Oxaliplatin plus fluoropyrimidines as adjuvant therapy for colon cancer in older patients: A subgroup analysis from the TOSCA trial.

BACKGROUND: Previous studies on oxaliplatin and fluoropyrimidines as adjuvant therapy in older patients with stage III colon cancer (CC) produced conflicting results. PATIENTS AND METHODS: We assessed the impact of age on time to tumour recurrence (TTR), disease-free survival (DFS), cancer-specific survival (CSS), and overall survival (OS) in 2360 patients with stage III CC (1667 aged <70 years and 693 ≥ 70 years) randomised to receive 3 or 6 months of FOLFOX or CAPOX within the frame of the phase III, TOSCA study. RESULTS: Older patients compared with younger ones presented more frequently an Eastern Cooperative Oncology Group performance status equal to 1 (10.5% vs 3.3%, p < 0.001), a greater number of right-sided tumours (40.9% vs 26.6%, p < 0.001), and were at higher clinical risk (37.2% vs 33.2%, p = 0.062). The treatments were almost identical in the two cohorts (p = 0.965). We found a greater proportion of dose reductions (46.7% vs 41.4%, p = 0.018), treatment interruptions (26.1% vs 19.3%, p < 0.001) and a higher proportion of recurrences (24.2% vs 20.3%, p = 0.033) in the older patients. The multivariable analysis of the TTR did not indicate a statistically significant effect of age (hazard ratio [HR]: 1.19; 95% confidence interval [CI]: 0.98-1.44; p = 0.082). The HR comparing older with younger patients was 1.34 (95% CI: 1.12-1.59; p = 0.001) for DFS, 1.58 (95% CI: 1.26-1.99; p < 0.001) for OS, and 1.28 (95% CI: 0.96-1.70; p = 0.089) for CSS. CONCLUSIONS: Worse prognostic factors and reduced treatment compliance have a negative impact on the efficacy of oxaliplatin-based adjuvant therapy in older patients.

Evaluation of Clear Cell, Papillary, and Chromophobe Renal Cell Carcinoma Metastasis Sites and Association With Survival.

Importance: There exists considerable biological and clinical variability between histologic variants of metastatic renal cell carcinoma (mRCC). Data reporting on patterns of metastasis in histologic variants of mRCC are sparse. Objective: To characterize sites of metastasis and their association with survival across the 3 most common histologic variants of mRCC: clear cell (ccRCC), papillary (pRCC), and chromophobe (chrRCC). Design, Setting, and Participants: In this multicenter, international cohort study, the International mRCC Database Consortium (IMDC) database was used to identify consecutive patients starting systemic therapy for mRCC between 2002 and 2019. Patients with mixed histologic subtype were excluded. Statistical analysis was performed from February to June 2020. Exposures: Data regarding histologic subtype and sites of metastatic involvement at the time of first systemic therapy initiation were collected. Main Outcomes and Measures: The primary outcomes were prevalence of metastatic site involvement and overall survival (OS) from time of systemic therapy initiation. Patients with multiple sites of metastatic involvement were included in analyses of all groups to which they had metastases. Results: A total of 10 105 patients were eligible for analysis. Median (interquartile range) age at diagnosis was 60 (53-67) years, 7310 (72.4%) were men and 8526 (84.5%) underwent nephrectomy. Of these, 9252 (92%) had ccRCC, 667 (7%) had pRCC, and 186 (2%) had chrRCC. The median number of sites of metastasis was 2 (range, 0-7). In ccRCC, the most common sites of metastasis were lung (70%; 6189 of 8804 patients [448 missing]), lymph nodes (45%; 3874 of 8655 patients [597 missing]), bone (32%; 2847 of 8817 patients [435 missing]), liver (18%; 1560 of 8804 [448 missing]), and adrenal gland (10%; 678 of 6673 patients [2579 missing]). Sites of metastasis varied between subtypes. Lung, adrenal, brain, and pancreatic metastases were more frequent in ccRCC, lymph node involvement was more common in pRCC, and liver metastases were more frequent in chrRCC. Median OS for ccRCC varied by site of metastatic involvement, ranging between 16 months (95% CI, 13.7-18.8 months) for the pleura and 50 months (95% CI, 41.1-55.5 months) for the pancreas. Compared with ccRCC, patients with pRCC tended to have lower OS, regardless of metastatic site. Conclusions and Relevance: Sites of metastatic involvement differ according to histologic subtype in mRCC and are associated with OS. These data highlight the clinical and biological variability between histologic subtypes of mRCC. Patterns of metastatic spread may reflect differences in underlying disease biology. Further work to investigate differences in immune, molecular, and genetic profiles between metastatic sites and histologic subtypes is encouraged.

