TEAM Study: Upfront Docetaxel Treatment in Patients With Metastatic Hormone-Sensitive Prostate Cancer: A Real-World, Multicenter, Retrospective Analysis.

BACKGROUND: Treatment of metastatic hormone-sensitive prostate cancer (mHSPC) dramatically changed. PEACE-1 and ARASENS trials established triplet therapy efficacy. Identifying prognostic factors supporting treatment choice is pivotal. METHODS: TEAM is an observational, retrospective study to evaluate prognostic role of variables in mHSPC patients receiving upfront docetaxel in 11 Italian centers. Outcome measures were progression-free survival (PFS) and overall-survival (OS). RESULTS: From September 2014 to December 2020, 147 patients were included. Median PFS and OS were 11.6 and 37.4 months. At univariate analysis, PFS-related variables were Gleason Score (GS) (P = .001), opioid use (P = .004), bone metastases number (P < .001), baseline PSA (P = .006), Hb (P < .001), ALP (P < .001) and LDH (P = .002), time between ADT and docetaxel start (P = .018), 3-month PSA (P < .001) and ALP (P < .001), and number of docetaxel cycles (P < .001). OS-related variables were PSA at diagnosis (P = .024), primary tumor treatment (P = .022), baseline pain (P = .015), opioid use (P < .001), bone metastases number (P < . 001), baseline Hb (P < .001), ALP (P < .001) and LDH (P = .001), NLR ratio (P = .039), 3-month PSA (P < .001) and ALP (P < .001) and docetaxel cycles number (P < .001). At multivariate analysis, independent prognostic variables were GS, opioid use, baseline LDH and time between ADT and docetaxel initiation for PFS, and baseline Hb and LDH for OS. CONCLUSION: Patients receiving upfront docetaxel with high GS, high disease burden, pain or opioid use, baseline unfavorable laboratory values had worse outcomes. Patients had greater docetaxel benefit when initiated early after ADT start. These parameters could be taken into account when selecting candidates for triplet therapy.

Sotorasib in KRASp.G12C mutated advanced NSCLC: Real-world data from the Italian expanded access program.

BACKGROUND: Sotorasib showed a significant improvement of progression free survival (PFS), safety and quality of life over docetaxel in patients with KRASp.G12C-mutated advanced non-small-cell lung cancer (NSCLC) within the CodeBreak-200 study. Here we report real-world efficacy and tolerability data from NSCLC patients who received sotorasib within the Italian expanded access program (EAP). METHODS: Sotorasib (960 mg, orally, once daily) was available on physician request for KRASp.G12C mutant advanced NSCLC patients. Clinical-pathological and molecular data were collected from the Italian ATLAS real-world registry. Patients underwent CT-scan and responses were evaluated by RECIST criteria. Efficacy and tolerability outcomes have been assessed. RESULTS: A total of 196 advanced NSCLC patients were treated across 30 Italian centers. Median age was 69 years old (range 33-86). Most patients were male (61 %), former (49 %) or current smokers (43 %), with ECOG-PS 0/1 (84 %) and adenocarcinoma subtype (90 %). 45 % and 32 % of patients received sotorasib in 2nd and 3rd line, respectively. Overall, response rate was 26 % and the median duration of response was 5.7 months (95 % CI: 4.4-7.0). Median PFS and OS were 5.8 months (95 % CI: 5 - 6.5) and 8.2 months (95 % CI: 6.3 - 9.9). Grade 3-4 TRAEs occurred in 16.5 % of patients, with Grade ≥ 3 liver enzyme increase and TRAEs-related discontinuation reported in 12 % and 4.6 % of cases. CONCLUSION: Real-world data from the Italian EAP confirm the tolerability and effectiveness of sotorasib in patients with KRASp.G12C-mutated advanced NSCLC and highlight the value of the national ATLAS network as source of real-world evidence driving the clinical management of NSCLC patients.

Syndrome of inappropriate anti-diuretic hormone secretion in cancer patients: results of the first multicenter Italian study.

