Francesco Maria Guida

Aprepitant for management of severe pruritus related to biological cancer treatments: a pilot study

BACKGROUND Itch is a common side-effect of treatment with anti-EGFR antibodies and tyrosine-kinase inhibitors. We designed a pilot single-centre study to assess the effects of aprepitant-a neurokinin receptor inhibitor-for management of severe pruritus induced by biological drugs. METHODS In this single-group, prospective study, we consecutively enrolled 45 outpatients with metastatic solid tumours treated with biological drugs at the Campus Bio-Medico Hospital of Rome, Rome, Italy, between September, 2010, and November, 2011. We classified patients into two groups: a refactory group, for patients with pruritis refractory to standard treatment, or a naive group, for patients who had not been previously treated for pruritis. Aprepitant (125 mg on day 1; 80 mg on day 3; 80 mg on day 5) was given to patients in the refractory group after at least 1 week of standard systemic treatment. In the naive group, aprepitant was given in the same schedule as the refractory group, after first onset of severe pruritus. Intensity of itch was evaluated by Visual Analogue Scale (VAS) score. The primary endpoint was change in median VAS score. This trial is registered with ClinicalTrials.gov, number NCT01683552. FINDINGS Median VAS in the refractory group was 8·00 (95% CI 7·93-8·57) at baseline and 1·00 (0·00-2·00) after 1 week of treatment with aprepitant (p<0·0001). In the naive group, VAS score was 8·00 (7·43-8·37) at baseline and 0·00 (0·06-1·08) after 1 week of treatment (p<0·0001). 41 (91%) patients responded to aprepitant (ie, had a >50% reduction in intensity of pruritis) and pruritus recurred in only six (13%) patients. No adverse events related to aprepitant occurred. INTERPRETATION Aprepitant decreases severe pruritus induced by biological treatments; it is an old drug, widely available, and therefore easy to add to the armamentarium of supportive treatment. Although to our knowledge no other studies of the anti-itch activity of aprepitant are planned, the results of our trial warrant confirmation in phase 2 and 3 trials. FUNDING None.

Natural history of malignant bone disease in hepatocellular carcinoma: final results of a multicenter bone metastasis survey.

Background Bone is an uncommon site of metastasis in patients with advanced hepatocellular carcinoma (HCC). Therefore, there are few studies concerning the natural history of bone metastasis in patients with HCC. Patients and Methods Data on clinicopathology, survival, skeletal-related events (SREs), and bone-directed therapies for 211 deceased HCC patients with evidence of bone metastasis were statistically analyzed. Results The median age was 70 years; 172 patients were male (81.5%). The median overall survival was 19 months. The median time to the onset of bone metastasis was 13 months (22.2% at HCC diagnosis); 64.9% patients had multiple bone metastases. Spine was the most common site of bone metastasis (59.7%). Most of these lesions were osteolytic (82.4%); 88.5% of them were treated with zoledronic acid. At multivariate analysis, only the Child Score was significantly correlated with a shorter time to diagnosis of bone metastases (p = 0.001, HR = 1.819). The median survival from bone metastasis was 7 months. At multivariate analysis, HCC etiology (p = 0.005), ECOG performance status (p = 0.002) and treatment with bisphosphonate (p = 0.024) were associated with shorter survival after bone disease occurrence. The site of bone metastasis but not the number of bone lesions was associated with the survival from first skeletal related event (SRE) (p = 0.021) and OS (p = 0.001). Conclusions This study provides a significant improvement in the understanding the natural history of skeletal disease in HCC patients. An early and appropriate management of these patients is dramatically needed in order to avoid subsequent worsening of their quality of life.

The role of macrophages polarization in predicting prognosis of radically resected gastric cancer patients

Tumour‐associated Macrophages (TAM) present two different polarizations: classical (M1) characterized by immunostimulation activity and tumour suppression; alternative (M2) characterized by tumour promotion and immune suppression. In this retrospective study, we evaluated the correlation between the two forms of TAM with survival time in radically resected gastric cancer patients. A total of 52 chemo‐ and radio‐naive patients were included. Two slides were prepared for each patient and double‐stained for CD68/NOS2 (M1) or CD68/CD163 (M2) and five representative high‐power fields per slide were evaluated for TAM count. The median value of the two macrophage populations density and the median value of M1/M2 ratio were used as cut‐off. Twenty‐seven patients with M1 density above‐the‐median had a significantly higher survival compared to those below the median. Twenty‐six patients with M1/M2 ratio above the median showed median OS of 27.2 months compared to 15.5 months of the patients below the median. No association between M2 macrophage density and patients outcome was found. In multivariate analysis, M1/M2 was a positive independent predictor of survival. The M1 macrophage density and M1/M2 ratio, as confirmed in multivariate analysis, are factors that can help in predicting patients survival time after radical surgery for gastric cancer.