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.

Deferred Cytoreductive Nephrectomy in Patients with Newly Diagnosed Metastatic Renal Cell Carcinoma.

BACKGROUND: The use of cytoreductive nephrectomy (CN) selectively for patients who show a favorable response to upfront systemic therapy may be an approach to select optimal candidates with metastatic renal cell carcinoma (mRCC) who are most likely to benefit. OBJECTIVE: We sought to characterize outcomes of deferred CN (dCN) after upfront sunitinib, outcomes relative to sunitinib alone, and outcomes of CN followed by sunitinib. DESIGN, SETTING, AND PARTICIPANTS: We used the prospectively maintained International mRCC Database Consortium (IMDC) database to identify patients with newly diagnosed mRCC (2006-2018). INTERVENTION: Sunitinib alone, upfront CN followed by sunitinib, sunitinib followed by dCN. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Outcomes were overall survival (OS) and time to sunitinib treatment failure (TTF). Kaplan-Meier and multivariable Cox regression analyses were performed; dCN was analyzed as a time-varying covariate to account for immortal time bias. RESULTS AND LIMITATIONS: We evaluated 1541 patients, of whom 651 (42%) received sunitinib alone, 805 (52%) underwent CN followed by sunitinib, and 85 (5.5%) received sunitinib followed by dCN, at a median of 7.8 mo from diagnosis. Median OS periods for patients treated with sunitinib alone, CN followed by sunitinib, and sunitinib followed by dCN were 10, 19, and 46 mo, respectively, while the median TTF values were 4, 8, and 13 mo, respectively. In multivariable regression analyses, sunitinib followed by dCN was significantly associated with improved OS (hazard ratio [HR] = 0.45, 95% confidence interval [CI] 0.33-0.60, p < 0.001) and TTF (HR = 0.62, 95% CI 0.46-0.85, p = 0.003) versus sunitinib alone. Among CN-treated patients, sunitinib followed by dCN was associated with improved OS (HR = 0.52, 95% CI 0.39-0.70, p < 0.001) and TTF (HR = 0.71, 95% CI 0.56-0.90, p = 0.005) compared with upfront CN followed by sunitinib. In various sensitivity analyses, dCN remained significantly associated with improved OS and TTF. CONCLUSIONS: Patients who received dCN were carefully selected and achieved long OS. With these benchmark outcomes, optimal selection criteria need to be identified and confirmation of the role of dCN in a clinical trial is warranted. PATIENT SUMMARY: We characterized benchmark survival outcomes for patients with metastatic kidney cancer treated with sunitinib alone, nephrectomy (kidney removal) followed by sunitinib, and sunitinib followed by nephrectomy. Patients who had their nephrectomy after an initial course of sunitinib had prolonged survival.

Cytoreductive Nephrectomy in Metastatic Papillary Renal Cell Carcinoma: Results from the International Metastatic Renal Cell Carcinoma Database Consortium.

