European e-Delphi process to define expert consensus on electrochemotherapy treatment indications, procedural aspects, and quality indicators in melanoma.

BACKGROUND: Skin metastases are an important co-morbidity in melanoma. Despite broad adoption, electrochemotherapy implementation is hindered by a lack of treatment indications, uncertainty regarding procedural aspects, and the absence of quality indicators. An expert consensus may harmonize the approach among centres and facilitate comparison with other therapies. METHODS: An interdisciplinary panel was recruited for a three-round e-Delphi survey. A literature-based 113-item questionnaire was proposed to 160 professionals from 53 European centres. Participants rated each item for relevance and degree of agreement on a five-point Likert scale, and received anonymous controlled feedback to allow revision. The items that reached concordant agreement in two successive iterations were included in the final consensus list. In the third round, quality indicator benchmarks were defined using a real-time Delphi method. RESULTS: The initial working group included 122 respondents, of whom 100 (82 per cent) completed the first round, thus qualifying for inclusion in the expert panel (49 surgeons, 29 dermatologists, 15 medical oncologists, three radiotherapists, two nurse specialists, two clinician scientists). The completion rate was 97 per cent (97 of 100) and 93 per cent (90 of 97) in the second and third rounds respectively. The final consensus list included 54 statements with benchmarks (treatment indications, (37); procedural aspects, (1); quality indicators, (16)). CONCLUSION: An expert panel achieved consensus on the use of electrochemotherapy in melanoma, with a core set of statements providing general direction to electrochemotherapy users to refine indications, align clinical practices, and promote quality assurance programmes and local audits. The residual controversial topics set future research priorities to improve patient care.

Electrochemotherapy is an effective locoregional therapy for skin metastases from melanoma, a problem faced by almost half of patients with metastatic disease. The lack of comparative studies and the heterogeneity of its clinical application among centres make it challenging to support consistent, evidence-based recommendations. To address this unmet need, a three-round online survey was conducted to establish a consensus on treatment indications, standard operating procedures, and quality indicators. In the survey, a panel of 100 European melanoma experts agreed on 56 statements that can be used to improve patient selection, homogenize treatment application, and monitor outcomes.

Nivolumab in Combination with Stereotactic Body Radiotherapy in Pretreated Patients with Metastatic Renal Cell Carcinoma. Results of the Phase II NIVES Study.

BACKGROUND: Nivolumab showed an overall survival (OS) benefit in pretreated metastatic renal cell carcinoma (mRCC). The role of stereotactic body radiotherapy (SBRT) in mRCC remains to be defined. OBJECTIVE: Our aim was to evaluate the efficacy and safety of SBRT in combination with nivolumab in second- and third-line mRCC patients. DESIGN, SETTING, AND PARTICIPANTS: The NIVES study was a phase II, single-arm, multicenter trial in patients with mRCC with measurable metastatic sites who progressed after antiangiogenic therapy, of whom at least one was suitable for SBRT. INTERVENTION: The patients received SBRT to a lesion at a dose of 10 Gy in three fractions for 7 d from the first infusion of nivolumab. Nivolumab was given at an initial dose of 240 mg every 14 d for 6 mo and then 480 mg q4-weekly in responding patients. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We hypothesized that nivolumab plus SBRT improves the objective response rate (ORR) compared with nivolumab alone from 25% (derived from historical controls) to 40%. Secondary endpoints were progression-free survival (PFS), OS, disease control rate (DCR) of irradiated and nonirradiated metastases, and safety. RESULTS AND LIMITATIONS: Sixty-nine patients were enrolled from July 2017 to March 2019. The ORR was 17% and the DCR was 55%. The median PFS was 5.6 mo (95% confidence interval [CI], 2.9-7.1) and median OS 20 mo (95% CI, 17-not reached). After 1.5 yr of follow-up, 23 patients died. The median time to treatment response was 2.8 mo and median duration of response was 14 mo. No new safety concerns arose. CONCLUSIONS: We did not find sufficient evidence to suggest that nivolumab in combination with SBRT provides an added benefit in pretreated mRCC patients; it should however be evaluated in patients with oligometastatic or oligoprogressive disease. PATIENT SUMMARY: Nivolumab in combination with stereotactic body radiotherapy does not provide evidence of increased outcomes in metastatic renal cell carcinoma patients. However this approach was safe and showed a good response of the irradiated lesions.

Maintenance versus discontinuation of androgen deprivation therapy during continuous or intermittent docetaxel administration in castration-resistant prostate cancer patients: A multicentre, randomised Phase III study by the Piemonte Oncology Network.