BACKGROUND: Hyponatremia in cancer patients is often caused by the syndrome of inappropriate antidiuretic hormone secretion (SIADH). The aim of this observational multicenter study was to analyze the medical and economic implications of SIADH in this setting. METHODS: This study included 90 oncological patients from 28 Italian institutions that developed SIADH between January 2010 and September 2015. Data on clinical-pathological characteristics, anticancer therapies, hyponatremia, and related treatments were statistically analyzed. RESULTS: The majority were lung cancer patients (73%) with metastatic disease at the onset of hyponatremia (83%). A total of 76 patients (84%) were hospitalized because of SIADH and less than half (41%) received tolvaptan for SIADH treatment. The duration of hospitalization was significantly longer in patients who did not receive tolvaptan and in those who do not reach sodium normalization during hospitalization. Patients who experienced a second episode of hyponatremia following tolvaptan dose modification/discontinuation presented a significantly lower serum sodium value at the time of hospitalization and minimum sodium value during hospitalization compared with patients who had not experienced another episode. The severity of hyponatremia, defined as minimum sodium value during hospitalization with a cut-off value of 110 mmol/l, and not obtaining sodium correction during hospitalization significantly correlated with overall survival rate. CONCLUSIONS: Hyponatremia due to SIADH could result in longer hospitalization and in a decreased overall survival when not adequately treated, and tolvaptan represents an effective treatment with a potential effect of both improving overall survival and decreasing duration of hospitalization.

Liquid Biopsy Testing Can Improve Selection of Advanced Non-Small-Cell Lung Cancer Patients to Rechallenge with Gefitinib.

The ICARUS trial is a phase II, open label, multicenter, single arm study conducted to investigate the efficacy, safety, and tolerability of a rechallenge treatment with the first-generation tyrosine kinase inhibitor (TKI) gefitinib in advanced non-small-cell lung cancer (NSCLC) patients carrying activating mutations of the epidermal growth factor receptor (EGFR). The ICARUS trial enrolled 61 patients who were rechallenged with gefitinib at progression after second-line chemotherapy. Serum-derived circulating cell-free DNA (cfDNA) collected before the rechallenge from a cohort of 29 patients, was retrospectively analyzed for the EGFR exon 19 deletions and for the p.L858R and p.T790M single nucleotide variants (SNV). The analysis of cfDNA detected the same EGFR activating mutation reported in the tumor tissue in 20/29 patients, with a sensitivity of 69%. Moreover, a p.T790M variant was found in 14/29 patients (48.3%). The median progression-free survival (PFS) was 2.7 months for p.T790M positive patients (CI 95% 1.4-3.1 months) versus 3.5 months for the p.T790M negative patients (CI 95% 1.6-5.3 months), resulting in a statistically significant difference (Long rank test p = 0.0180). These findings confirmed the role of the p.T790M mutation in the resistance to first-generation TKIs. More importantly, our data suggest that TKI rechallenge should be guided by biomarker testing.

Practical issues for the management of hyponatremia in oncology.

Hyponatremia is common in cancer patients and has a negative impact on outcomes and survival. Both the diagnosis and treatment of hyponatremia are challenging. Easy-to-use, practical guidelines are needed. The aim of this article is to discuss practical issues related to the diagnostic workup and management of hyponatremia, with particular attention to complex patients, such as those affected by neoplastic diseases. Admittedly, these patients may present several comorbidities, which may cause sodium alterations. In addition, multidrug therapy may precipitate serum sodium fall. An algorithm for the diagnosis and treatment of hyponatremia was also developed, based on the discussion of the results of a questionnaire completed by the authors and of the published recommendations/guidelines on hyponatremia. The goal was to produce an algorithm that was as simple as possible but still comprehensive, without compromising information completeness. Many explanatory notes were added with the aim of guiding clinicians throughout the management of complex patients with hyponatremia, such as those with cancer. The resulting algorithm and supporting literature are presented.

Androgen receptor status predicts development of brain metastases in ovarian cancers.