BACKGROUND: There is evidence that cytoreductive nephrectomy (CN) may be beneficial in metastatic renal cell carcinoma (mRCC). This has been studied predominantly in clear-cell RCC, with more limited data on the role of CN in patients with papillary histology. OBJECTIVE: To determine the benefit of CN in synchronous metastatic papillary RCC. DESIGN, SETTING, AND PARTICIPANTS: Using the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) database, a retrospective analysis was performed for patients with papillary mRCC treated with or without CN. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Median overall survival (OS) and progression-free survival (PFS) were determined for both patient groups. Cox regression analysis was performed to control for imbalances in individual IMDC risk factors. RESULTS AND LIMITATIONS: In total, 647 patients with papillary mRCC were identified, of whom 353 had synchronous metastatic disease. Of these, 109 patients were treated with CN and 244 were not. The median follow-up was 57.1mo (95% confidence interval [CI] 32.9-77.8) and the OS from the start of first-line targeted therapy for the entire cohort was 13.2mo (95% CI 12.0-16.1). Median OS for patients with CN was 16.3mo, compared to 8.6mo (p<0.0001) in the no-CN group. When adjusted for individual IMDC risk factors, the hazard ratio (HR) of death for CN was 0.62 (95% CI 0.45-0.85; p=0.0031). Limitations include the retrospective nature of the analysis. CONCLUSIONS: The use of CN in patients with mRCC and papillary histology appears to be associated with better survival compared to no CN after adjustment for risk criteria. Selection of appropriate candidates for CN is crucial. A clinical trial in this rare population may not be possible. PATIENT SUMMARY: In a population of patients with advanced papillary kidney cancer, we found that surgical removal of the primary kidney tumor was associated with better overall survival.

An individual patient-data meta-analysis of metronomic oral vinorelbine in metastatic non-small cell lung cancer.

INTRODUCTION: Several non-comparative phase II studies have evaluated metronomic oral vinorelbine (MOV) in metastatic non-small cell lung cancer (NSCLC) but the small size of each study limits their conclusions. PURPOSE: To perform an individual patient-data metaanalysis of studies evaluating MOV in metastatic NSCLC in order to measure survival and safety of treatment with this regimen. METHODS: Studies were selected if (1) administration of oral vinorelbine thrice a week; (2) fixed daily dose comprised between 30 and 50 mg, and; (3) being published before October 4th 2018. Database encompassed 8 variables characterizing disease and demography, 3 informing therapy, and 12 describing survival and toxicity. RESULTS: Nine studies encompassing 418 patients fulfilled the selection criteria, 80% of them having frailty characteristics. Median overall survival (OS) was 8.7 months (95%CI: 7.6-9.5). OSrates at 6 months, one year and at two years after starting vinorelbine were 64%, 30.3% and 8.9%, respectively. In the Cox model, Eastern Cooperative Oncology Group (ECOG) performance status (PS) = 2, and anemia of any grade were significant determinants of shorter OS. Median progression-free survival(PFS) was 4.2 months (95%CI: 3.9-5). At 6 months and at one-year, PFS rates were 35% and 11.9% respectively. In the Cox model stratified for the variable "study", PS = 2and stage IV were significant determinants of shorter PFS. No toxicity was reported for 40% of patients, and 66 (15.8%) patients experienced a grade 3-4 toxicity. The most frequent toxicity was anemia of any grade (35.8%) that was higher with the 50 mg dosage. CONCLUSION: MOV is an active and well-tolerated chemotherapy in metastatic NSCLC and is a manageable therapy in frail patients.

Oral maintenance metronomic vinorelbine versus best supportive care in advanced non-small-cell lung cancer after platinum-based chemotherapy: The MA.NI.LA. multicenter, randomized, controlled, phase II trial.