Modification of Abdominal Fat Distribution After Aromatase Inhibitor Therapy in Breast Cancer Patients Visualized Using 3-D Computed Tomography Volumetry

INTRODUCTION/BACKGROUND The purpose of this study was to describe modification of subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) distributions in breast cancer patients after aromatase inhibitor (AI) therapy using computed tomography (CT) volumetric measurement of abdominal body fat distribution. PATIENTS AND METHODS Sixty-four consecutive patients who were receiving adjuvant AI therapy were included in this study. Patients were evaluated using CT before and after at least 6 months of AI therapy with imaging follow-up of 4.3 ± 2.2 years. Abdominal fat distribution was automatically calculated using a workstation that obtained total abdominal adipose tissue (TAAT) area (mm(3)). SAT was manually segmented and VAT was determined as TAAT - SAT. Percentages were calculated for change of TAAT, VAT, and SAT. VAT/SAT ratio was calculated. RESULTS Percentage of TAAT after AI therapy was increased by a mean of 9.1% from baseline (16,280.3 ± 6953.3 mm(3)) to (17,763.6 ± 6850.8 mm(3)). Two groups of patients were observed; those with an increase in TAAT and those with a decrease. Modification of VAT/SAT ratio was observed (from 1.38 to 1.69) in all subjects, reflecting a relative increased volume of VAT (mean, 18%) and slight mean reduction of SAT (mean 1.9%). CONCLUSION In our study, therapy with AI in breast cancer patients was accompanied with a change in fat distribution to relatively greater VAT/SAT ratio in patients, regardless of whether they gained or lost weight after therapy. Because this pattern of fat distribution is associated with metabolic disorders, attention must be paid to these clinical manifestations in patients during their follow-up management.

The Changes of Lipid Metabolism in Advanced Renal Cell Carcinoma Patients Treated with Everolimus: A New Pharmacodynamic Marker?

Background Everolimus is a mammalian target of rapamycin (mTOR) inhibitor approved for the treatment of metastatic renal cell carcinoma (mRCC). We aimed to assess the association between the baseline values and treatmentrelated modifications of total serum cholesterol (C), triglycerides (T), body mass index (BMI), fasting blood glucose level (FBG) and blood pressure (BP) levels and the outcome of patients treated with everolimus for mRCC. Methods 177 patients were included in this retrospective analysis. Time to progression (TTP), clinical benefit (CB) and overall survival (OS) were evaluated. Results Basal BMI was significantly higher in patients who experienced a CB (p=0,0145). C,T and C+T raises were significantly associated with baseline BMI (p=0.0412, 0.0283 and 0.0001). Median TTP was significantly longer in patients with T raise compared to patients without T (10 vs 6, p=0.030), C (8 vs 5, p=0.042) and C+T raise (10.9 vs 5.0, p=0.003). At the multivariate analysis, only C+T increase was associated with improved TTP (p=0.005). T raise (21.0 vs 14.0, p=0.002) and C+T increase (21.0 vs 14.0, p=0.006) were correlated with improved OS but were not significant at multivariate analysis. Conclusion C+T raise is an early predictor for everolimus efficacy for patients with mRCC.

Body mass index and impaired fasting blood glucose as predictive factor of time to progression (TTP) in cetuximab-based colorectal cancer treatment.