Brain metastases are uncommon localizations in epithelial ovarian cancer (EOC), their reported incidence is increasing and no predictive biomarkers have been identified yet. Goals of this study were: i) to define a possible association between Estrogen Receptor (ER), Progesterone Receptor (PR), Androgen Receptor (AR),human EGF receptor 2 (HER2) and brain progression in EOC patients, and ii) to identify differences in ER, PR, AR and HER2 protein expression from primary EOC and its matched resected brain metastasis. A retrospective series of 11 EOC with matched brain metastasis surgically removed was collected. For comparison, a "Control dataset" of 22 patients, without evidence of brain involvement after an adequate follow up was matched. ER, PR, AR and HER2 status were analyzed by means of immunohistochemistry forCases (both primary and metastatic lesions) and Controls.Univariate analysis showed that AR status was significantly associated with brain localization, both considered as discrete variable (cut-off: 10%, p=0.013) and as continuous one (p=0.035). Multivariate analysis confirmed this trend (p=0.053). When considered as continuous variables, ER and AR showed greater expression in primary tumors in comparison with brain metastases (p=0.013 and p=0.032, respectively).In our series, AR predicts brain involvement, with a 9.5 times higher propensity for AR-negative EOC. Moreover, brain dissemination is probably the result of progressive dedifferentiation of primary tumor, shown by reduction of ER and AR expression in metastases. Further studies are required, in order to anticipate and improve multimodal treatment of brain metastases.

Clinical and radiological features driving patient selection for antiangiogenic therapy in non-small cell lung cancer (NSCLC).

BACKGROUND: The use of antiangiogenic therapy in non-small cell lung cancer (NSCLC) requires thorough evaluation of patient characteristics in order to avoid potential safety issues, particularly pulmonary haemorrhage (PH). The aim of this consensus by a panel of experts was to identify important criteria for the selection of patients with NSCLC who would benefit from antiangiogenic therapy. METHODS: Radiologists and oncologists were selected for the expert panel. The nominal group technique (NGT) and the Delphi questionnaire were used for consensus generation. The NGT consisted of four steps, the result of which was used to set the Delphi questionnaire. A final report was generated based on the opinions of the experts from the panel. RESULTS: An extremely important prerequisite for the evaluation of an antiangiogenic therapeutic approach in patients with NSCLC was thorough clinical and radiological analysis of the relationships between tumour and vascular or anatomical structures (performed in close co-operation by oncologists and radiologists). The panel identified major parameters to be considered before the use of antiangiogenic treatment, collectively agreeing on the relevance of tumour cavitation, vascular infiltration, endobronchial growth and thromboembolism for chest tumour sites, and of the presence of aneurysms, extra-thoracic bleeding, brain metastases or thrombi for extra-thoracic sites. Moreover, a structured report containing information not only on the tumour but also on the general vascular status is essential to guide the treatment choice The experts agreed that tumour localization in the absence of vessel infiltration, cavitation, and the use of antiplatelet therapy are relevant parameters to be assessed, but their presence should not necessarily exclude a patient from receiving antiangiogenic therapy. CONCLUSION: Close co-operation between oncologists and radiologists in the diagnosis, treatment selection, and assessment of response is essential for ensuring therapeutic appropriateness in the NSCLC setting. It should be noted that neither the use of antiplatelet therapy nor tumour localisation are to be considered as contraindications to antiangiogenic treatment.

Efficacy and safety of rechallenge treatment with gefitinib in patients with advanced non-small cell lung cancer.