BACKGROUND: Oral vinorelbine administered at the maximum tolerated dose has already showed activity and a good safety profile in advanced non-small-cell lung cancer (NSCLC). The MA.NI.LA study was a phase II, multicenter, randomized, controlled trial that aimed to assess the effects of a 'switched maintenance' regimen with oral metronomic vinorelbine (OMV) in patients with NSCLC who had not progressed after first-line platinum-based chemotherapy. PATIENTS AND METHODS: Patients were randomly assigned in a 1:1 ratio to either OMV (50 mg three-times weekly) as maintenance treatment or best supportive care (BSC). The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective disease control rate (DCR, CR + PR + SD), safety and quality of life. RESULTS: In total, 61 and 59 patients were assigned to OMV and BSC, respectively. At a median follow-up of 23.9 (IQR 10.2-38.2) months, patients treated with OMV reported a significantly lower progression rate compared to patient in the BSC arm (89% [54/61] vs 96% [56/58]; HR 0.73; 90% CI 0.53-0.999, p = 0.049). Median PFS for patients treated with vinorelbine was 4.3 months (95% CI 2.8-5.6) vs 2.8 months (95% CI 1.9-4.5) for patients receiving BSC. This benefit was specifically evident in patients aged ≥70 years, in current smokers, and in those who reported disease stabilization as best response to induction chemotherapy. OS and response rate and quality of life were similar in the two arms. Drop-out rate for major toxicity with OMV was unexpectedly high (25%, 14/61) mainly due to grade 3-4 neutropenia (11%, 7/61). Conclusions In patients with unselected NSCLC achieving disease control after platinum-based chemotherapy switch maintenance therapy with OMV prolonged PFS compared to BSC; however, the optimal dose of OMV requires further investigation.

Clinical outcomes of oral metronomic vinorelbine in advanced non-small cell lung cancer: correlations with pharmacokinetics and MDR1 polymorphisms.

PURPOSE: This study investigated correlations of the clinical outcomes of oral metronomic vinorelbine (VNR) with VNR pharmacokinetics and MDR1 polymorphisms. METHODS: Eighty-two patients with metastatic non-small cell lung cancer (NSCLC) unfit for standard chemotherapy were treated with VNR at the oral doses of 20-30 mg every other day or 50 mg three times a week. They had a performance status (PS) ≤ 3, were > 70-year-old and drug-naïve or cisplatin-pretreated. MDR1 2677G > T and 3435C > T polymorphisms were analysed and blood concentrations of VNR and desacetyl-VNR (dVNR: active metabolite) assayed. Overall survival (OS), treatment duration and drug-related toxicity were the main endpoints. RESULTS: Median OS and treatment duration were 27 weeks (range 1.3-183) and 15 weeks (range 1.3-144), respectively. OS was directly correlated with the duration of VNR treatment and number of therapy lines after VNR treatment (multiple linear regression: adjusted r2 = 0.71; p < 0.00001). Neither MDR1 genotypes nor VNR/dVNR concentrations predicted OS. VNR blood levels were positively correlated with platelet counts (r2 = 0.12; p = 0.0036). Patients who had long-term benefit (treated for ≥ 6 month without toxicity) showed lower VNR concentrations than those who had not. Twelve patients stopped therapy due to grade 3-4 toxicity. Toxicity was associated with blood concentrations of VNR ≥ 1.57 ng/mL and dVNR ≥ 3.04 ng/mL, but not with MDR1 polymorphisms. CONCLUSIONS: Neither pharmacokinetic nor pharmacogenetic monitoring seem useful to predict OS. On the other hand, high VNR and dVNR blood levels were associated with severe toxicity.

Oral Metronomic Vinorelbine (OMV) in elderly or pretreated patients with advanced non small cell lung cancer: outcome and pharmacokinetics in the real world.

Background Oral metronomic therapy (OMV) is particularly suitable for palliative care, and schedules adapted for unfit patients are advisable. This study investigated the effects of oral vinorelbine given every other day without interruption and its pharmacokinetic profile in patients with advanced lung cancer. Materials and Methods Ninety-two patients received OMV at doses of 20, 30 or 50 mg. Toxic events, clinical benefit and overall survival were analysed. Blood pharmacokinetics were evaluated in 82 patients. Results Median treatment duration and overall survival were 15 (range 1.3-144) and 32.3 weeks, respectively; fourty-eight (60%) patients experienced clinical benefit. Outcomes were unrelated to previous therapies, age, histology or comorbidities. Toxicity was associated with higher blood concentrations of the drug. Pharmacokinetics were stable for up to two years, and were not influenced by treatment line or age. Conclusions OMV produced non-negligible survival in patients and also showed stable long-term blood concentrations. The schedule of 20-30 mg every other day without interruption gave good tolerability and clinical benefit.

