Phase II Study of Dehydroepiandrosterone in Androgen Receptor-Positive Metastatic Breast Cancer.

LESSONS LEARNED: The androgen receptor (AR) is present in most breast cancers (BC), but its exploitation as a therapeutic target has been limited.This study explored the activity of dehydroepiandrosterone (DHEA), a precursor being transformed into androgens within BC cells, in combination with an aromatase inhibitor (to block DHEA conversion into estrogens), in a two-stage phase II study in patients with AR-positive/estrogen receptor-positive/human epidermal growth receptor 2-negative metastatic BC.Although well tolerated, only 1 of 12 patients obtained a prolonged clinical benefit, and the study was closed after its first stage for poor activity. BACKGROUND: Androgen receptors (AR) are expressed in most breast cancers, and AR-agonists have some activity in these neoplasms. We investigated the safety and activity of the androgen precursor dehydroepiandrosterone (DHEA) in combination with an aromatase inhibitor (AI) in patients with AR-positive metastatic breast cancer (MBC). METHODS: A two-stage phase II study was conducted in two patient cohorts, one with estrogen receptor (ER)-positive (resistant to AIs) and the other with triple-negative MBC. DHEA 100 mg/day was administered orally. The combination with an AI aimed to prevent the conversion of DHEA into estrogens. The main endpoint was the clinical benefit rate. The triple-negative cohort was closed early. RESULTS: Twelve patients with ER-positive MBC were enrolled. DHEA-related adverse events, reported in four patients, included grade 2 fatigue, erythema, and transaminitis, and grade 1 drowsiness and musculoskeletal pain. Clinical benefit was observed in one patient with ER-positive disease whose tumor had AR gene amplification. There was wide inter- and intra-patient variation in serum levels of DHEA and its metabolites. CONCLUSION: DHEA showed excellent safety but poor activity in MBC. Although dose and patient selection could be improved, high serum level variability may hamper further DHEA development in this setting.

Impact of Metformin Use and Diabetic Status During Adjuvant Fluoropyrimidine-Oxaliplatin Chemotherapy on the Outcome of Patients with Resected Colon Cancer: A TOSCA Study Subanalysis.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is associated with increased risk of colon cancer (CC), whereas metformin use seems to be protective. However, the impact of metformin use on the risk of death or disease recurrence after radical surgery for CC remains uncertain. MATERIALS AND METHODS: This is a substudy conducted in patients with high-risk stage II or stage III CC randomized in the TOSCA trial, which compared 3 versus 6 months of fluoropyrimidine-oxaliplatin adjuvant chemotherapy. Objective of the study was to investigate the impact of metformin exposure during adjuvant chemotherapy on overall survival (OS) and relapse-free survival (RFS). We also evaluated the impact of T2DM or metformin dosage on clinical outcomes. RESULTS: Out of 3,759 patients enrolled in the TOSCA trial, 133 patients with diabetes (9.2%) and 1,319 without diabetes (90.8%) were recruited in this study. After excluding 13 patients with diabetes without information on metformin exposure, 76 patients with T2DM (63.3%) were defined as metformin users and 44 (36.7%) as metformin nonusers. After a median follow-up of 60.4 months, 26 (21.7%) patients relapsed and 16 (13.3%) died. Metformin use was neither associated with OS (adjusted hazard ratio [HR], 1.51; 95% confidence interval [CI], 0.48-4.77; p = .4781) nor with RFS (HR, 1.56; 95% CI, 0.69-3.54; p = .2881). Similarly, we found no association between T2DM or metformin dosage and OS or RFS. CONCLUSIONS: Metformin use and T2DM did not impact on OS or RFS in patients with resected CC treated with adjuvant fluoropyrimidine-oxaliplatin chemotherapy. Larger studies and longer follow-up are required to clarify the potential efficacy of metformin in improving the prognosis of patients with CC. IMPLICATIONS FOR PRACTICE: The role of the antidiabetic drug metformin in colon cancer prevention and treatment is highly debated. While low-dose metformin reduced the incidence of colorectal adenomas in two prospective studies, its effect in patients with already established colon cancer remains unclear. In this study, the potential impact of metformin on the survival of resected colon cancer patients who received adjuvant chemotherapy was investigated in the context of the TOSCA study. We did not find any association between metformin use or dosages and patient survival. Prospective studies are required to draw definitive conclusions about metformin impact on colon cancer recurrence and survival.

Prognostic Value of Body Mass Index in Stage II/III Colon Cancer: Posthoc Analysis From the TOSCA Trial.

