplatin regimens for squamous cell and adenocarcinoma and support the use of both lymph node and primary tumor for the expression profiling of NSCLC.