Rapid LC-MS/MS method for quantification of vinorelbine and 4-O-deacetylvinorelbine in human whole blood suitable to monitoring oral metronomic anticancer therapy.

A rapid and sensitive LC-MS/MS method for therapeutic drug monitoring oral vinorelbine (VRL) metronomic anticancer chemotherapy has been developed and validated. Analysis of VRL and its main active metabolite 4-O-deacetylvinorelbine (M1) was performed in whole blood matrix. Both analytes were extracted by protein precipitation and separated on an Onyx monolith C18 , 50 × 2 mm column then quantified by positive electrospray ionization and multiple reaction monitoring mode. The LLOQ was 0.05 ng/mL for both VRL and M1. Linearity was up to 25ng/mL with R2 ≥ 0.994. The intra- and inter-assay precisions were ≤ 11.6 and ≤ 10.4% while the ranges of accuracy were [-8.7%; 10.3%] and [-10.0; 7.4%] for VRL and M1, respectively. The clinical suitability of the method has been proved by the determination of the CTrough blood concentrations of VRL and M1 in 64 nonsmall cell lung cancer elderly patients. The analytical performance of the assay was suitable for pharmacokinetic monitoring of VRL and M1, allowing the personalization of the VRL metronomic treatments.

Is It Possible to Improve Prognostic Classification in Patients Affected by Metastatic Renal Cell Carcinoma With an Intermediate or Poor Prognosis?

BACKGROUND: The International mRCC (metastatic renal cell carcinoma) Database Consortium (IMDC) is the standard classification for mRCC. We aimed to evaluate the outcomes of a large cohort of patients with an intermediate or a poor prognosis treated with sunitinib using a different cutoff point for IMDC to improve the classification. PATIENTS AND METHODS: Patients with an intermediate or a poor prognosis according to the IMDC criteria and treated with sunitinib were included in the present study. A new cutoff point was used to categorize the patients. The new score was validated in an independent cohort of patients. RESULTS: A total of 457 patients were included in the present study. Significant differences in overall survival (OS) were highlighted regarding the number of prognostic factors. Three categories were identified according to the presence of 1 (ie, favorable-intermediate group), 2 (ie, real-intermediate group), and > 2 (ie, poor group) factors. The corresponding median OS periods were 32.9, 20.0, and 8.9 months, with significant differences among the groups. The validation cohort included 389 patients. The median OS period for the favorable-intermediate group, real-intermediate group, and poor group was 34.3, 19.4, and 9.0 months, respectively, with confirmed significant differences among the groups. CONCLUSION: Our analysis revealed significant differences among patients with an intermediate prognosis using the IMDC prognostic factors. Further investigations to optimize the use of available and upcoming therapies are required.

FOLFOX or CAPOX in Stage II to III Colon Cancer: Efficacy Results of the Italian Three or Six Colon Adjuvant Trial.

Purpose Given the cumulative neurotoxicity associated with oxaliplatin, a shorter duration of adjuvant therapy, if equally efficacious, would be advantageous for patients and health-care systems. Methods The Three or Six Colon Adjuvant trial is an open-label, phase III, multicenter, noninferiority trial randomizing patients with high-risk stage II or stage III colon cancer to receive 3 months or 6 months of FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CAPOX (capecitabine plus oxaliplatin). Primary end-point is relapse-free survival. Results 3,759 patients were accrued from 130 Italian sites, 64% receiving FOLFOX and 36% CAPOX. Two-thirds were stage III. The median time of follow up was 62 months and 772 relapses or deaths have been observed. The hazard ratio (HR) of the 3 months versus 6 months for relapse/death was 1.14 (95% CI, 0.99 to 1.32; P [for noninferiority] = .514) and the CI crossed the noninferiority limit of 1.20. However, the absolute difference in 3-year RFS was 1.9% (95% CI, -0.7% to 4.4%). Counter-intuitively, while the RFS curves were similar for stage III (HR, 1.07; 95% CI, 0.91 to 1.26) and for CAPOX treated patients (HR, 0.98; 95% CI, 0.77 to 1.26), they were not for stage II and for FOLFOX treated patients, with HR of 1.41 (95% CI, 1.05 to 1.89) and 1.23 (95% CI, 1.03 to 1.46), respectively, favoring the 6 months of treatment. Conclusion The Three or Six Colon Adjuvant trial failed to formally show noninferiority of 3 versus 6 months of treatment to the predefined margin of 20% relative increase. The results depended on the adjuvant regimen and risk. For CAPOX, 3 months were as good as 6 months; for FOLFOX, 6 months added extra benefit. Counter-intuitively, the low-risk patients benefitted more than the high-risk population from the 6-month duration. The choice of regimen and duration should depend on patient characteristics and be balanced against the extra toxicity of longer therapy.