Cetuximab is an anti-EGFR monoclonal antibody with antitumor efficacy in metastatic colorectal cancer harboring wild-type K-Ras gene. However, not all patients K-Ras wild-type benefit from Cetuximab, underscoring the need for additional markers to help in patient selection. Preclinical evidence suggests that the EGFR and insulin-like growth factor-1 receptor (IGF-1R) pathways interact to drive tumor growth and survival.1 Scartozzi et al. demonstrated that the hyperinsulinemic state and higher insulin levels upregulate IGF-I production, leading this state a potential biomarker for Cetuximab efficacy in K-RAS wild type colorectal cancer patients treated with cetuximab and irinotecan.2 The aim of our study was to evaluate the feasibility to stratify patients more likely to benefit from Cetuximab treatment using two well-known signs of hyperinsulinemic state such as the high Body Mass Index (BMI) and impaired Fasting Blood Glucose (FBG). We retrospectively collected 250 metastatic colorectal cancer patients K-Ras wild type treated with Cetuximab containing regimens. From this cohort we selected 99 patients who received Cetuximab + chemotherapic regimens as first line and 77 patients who previously progressed under CPT11 based combination regimens and were subsequently treated with Cetuximab + CPT11 regimen. We dichotomized each subset into two groups according the presence of both elevated BMI (cut-off v 24.99 sec. WHO Criteria) and high fasting blood glucose (cut-off 100 mg/dL sec American Diabetes Association), and we evaluated the Time to progression (TTP) of these two groups. In the 77 CPT11- refractory patients (mean age 63.8; female: male 22: 54) during Cetuximab + CPT11 treatment, we observed a statistically significant lower TTP in the group with both elevated BMI and FBG compared with group with presence of none or only one of the two parameters (52: 25 pts; Median TTP 6.8 mo vs. 4.5 mo; p = 0.034). Copresence of both BMI and FBG was confirmed as predictive factor independent from age, sex and treatment line (2th, 3th, 4th or 5th) by multivariate Cox proportional hazards analysis (p = 0,018 ; HR 1,899). TTP was not significantly shorter in patients with only elevated fasting blood glucose (35: 42 pts.; p = 0,178; Median TTP 7.1 mo vs 5.5 mo) or BMI (38: 39 pts.; p = 0,305; Median TTP 6.8 mo vs. 5.6 mo). On the other hand, in the 99 patients (mean age 64; female: male 49: 50) treated with Cetuximab + chemotherapy (Folfox/Folfiri) as first line, we did not found any statistically difference between population with both elevated BMI and FBG compared with patients with presence of none or only one of the two parameters (75: 24 pts. ; Median TTP 8.3 mo vs. 7.7 mo; p = 0.624). TTP was also not significantly different evaluating only FBG (54: 45 pts.; Median TTP 7.2 mo vs. 7.9 mo; p = 0.941) and only BMI alone (48: 29 pts. Median TTP 7.0 mo vs. 6.5 mo; p = 0.135). The statistically significant poorer outcome in patients with both BMI and FBG treated with Cetuximab + CPT11 after CPT11 failure could be explained by the reduction in Cetuximab efficacy due to the probable presence of upregulation of vicar pathways such as IGF I R linked to hyperinsulinemic state. The absence of the predictive value of these two markers combination in chemonaive patients could be related to the strong masking effect related to concurrent chemotherapy. These preliminary observations need to be confirmed in larger and perspective populations.

Sunitinib in malignant melanoma: a treatment option only for KIT-mutated patients?

Sunitinib has previously been reported to be potentially effective in the treatment of malignant melanomas expressing c-KIT. Here we report on the case of a 77-year-old gentleman affected by a metastatic clear cell carcinoma of the kidney and a metastatic malignant melanoma with liver and lung metastases. Despite the negativity for CD117 and the absence of KIT amplification or mutations in the melanoma specimen, he achieved a partial response both in the lungs and in the liver while on sunitinib (50 mg once/day, 4 weeks on/2 weeks off) for the treatment of kidney cancer. To our knowledge, this represents the first evidence of sunitinib activity in KIT wild-type melanoma. Further studies should be performed to confirm these preliminary data.

836PTREATMENT AND OUTCOME(S) OF A LARGE COHORT OF POOR RISK METASTATIC RENAL CELL CARCINOMA (PRRCC) PATIENTS (PTS)

ABSTRACT Aim: With the exception of the Temsirolimus (Tem) registration trial, prRCC is grossly underrepresented in clinical trials. Methods: We collected information on a large cohort of prRCC (239 pts) from 20 Italian and 2 Spanish centers. Results: Three prognostic models (MSKCC, modified MSKCC - mMSKCC, International Metastatic RCC Database Consortium - DC) and 8 individual risk factors (RF) were considered: multiple metastatic sites (89%), time from diagnosis to treatment (82%), and anaemia (77%) were the most frequent individual RF. Eighty-nine percent, 63%, and 61% of pts had at least 3 RF according to mMSKCC, MSKCC, and DC, respectively; mMSKCC had the best discriminating power between intermediate and prRCC (median OS: 28 vs 8 mos, respectively; p 6 mos) was 44% and was significantly higher for pts receiving first-line TKI versus Tem (50% vs 26%, p = 0.002). Age, nephrectomy status, mMSKCC, and total number of RF, but not the type of treatment received (Tem vs VEGFR-TKI), were independently associated with OS at multivariate analysis. Thirty seven percent of prRCC pts survived >12 mos (29% and 40% in pts receiving Tem and VEGFR-TKI, respectively). Basal Hb and calcium levels within normal limits were significantly associated with higher chances of achieving long-term survival upon VEGFR-TKI treatment, while a non-significant trend towards a higher proportion of long-term survivors upon Tem treatment was observed for longer time from diagnosis to treatment and normal LDH levels, in an exploratory analysis of predictive factors. Conclusions: Despite heterogeneity, prRCC may benefit from systemic treatment across multiple lines of therapy. Further prognostic/predictive stratification within the prRCC group is clearly necessary (see also the abstract by Guida et al. at this Meeting). Disclosure: All authors have declared no conflicts of interest.

