Real-World Treatment with Nivolumab or Cabozantinib for Metastatic Renal Cell Carcinoma (mRCC) in the Veneto Region of Italy: Results of AMOUR Study.

BACKGROUND: Second- or third-line treatment options for metastatic renal cell carcinoma (mRCC) have dramatically changed in the last few years. There are no criteria for the choice between nivolumab and cabozantinib, which both demonstrated overall survival (OS) gain in pivotal trials. OBJECTIVE: We conducted an analysis of oncological outcomes in patients treated in the Veneto Region (Italy), studying different sequences of TKI-nivolumab-cabozantinib or TKI-cabozantinib-nivolumab in a publicly funded healthcare system. PATIENTS AND METHODS: We conducted a retrospective, real-world analysis of all consecutive patients with mRCC treated with nivolumab or cabozantinib in 2017-2018 at 19 Oncology Units in the Veneto Region. RESULTS: We identified 170 patients, 73 % males, median age 68.4 years. All patients started second-line treatment, 59 % received a third-line therapy. Patients with NLR > 3 had a shorter OS (p < 0.0001). In the second-line treatment, nivolumab was administered to 108 patients (63 %), cabozantinib to 29 (17 %); in the third-line treatment nivolumab was administered to 42 patients (25 %), cabozantinib to 49 (29 %). Median OS and PFS in second line treatment were 28.4 and 6.6 months for nivolumab, 16.8 and 6.6 months for cabozantinib. Median OS and PFS in third-line treatment were 27 and 5.2 months for nivolumab, 16.6 and 7.5 months for cabozantinib. Median OS for nivolumab>cabozantinib sequence versus cabozantinib > nivolumab was 28.8 versus 19.9 months (p = 0.2); median PFS for both the sequences were similar at 5.7 months. A cost effectiveness per month of survival of the two sequences analysis was performed: the cost per month for the nivolumab > cabozantinib sequence was 1738.60whereas the cost for the other one was €1624.80. CONCLUSIONS: In our real-world cohort, most patients received nivolumab as second-line treatment. Outcomes of single drugs are superimposable with those in the published literature. Both the sequences of nivolumab and cabozantinib appear to be viable, effective strategies from an OS and cost-effective perspective.

Predicting steady-state endoxifen plasma concentrations in breast cancer patients by CYP2D6 genotyping or phenotyping. Which approach is more reliable?

In previous studies, steady-state Z-endoxifen plasma concentrations (ENDOss) correlated with relapse-free survival in women on tamoxifen (TAM) treatment for breast cancer. ENDOss also correlated significantly with CYP2D6 genotype (activity score) and CYP2D6 phenotype (dextromethorphan test). Our aim was to ascertain which method for assessing CYP2D6 activity is more reliable in predicting ENDOss. The study concerned 203 Caucasian women on tamoxifen-adjuvant therapy (20 mg q.d.). Before starting treatment, CYP2D6 was genotyped (and activity scores computed), and the urinary log(dextromethorphan/dextrorphan) ratio [log(DM/DX)] was calculated after 15 mg of oral dextromethorphan. Plasma concentrations of TAM, N-desmethyl-tamoxifen (ND-TAM), Z-4OH-tamoxifen (4OH-TAM) and ENDO were assayed 1, 4, and 8 months after first administering TAM. Multivariable regression analysis was used to identify the clinical and laboratory variables predicting log-transformed ENDOss (log-ENDOss). Genotype-derived CYP2D6 phenotypes (PM, IM, NM, EM) and log(DM/DX) correlated independently with log-ENDOss. Genotype-phenotype concordance was almost complete only for poor metabolizers, whereas it emerged that 34% of intermediate, normal, and ultrarapid metabolizers were classified differently based on log(DM/DX). Multivariable regression analysis selected log(DM/DX) as the best predictor, with patients' age, weak inhibitor use, and CYP2D6 phenotype decreasingly important: log-ENDOss = 0.162 - log(DM/DX) × 0.170 + age × 0.0063 - weak inhibitor use × 0.250 + IM × 0.105 + (NM + UM) × 0.210; (R2  = 0.51). In conclusion, log(DM/DX) seems superior to genotype-derived CYP2D6 phenotype in predicting ENDOss.

Immune Modulation in Prostate Cancer Patients Treated with Androgen Receptor (AR)-Targeted Therapy.