First Prospective Multicenter Italian Study on the Impact of the 21-Gene Recurrence Score in Adjuvant Clinical Decisions for Patients with ER Positive/HER2 Negative Breast Cancer.

BACKGROUND: The Breast DX Italy prospective study evaluated the impact of the 21-gene recurrence score (RS) result on adjuvant treatment decisions for patients with early breast cancer. MATERIALS AND METHODS: Nine centers (two Hub and seven Spoke centers of the Veneto Oncology Network) participated. Consecutive patients with estrogen receptor positive, human epidermal growth receptor negative, T1-T3, N0-N1 early breast cancer were prospectively registered; only those meeting protocol-defined clinicopathological "intermediate risk" criteria were eligible for the RS test. Pre-RS and post-RS physicians' treatment recommendations and treatment actually received were collected. RESULTS: A total of n = 124 N0 and n = 126 N1 patients underwent the RS assay. The majority had Grade 2 tumors (71%); median age was 55 years, median tumor size was 16 mm, and median Ki67 expression was 20%. Patients enrolled at Hub centers presented higher-risk features. The distribution of RS results was <18 (60.8%), 18-30 (32.4%), and >30 (6.8%). The indication before RS was hormonal therapy (HT) alone in 52% of cases. An indication before RS of chemotherapy (CT)+HT was more frequent for patients with N1 versus N0 tumors (57% vs. 39%, p = .0035) and for patients enrolled at Hub versus Spoke centers (54% vs. 36%, p = .007).The overall rate of change in treatment decision was 16% (n = 40), mostly from CT+HT to HT (n = 30). According to nodal status, rate of change in treatment decision was 12% for the N0 cohort and 20% for the N1 cohort. The proportion of patients recommended to CT+HT was significantly reduced from before to after RS (48% to 40%, p < .0016), especially in the N1 cohort (57% to 45%, p = .0027) and at Hub centers (54% to 44%, p = .001). CONCLUSION: Despite frequent indication of HT before RS, the use of the RS assay further contributed to sparing CT, especially for patients with N1 tumors and at Hub centers. IMPLICATIONS FOR PRACTICE: This study shows that, although a high proportion of patients were recommended to receive endocrine treatment alone before knowing the recurrence score (RS) assay, the RS test further contributed in sparing chemotherapy for some of these patients, especially in case of the N1 stage or for patients enrolled at referral centers. These data highlight the need for further work in collaboration with health authorities and companies in order to define strategies for the implementation of the use of RS testing in clinical practice in the Italian setting.

Characterizing the outcomes of metastatic papillary renal cell carcinoma.

Outcomes of metastatic papillary renal cell carcinoma (pRCC) patients are poorly characterized in the era of targeted therapy. A total of 5474 patients with metastatic renal cell carcinoma (mRCC) in the International mRCC Database Consortium (IMDC) were retrospectively analyzed. Outcomes were compared between clear cell (ccRCC; n = 5008) and papillary patients (n = 466), and recorded type I and type II papillary patients (n = 30 and n = 165, respectively). Overall survival (OS), progression-free survival (PFS), and overall response rate (ORR) favored ccRCC over pRCC. OS was 8 months longer in ccRCC patients and the hazard ratio of death was 0.71 for ccRCC patients. No differences in PFS or ORR were detected between type I and II PRCC in this limited dataset. The median OS for type I pRCC was 20.0 months while the median OS for type II was 12.6 months (P = 0.096). The IMDC prognostic model was able to stratify pRCC patients into favorable risk (OS = 34.1 months), intermediate risk (OS = 17.0 months), and poor-risk groups (OS = 6.0 months). pRCC patient outcomes were inferior to ccRCC, even after controlling for IMDC prognostic factors. The IMDC prognostic model was able to effectively stratify pRCC patients.