837PPOOR RISK METASTATIC RENAL CELL CARCINOMA (MRCC) PATIENTS ARE NOT A HOMOGENEOUS GROUP: A NEW STRATIFICATING MODEL IN THE ERA OF TARGETED THERAPY

ABSTRACT Aim: The prognostic stratification of poor risk mRCC patients in the era of targeted therapy represents an unmet medical need. We analyzed, individually, each prognostic factor included in modified Memorial Sloan-Kettering Cancer Center (MSKCC) and Heng criteria to investigate their prognostic relevance in poor risk mRCC patients and proposed a model to stratify poor risk patients into 3 separate subgroups. Methods: Data were collected from 20 Italian and 2 Spanish centers. Overall survival (OS) was estimated using Kaplan-Meier method. Hemoglobin, Performance Status, Thrombocytosis, Neutrophilia, Number of metastatic sites, Time from diagnosis to treatment, LDH and Hypercalcemia, according to modified MSKCC and Heng criteria, were included in the Cox analysis. Results: 239 (151 males; 205 clear cell) poor risk mRCC pts were enrolled according to, at least, three of MSKCC, or modified MSKCC or Heng criteria. 233 pts were treated with a first line therapy (56 pts with temsirolimus, 163 pts with tyrosine kinase inhibitors (TKI), 14 pts with other agents); 101 pts with a second line (50 everolimus, 49 TKI, 2 other agents) and 31 pts with a third line ( 4 everolimus; 20 TKI, 7 other agents). Only Hemoglobin (13 vs 8 months; p = 0.005), Performance Status (14 vs 7 months; p = 0.002), and Time from diagnosis to treatment (22 vs. 8 months; p Conclusions: This is the first study that identifies three different prognostic subgroups among poor risk RCC patients. Kaplan Meier survival curves of each subgroup will be presented during the meeting. Disclosure: All authors have declared no conflicts of interest.

Comment and reply on: Pegfilgrastim is safe and effective in the prevention of neutropenia and treatment delays in biweekly regimens

Pegfilgrastim is regarded today as the standard therapy in the primary prophylaxis of febrile neutropenia induced by three-weekly chemotherapy regimens while its use with biweekly regimens is still controversial [1]. Pegfilgrastim clearance is mainly mediated by binding to granulocyte colony stimulating factor (G-CSF) receptors found on myeloid bone marrow elements and neutrophils and the recovery of neutrophils count to levels in excess of 1.000/ml is associated with subtherapeutic levels of pegfilgrastim [2]. Silvestris et al. confirmed that a single dose of pegfilgrastim in appropriate patients provides a more convenient and effective strategy for assisting neutrophil recovery [3]. Given these data, the authors designed a prospective study in which they administered one dose of pegfilgrastim (6 mg s.c. 48 h after treatment completion) to 20 consecutively enrolled patients affected by colorectal cancer (13), pancreas cancer (2), biliary tract cancer (2) and other type of cancers (3), who developed at least a grade 3 neutropenia during a biweekly regimen despite receiving filgrastim 30/0.6, 1 s.c. for 5 days. The study design was approved by internal ethical committee. Patients received Folfiri (7), Folfox (6), Folfoxiri (2) or other biweekly regimens (4). The basal value of white blood cells (WBCs) and polymorphonuclear leukocytes (PMNs) was recorded at days 14 and 28 as well as the incidence of treatment delays. The median basal value of WBCs and PMNs was 5.280/mmc (95% confidence interval (CI) 4.385 -8.247) and 3.140/mmc (95% CI 2.183 -5.820), respectively. After the chemotherapy cycle and the first pegfilgrastim injection, at day 14, median values were 6.400/mmc (95% CI 5.450 -11.130) and 3.900/mmc (95% CI 3.294 -8.283), respectively. At day 28, median values were 6.930/mmc (95% CI 6.154 -9.779) and 4.760/mmc (95% CI 4.090 -6.487), respectively. Interestingly, for both WBCs and PMNs the difference between the basal median value and day 14 median value was statistically significant (p = 0.034 and 0.036), while the difference between day 14 and 28 was not statistically significant (p = 0.56 and 0.39). No treatment delays were recorded. The principal side effect was bone pain, reported by eight patients (38%), mild in all cases (median visual-analog score (VAS): 5) and easily manageable with paracetamol or non-steroidal anti-inflammatory drugs (NSAIDs). The results, consistently with previous Phase II studies, confirmed the safety of pegfilgrastim in biweekly regimens and its efficacy in avoiding treatment delays [4,5]. The authors demonstrated how the increase in WBCs and PMNs levels, usually recorded after the first administration, is transient and settles