OBJECTIVES: Although patients with advanced non-small cell lung cancer (NSCLC) and an activating epidermal growth factor receptor (EGFR) mutation benefit from the use of EGFR-tyrosine kinase inhibitors (TKI), most of them progress within 12 months from treatment start due to acquired resistance. In clinical practice, many physicians frequently offer these patients retreatment with EGFR-TKIs after a chemotherapy break, based on small or retrospective studies. MATERIALS AND METHODS: A phase II trial was conducted in patients with stage III/IV NSCLC, to assess the efficacy, safety and impact on quality of life (QoL) and disease-related symptoms of gefitinib rechallenge. Eligible patients had initially responded to first-line gefitinib and progressed after second-line chemotherapy. RESULTS: Of 61 enrolled patients, 73.8% were female, 100% had EGFR-mutated adenocarcinoma and 67.2% were never-smokers. Thirty-two (52.5%) patients obtained a clinical benefit, with 3 (4.9%) achieving a partial response and 29 (47.5%) having stable disease. Median progression-free survival was 2.8 months, overall survival 10.2 months and duration of gefitinib treatment 3.6 months. The most common all grade-adverse events were diarrhea (27.6%), nausea and/or vomiting (20.3%), rash (14.7%) and dyspnea (10.3%); no new toxicities were apparent. CONCLUSION: Findings from this study indicate that gefitinib rechallenge offers modest benefit and may be taken into consideration only for patients for whom no other treatment option exists.

Frequency of O6-methylguanine-DNA methyltransferase promoter methylation in cytological samples from small cell lung cancer.

BACKGROUND: In a phase II study for patients with relapsed small cell lung cancer (SCLC), the administration of Temozolomide, an alkylating agent used in gliomas and anaplastic astrocytoma, showed a effective activity when O(6) -methylguanine-DNA methyltransferase (MGMT) gene promoter was methylated. METHODS: We tested the feasibility of MGMT promoter status evaluation in small biopsies and cytological specimens routinely processed for diagnostic purposes. We tested samples from 56 patients with SCLC: 30 tissue biopsies, 17 fine-needle aspiration biopsy, 8 bronchial washing, and 1 was a sputum. Biopsies and fine-needle aspiration biopsy were fixed in formalin, bronchial washing and sputum in Dubosq Brazil. DNA was extracted after macrodissection of the areas containing the maximum number of cancer cells. MGMT promoter methylation status was assessed by methylation specific PCR. RESULTS: Methylation analysis was obtained in 54 samples (54/56) and failed in two bronchial wash. MGMT promoter was methylated in 35.2% of the cases without any significant difference between histological and cytological samples (37.9% vs. 32%). CONCLUSION: MGMT promoter methylation is present in SCLC and cytological samples are perfectly adequate for methylation analysis, even if they were taken during routine diagnostic procedures, using different fixative and with low number and percentage of cancer cells.

Multicenter institutional experience of surgically resected thymic epithelial tumors (TETs): an observational report on behalf of F.O.N.I.C.A.P. (Forza Operativa Nazionale Interdisciplinare Contro il Cancro del Polmone).

BACKGROUND: This multicenter analysis evaluated patient outcome and clinical pathologic features of thymic epithelial tumors after complete surgical resection and adjuvant treatment. METHODS: Histologic classification and clinical staging were performed according to WHO classification and Masaoka staging system, respectively. RESULTS: We analyzed 62 patients, 20 (32%) of whom had myasthenia at diagnosis. Clinical and pathologic staging was as follows: 31 (50%) and 30 (48%) patients had stage I disease, 19 (30%) and 22 (35%) stage II, 5 (8%) and 3 (6%) stage III, 2 (4%) and 2 (3%) stage IVa, and 5 (8%) and 5 (8%) stage IVb, respectively. Histologic examination revealed 11 (19%) type A tumors, 19 (30%) type AB tumors, 7 (12%) type B1 tumors, 11 (17%) type B2 tumors, 11 (17%) type B3 tumors, and 3 (5%) type C tumors. Adjuvant therapies comprised chemotherapy in 3 (5%) patients and radiotherapy in 16 (26%) patients. Median follow-up was 71 months (range 1-145). DFS and OS at 48, 60, and 72 months were 89 and 89%, 86 and 97%, and 95% and 92%, respectively. Myasthenia at the onset of disease (P=0.18 for DFS; P=0.97) and tumor size>5 cm (P=0.94 for DFS; P=0.56) were not prognostic factors. CONCLUSIONS: TETs are rare and indolent tumors. Complete surgical resection followed by adjuvant therapies, such as chemotherapy and/or radiotherapy, in patients at risk of recurrence show very good DFS and OS results, even in cases with radically resected pleural-pulmonary metastases.