Plasma matrix metalloprotease 9 correlates with blood lymphocytosis, leukemic cell invasiveness, and prognosis in B-cell chronic lymphocytic leukemia.

The complex biology underlying chronic lymphocytic leukemia cell migration and tissue invasiveness is not yet completely understood and might provide novel predictive markers and therapeutic targets. A total of 36 patients out of treatment from at least 3 months were enrolled and followed up for a median period of 44.2 months (range: 4.4-99.2). Matrix metalloprotease 9 and tissue inhibitor of metalloproteases 1 plasma levels and production/release from lymphoid cells were measured by zymography and enzyme-linked immunosorbent assay (ELISA) analysis. Malignant and normal lymphocyte mobility and matrix-degradation capability were studied using a Boyden chamber system, with and without autologous plasma. Free matrix metalloprotease 9 plasma levels were related with blood lymphocytosis, especially in more advanced stages (p = 0.003), and higher concentrations were associated with an increased disease progression risk (hazard ratio = 9.0, 95% confidence interval = 1.5-13.8). Leukemic cells expressed and secreted very little matrix metalloprotease 9. On the contrary, normal lymphocytes derived from the same leukemic patients showed matrix metalloprotease 9 intracellular levels that were lower in subjects with higher blood lymphocytosis (p = 0.024) and more advanced stages (p = 0.03); the released quantities were inversely associated with matrix metalloprotease 9 plasma concentrations (p = 0.035). Leukemic cells had a reduced spontaneous mobility and matrix-degradation capability that were stimulated by autologous plasma (p = 0.001) and normal lymphocytes (p = 0.005), respectively. Matrix metalloprotease 9 affected cell invasiveness depending on concentration and disease stage. In conclusion, chronic lymphocytic leukemia cells have a reduced mobility, matrix-degradation capability, and matrix metalloprotease 9 production compared to their own autologous normal lymphocytes. They are exposed to matrix metalloprotease 9 of prevalently systemic origin whose higher levels are associated with both leukemic and normal lymphocyte accumulation in the peripheral blood and have a negative prognostic value.

Targeted therapies for advanced and metastatic adenocarcinoma of the gastroesophageal junction: is there something new?

Despite improvements in systemic chemotherapy (CT), the prognosis of metastatic adenocarcinoma of the gastroesophageal junction remains poor. Over the years, new targeting agents have become available and were tested, with or without CT, in first or subsequent lines of therapy. The epidermal growth factor receptor family was targeted with monoclonal antibodies (MoAbs) (trastuzumab, cetuximab, panitumumab) and tyrosin kinase inhibitors (TKIs) (lapatinib, erlotinib, gefitinib). Only trastuzumab, in combination with cisplatin and fluoropyrimidines, significantly improved overall survival (OS) in first-line therapy (13.8 vs. 11.1 months). Angiogenesis also was targeted with MoAbs (bevacizumab and ramucirumab); ramucirumab, a vascular endothelial growth factor-receptor 2 antagonist, enhanced OS in two phase III studies in the first (9.6 vs. 7.4 months) and subsequent lines of treatment (5.2 vs. 3.8 months), while the bevacizumab study was negative. TKIs (sunitinib, sorafenib, regorafenib, apatinib) were tested in this setting in phase II studies in the second/third line, only showing modest antitumor activity. The hepatocyte growth factor receptor (MET) was targeted in untreated patients in a phase III trial with MoAb rilotumumab, with or without CT, but the study was stopped because of mortality excess in the rilotumumab arm. Mammalian target of rapamycin (MTOR) pathway inhibition with everolimus was tested in pretreated patients in a placebo-controlled phase III trial who failed to improve OS (5.4 vs. 4.3 months). In conclusion, considering the modest survival gain obtained overall, the high cost of these therapies and the quality of life issue must be primarily considered in treating these patients.