BACKGROUND: This study was designed to demonstrate the non-inferiority (NI) in overall survival (OS) of suspension of androgen deprivation therapy (ADT) versus maintenance and intermittent versus continuous docetaxel administration in metastatic castration-resistant prostate cancer (mCRPC) patients. PATIENTS AND METHODS: mCRPC patients were randomised to first-line docetaxel with maintenance or suspension of ADT. Patients attaining a prostate-specific antigen (PSA) response after four chemotherapy cycles underwent second randomisation to receive continuous or intermittent docetaxel therapy. Six hundred patients were to be randomised to achieve 80% statistical power to demonstrate an NI hazard ratio (HR) of 1.25 of interruption versus maintenance of ADT. RESULTS: The trial was prematurely closed when 198 participants were randomised. OS was similar in patients who continued (N = 96) versus those who interrupted (n = 102) ADT during docetaxel therapy (HR 0.98, 95% confidence interval [CI] 0.72-1.33] and those on a continuous (N = 35) versus an intermittent (N = 42) docetaxel schedule (HR 0.86, 95% CI 0.55-1.43). No difference in radiological progression-free survival, PSA response, or toxicity was observed between the study arms. The actual NI hazard margins of OS in Arms A and B patients were 1.33 and 1.43, respectively. CONCLUSIONS: This trial enrolled one-third of the planned patients; this main weakness dramatically limits the interpretation of the results. ADT discontinuation and switching to an intermittent schedule did not seem to affect docetaxel efficacy. The absence of testosterone recovery in the majority of patients could have been a contributory factor. In men with mCRPC, ADT discontinuation should only be done with regular biochemical and clinical monitoring, with the option of quickly restarting ADT at disease progression.

Results From a Large, Multicenter, Retrospective Analysis On Radium223 Use in Metastatic Castration-resistant Prostate Cancer (mCRPC) in the Triveneto Italian Region.

BACKGROUND: Radium 223 was introduced for metastatic castration-resistant prostate cancer based on the results of a randomized controlled trial showing risk reduction for death and skeletal events. Our aim was to evaluate the outcome of patients receiving radium 223 in a real-world setting. PATIENTS AND METHODS: We conducted a multicenter retrospective analysis in the Triveneto region of Italy. RESULTS: One hundred fifty-eight patients received radium 223 in our region. After a median follow-up of 9.5 months, 75 patients died. The median overall survival (OS) was 14.2 months, and the median progression-free survival (PFS) was 6.2 months. Seventy-one (45%) patients achieved progression as best response. Thirty-seven (23%) patients stopped the treatment early because of progression. Eastern Cooperative Oncology Group performance status was prognostic for OS (18.4 vs. 12.3 vs. 7.5 months; 0 vs. 1, P = .0062; 0 vs. 2, P = .0002), whereas previous prostatectomy or docetaxel exposure were not. A neutrophil to lymphocytes ratio ≥ 3 significantly impacted OS (18.1 vs. 9.7 months; P < .001) and slightly impacted PFS (6.6 vs. 5.6 months; P = .05). Patients with a baseline alkaline phosphatase (ALP) value ≥ 220 U/L had worse OS and PFS (24.1 vs. 10.5 months; 7.2 vs. 5.5 months; P < .001). Patients with changes in ALP value achieved better OS (P = .029) and PFS (P = .002). There was no difference according to the line of therapy (0 vs. ≥ 1; P = .490). The main grade 3/4 toxicities were anemia, asthenia, and thrombocytopenia. CONCLUSION: This large real-world report confirms comparable OS and PFS data when compared with the pivotal study, as well as the predictive role of ALP and neutrophil to lymphocytes ratio. The definition of the optimal position of radium 223 in the treatment of metastatic castration-resistant prostate cancer has still to be defined.

Effectiveness of an additional individualized multi-component complementary medicine treatment on health-related quality of life in breast cancer patients: a pragmatic randomized trial.