Androgen deprivation therapy (ADT) is a cornerstone of treatment for prostate cancer and, in recent years, androgen receptor (AR)-targeted therapies (abiraterone and enzalutamide) have both been used for the treatment of castration-resistant prostate cancer (CRPC). In our study, we sought to investigate the association between ADT and immune disorders, considering a potential role of androgens in the immune modulation. We retrospectively evaluated CRPC patients treated with abiraterone/enzalutamide between July 2011 and December 2018. We assessed the risk of developing immune alterations and their impact on outcome. We included 844 CRPC patients receiving AR-directed therapies, of whom 36 (4.3%) had autoimmune diseases and 47 (5.6%) second tumors as comorbidities. Median age was 70 years [interquartile range (IQR) = 63-75)]. We showed higher significant incidence of autoimmune diseases during their hormone sensitive status (p = 0.021) and the presence of autoimmune comorbidities before starting treatment with abiraterone/enzalutamide was significantly associated with worse overall survival (OS) (10.1 vs. 13.7 months, HR = 1.59, 95% CI 1.03-2.27, p = 0.038). In a multivariate analysis, the presence of autoimmune disorders was an independent predictor of OS (HR = 1.65, 95% CI 1.05-2.60, p = 0.031). In conclusion, CRPC patients with autoimmune alterations before starting AR-directed therapies may have worse prognosis. Further prospective studies are warranted to assess the role of immune modulation in the management of prostate cancer patients.

Impact of palliative care unit admission on symptom control evaluated by the edmonton symptom assessment system.

The aim of the present study was to evaluate the impact of palliative care on patients' symptoms, using the Edmonton Symptom Assessment System (ESAS) to measure symptom intensity at the time of admission and variations registered during the first 7 days' hospitalization. Three hundred fourteen patients were admitted to the unit during its first year of activity. Of these, 162 patients (51.6%) completed, 62 (19.7%) partially completed, and 90 (28.7%) did not complete the ESAS. The mean (+/-SD) value of the Symptom Distress Score (SDS) (sum of the values of the different symptoms) for the 162 evaluable patients on Day 1 was 33.93 (+/-16.24). On Day 7 the mean was 28.14 (+/-15.11) (ANOVA for repeated measurements, P < 0.0001). ESAS values for patients with moderate-severe symptom intensity (average values Day 1-Day 7 and P value, ANOVA for repeated measurements) were as follows: pain (7.12-4.23, P < 0.0001), fatigue (7.46-5.68, P < 0.0001), nausea (7.12-1.96, P < 0.0001), depression (7.26-5.28, P < 0.0001), anxiety (7.13-5.14, P < 0.0001), drowsiness (7.42-6.40, P = 0.002), anorexia (7.33-4.33, P < 0.0001), well-being (6.83-3.85, P < 0.0001), and dyspnea (7.08-3.86, P < 0.0001). These data seem to indicate that the patients who benefit most from inpatient palliative care are those with the most complex symptomatology.

[Clinical postoperative surveillance of breast carcinoma]. / Sorveglianza clinica post-operatoria del carcinoma mammario.

The problem of post-surgical clinical follow-up for breast cancer patients is still open. A lot of comparative studies between intensive and minimal follow-up showed no advantage of the former vs. the latter modality. The above data have been confirmed also from sistematic revisions and from pharmaco-economic studies. The ASCO guidelines confirm the importance of clinical surveillance, together with annual mammography and pelvic examination, while no blood tests or other instrumental examinations are indicated in absence of specific symptoms. The follow-up program needs to be realized under the supervision of a specialist with specific experience in the oncologic evaluation. Concerning the patients with high risk of recurrence, there is no agreement, even if no advantage seems to exist with an intensive follow-up program in terms of quality or quantity of life. The Authors suggest that the standard follow-up program should include a thoracic X-ray picture and an abdominal USG, in order to detect early a small number (< or = 2 sites) of visceral metastases, amenable of a treatment. The above program should be realized from a multidisciplinary team (surgeon, medical oncologist, radiotherapist) gaining in terms of quality and sparing time and resources.

A validation study of the WHO analgesic ladder: a two-step vs three-step strategy.

GOALS OF WORK: The aims of the present study were to verify whether an innovative therapeutic strategy for the treatment of mild-moderate chronic cancer pain, passing directly from step I to step III of the WHO analgesic ladder, is more effective than the traditional three-step strategy and to evaluate the tolerability and therapeutic index in both strategies. METHODS: Patients aged 18 years or older with multiple viscera or bone metastases or with locally advanced disease were randomized. Pain intensity was assessed using a 0-10 numerical rating scale based on four questions selected from the validated Italian version of the Brief Pain Inventory. Treatment-specific variables and other symptoms were recorded at baseline up to a maximum follow-up of 90 days per patient. RESULTS: Fifty-four patients were randomized onto the study, and pain intensity was assessed over a period of 2,649 days. The innovative treatment presented a statistically significant advantage over the traditional strategy in terms of the percentage of days with worst pain > or =5 (22.8 vs 28.6%, p < 0.001) and > or =7 (8.6 vs 11.2%, p = 0.023). Grades 3 and 4 anorexia and constipation were more frequently reported in the innovative strategy arm, although prophylactic laxative therapy was used less in this setting. CONCLUSIONS: Our preliminary data would seem to suggest that a direct move to the third step of the WHO analgesic ladder is feasible and could reduce some pain scores but also requires careful management of side effects.