First-line sunitinib versus pazopanib in metastatic renal cell carcinoma: Results from the International Metastatic Renal Cell Carcinoma Database Consortium.

BACKGROUND: Sunitinib (SU) and pazopanib (PZ) are standards of care for first-line treatment of metastatic renal cell carcinoma (mRCC). However, how the efficacy of these drugs translates into effectiveness on a population-based level is unknown. PATIENTS AND METHODS: We used the International mRCC Database Consortium (IMDC) to assess overall survival (OS), progression-free survival (PFS), response rate (RR) and performed proportional hazard regression adjusting for IMDC prognostic groups. Second-line OS (OS2) and second-line PFS (PFS2) were also evaluated. RESULTS: We obtained data from 7438 patients with mRCC treated with either first-line SU (n = 6519) or PZ (n = 919) with an overall median follow-up of 40.4 months (95% confidence interval [CI] 39.2-42.1). There were no significant differences in IMDC prognostic groups (p = 0.36). There was no OS difference between SU and PZ (22.3 versus 22.6 months, respectively, p = 0.65). When adjusted for IMDC criteria, the hazard ratio (HR) of death for PZ versus SU was 1.03 (95% CI 0.92-1.17, p = 0.58). There was no PFS difference between SU and PZ (8.4 versus 8.3 months, respectively, p = 0.17). When adjusted for IMDC criteria, the HR for PFS for PZ versus SU was 1.08 (95% CI 0.981-1.19, p = 0.12). There was no difference in RR between SU and PZ (30% versus 28%, respectively, p = 0.15). We also found no difference in any second-line treatment between either post-SU or post-PZ groups for OS2 (13.1 versus 11 months, p = 0.27) and PFS2 (3.7 versus 5.0 months, p = 0.07). CONCLUSIONS: We confirmed in real-world practice that SU and PZ have similar efficacy in the first-line setting for mRCC and do not affect outcomes with subsequent second-line treatment.

Pituitary Non-Functioning Adenoma Disclosed at 18F-Choline PET/CT to Investigate a Prostate Cancer Relapse.

We report the incidental finding of a pituitary macroadenoma on an F-choline PET/CT in a patient with recurrent prostate cancer. The pituitary gland was clearly enlarged and intensely FDG avid (SUVmax, 6.6). The diagnosis was confirmed by a subsequent contrast-enhanced MR evaluation, and the macroadenoma was classified as nonfunctioning on the basis of normality of the specific serum hormonal profile. A follow-up F-choline PET/CT scan performed after 6 months revealed stable dimension, and uptake of the pituitary macroadenoma patient deceased 1 month later. At autopsy, intracytoplasmic vesicles containing growth and prolactin hormones were observed at immunohistochemistry.

Plasma Expression Levels of Circulating miR-21 are not Useful for Diagnosing and Monitoring Colorectal Cancer.

BACKGROUND: Recent evidence suggests that microRNAs play an important role in cancer diagnostics. We assessed plasma microRNA-21 levels in patients with colorectal cancer (CRC) at different stages and in patients with benign polyps. METHODS: Plasma levels of miR-21 were assessed by quantitative reverse transcription polymerase chain reaction assay in plasma samples of 76 CRC patients and in 20 patients with benign polyps. Differences between groups were evaluated with Mann-Whitney and Kruskal-Wallis tests. RESULTS: No significant differences of miR-21 plasma levels were observed between CRC patients and subjects with benign polyps (p > 0.05). Also, no significant differences were found between CRC patients with advanced (III-IV) or early cancer stages (I-II) (p > 0.05). CONCLUSIONS: These results do not support the hypothesis that circulating miR-21 expression is increased in adenoma-carcinoma-advanced carcinoma sequence. Accordingly, plasma miR-21 assessment does not appear to be a useful biomarker for diagnosing and staging CRC.