The aim of this study was to evaluate the effectiveness of an additional, individualized, multi-component complementary medicine treatment offered to breast cancer patients at the Merano Hospital (South Tyrol) on health-related quality of life compared to patients receiving usual care only. A randomized pragmatic trial with two parallel arms was performed. Women with confirmed diagnoses of breast cancer were randomized (stratified by usual care treatment) to receive individualized complementary medicine (CM group) or usual care alone (usual care group). Both groups were allowed to use conventional treatment for breast cancer. Primary endpoint was the breast cancer-related quality of life FACT-B score at 6 months. For statistical analysis, we used analysis of covariance (with factors treatment, stratum, and baseline FACT-B score) and imputed missing FACT-B scores at 6 months with regression-based multiple imputation. A total of 275 patients were randomized between April 2011 and March 2012 to the CM group (n = 136, 56.3 ± 10.9 years of age) or the usual care group (n = 139, 56.0 ± 11.0). After 6 months from randomization, adjusted means for health-related quality of life were higher in the CM group (FACT-B score 107.9; 95 % CI 104.1-111.7) compared to the usual care group (102.2; 98.5-105.9) with an adjusted FACT-B score difference between groups of 5.7 (2.6-8.7, p < 0.001). Thus, an additional individualized and complex complementary medicine intervention improved quality of life of breast cancer patients compared to usual care alone. Further studies evaluating specific effects of treatment components should follow to optimize the treatment of breast cancer patients.

Fatal interstitial pneumonitis associated with docetaxel administration in a patient with hormone-refractory prostate cancer.

Taxanes are widely used chemotherapeutic agents with the potential to induce pulmonary injury through a variety of mechanisms. Patients receiving these agents are at risk of acute or subacute pulmonary damage. The case is presented of a 72-year-old man with hormone-refractory prostate cancer and weekly administration of 30 mg/m2 docetaxel who developed subacute interstitial pneumonitis-related pulmonary fibrosis after seven doses and died despite mechanical ventilation and high-dose corticosteroid treatment. Even though only a few cases of this adverse event have been reported in the literature, severe docetaxel-induced pulmonary toxicity needs to be considered in the differential diagnosis when such patients present with respiratory symptoms.

Combined effects of protein kinase inhibitors and 5-fluorouracil on CEA expression in human colon cancer cells.

Previous studies showed that 5-fluorouracil (5-FU) and Staurosporine (ST), a protein kinase inhibitor (PKI), were able to increase the expression of carcinoembryonic antigen (CEA) in human colon cancer cells. In the present study, we examined the in vitro effects of five PKIs, i.e. ST, 1-5-isoquinolinyl-sulfonyl-2-methylpiperazine (H-7), bisindolylmaleimide-I (BIS), Genistein (GEN), and Herbimycin A (HERB) alone or in combination with 5-FU on CEA expression. C22-20, a clonal subline, derived from colon cancer HT-29 line, selected for low expression of CEA, was used in our experimental model. Among the PKIs tested, only ST, at non-toxic concentrations of 5 nM, was capable of increasing the level of CEA. The other PKIs did not modify CEA expression when used either alone or in combination with 5-FU. Flow cytometric analysis showed that treatment of cells with 5-FU + ST resulted in a synergistic increase of CEA expression, being higher than that obtainable with both agents alone. Moreover, the increase of CEA expression occurred not only in membrane fractions but also in cytosolic compartments, as indicated by Western blot analysis. The present study suggests that ST-mediated induction of CEA expression in cancer cells is PKC independent and could be of potential clinical interest for the development of new diagnostic and/or immunotherapeutic approaches.

Pharmacological modulation of carcinoembryonic antigen in human cancer cells: studies with staurosporine.

Preliminary studies, performed in our laboratory, showed that staurosporine (ST), a protein-kinase (PK) inhibitor, increases the expression of the carcinoembryonic antigen (CEA) in a human colon cancer cell line. The present study explores the cellular and molecular effects of ST on the CEA expression in breast cancer MCF-7 line and in a number of colon cancer cell lines characterized by the different basal levels of the antigen, including two cloned sublines (i.e. C22.20 and C6.6, expressing low and high CEA levels, respectively). In all cases, increase of the CEA expression was observed at drug concentrations devoid of marked cytostatic effects (e.g. 5 nM) and was accompanied by the enhanced CEA shedding in the supernatant. Moreover, the increase of the CEA levels both occurred in the cell membranes and in the cytosolic compartments and appeared to be the result of the enhanced CEA gene transcription. Similar results have been previously obtained with interferon-gamma. However, ST treatment, different from interferon-gamma, did not up-regulate the level of the HLA class I molecules. A preliminary investigation also showed that other PKC inhibitors did not substantially modulate the CEA expression. Therefore, the biochemical mechanism underlying the effect of ST should not be correlated with that involved in the PKC inhibition. The present study suggests that ST and, presumably, its analogs used in the cancer treatment could enhance the CEA expression on neoplastic cells in patients affected by the CEA-positive malignancies. This appears to be of potential clinical interest for the development of new immunotherapeutic or diagnostic approaches based on the pharmacological modulation of this antigenic marker.