BACKGROUND: High body mass index (BMI) plays a key role in the development of colon cancer (CC). Our post-hoc analysis from the TOSCA trial analyzed the association between BMI and survival outcomes in terms of relapse-free survival (RFS) and overall survival (OS) in stage II/III CC patients. PATIENTS AND METHODS: Patients enrolled in the TOSCA trial between 2007-2013 with BMI data entered the study. The prognostic impact of BMI on survival outcomes was investigated through uni- and multivariable Cox regression analyses. RESULTS: Overall, 1455 patients with stage II/III CC patients were included. The median follow-up was of 61.5 months; 16.1% of patients relapsed, 11.2% died and 19.5% patients relapsed or died. No impact of BMI on RFS was detected at univariate or multivariable analyses. By univariate analysis for OS, a significantly impact of a BMI > 30 kg/m2 was reported (HR [>30 vs <25] 1.57, 95% CI 1.00-2.47, p = 0.049; HR [>30 vs <30] 1.55, 95% CI 1.01-2.37, p = 0.045). Multivariable analyses did not confirm this data. In the subgroup of stage III patients, a negative survival impact of BMI was found in univariate and multivariable models both for RFS and for OS. CONCLUSIONS: In our study, obesity with BMI > 30 kg/m2 was an independent prognostic factor for RFS and OS in CC patients treated with adjuvant chemotherapy, regardless of its duration (3 or 6 months). However, the prognostic impact of adiposity and body composition measurement should be considered to better classify patients with high visceral fat and refine their risk assessment.

Author Correction: Sex-Related Differences in Impact on Safety of Pharmacogenetic Profile for Colon Cancer Patients Treated with FOLFOX-4 or XELOX Adjuvant Chemotherapy.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Sex-Related Differences in Impact on Safety of Pharmacogenetic Profile for Colon Cancer Patients Treated with FOLFOX-4 or XELOX Adjuvant Chemotherapy.

Polymorphisms contribute to inter-individual differences and show a promising predictive role for chemotherapy-related toxicity in colon cancer (CC). TOSCA is a multicentre, randomized, non-inferiority, phase III study conducted in high-risk stage II/stage III CC patients treated with 6 vs 3 months of FOLFOX-4 or XELOX adjuvant chemotherapy. During this post-hoc analysis, 218 women and 294 men were genotyped for 17 polymorphisms: TYMS (rs34743033, rs2853542, rs11280056), MTHFR (rs1801133, rs1801131), ERCC1 (rs11615), XRCC1 (rs25487), XRCC3 (rs861539), XPD (rs1799793, rs13181), GSTP1 (rs1695), GSTT1/GSTM1 (deletion +/-), ABCC1 (rs2074087), and ABCC2 (rs3740066, rs1885301, rs4148386). The aim was to assess the interaction between these polymorphisms and sex, on safety in terms of time to grade ≥3 haematological (TTH), grade ≥3 gastrointestinal (TTG) and grade ≥2 neurological (TTN) toxicity. Interactions were detected on TTH for rs1801133 and rs1799793, on TTG for rs13181 and on TTN for rs11615. Rs1799793 GA genotype (p = 0.006) and A allele (p = 0.009) shortened TTH in men. In women, the rs11615 CC genotype worsened TTN (co-dominant model p = 0.008, recessive model p = 0.003) and rs13181 G allele improved the TTG (p = 0.039). Differences between the two sexes in genotype distribution of rs1885301 (p = 0.020) and rs4148386 (p = 0.005) were found. We highlight that polymorphisms could be sex-specific biomarkers. These results, however, need to be confirmed in additional series.

Bolus fluorouracil and leucovorin with oxaliplatin as first-line treatment in metastatic colorectal cancer.

PURPOSE: A phase II trial investigated the activity and toxicity of a bolus administration schedule of oxaliplatin, fluorouracil (5-FU), and leucovorin (LV) therapy in patients with untreated advanced colorectal cancer. PATIENTS AND METHODS: Forty-five patients in this multicenter, open, nonrandomized study received oxaliplatin 130 mg/m(2) on the first day of each course and 5-FU and LV 350 mg/m(2) and 20 mg/m(2), respectively, as a daily bolus for 5 days, every 21 days, for a maximum of six courses. RESULTS: Partial responses occurred in 18 patients, giving an intent-to-treat response rate of 40.0%. Median time to response was 12.7 weeks; median duration of response was 18.4 weeks. Median progression-free survival was 5.9 months; median survival was 14 months. The independent prognostic factors for improved overall survival were good performance status and negative carcino-embryonic antigen blood level. Incidences of adverse effects were reduced after the 5-FU dose was reduced to 300 mg/m(2). Reversible neurologic toxicity occurred in 44.4% of patients. CONCLUSION: Bolus administration of oxaliplatin, 5-FU, and LV as first-line therapy for untreated advanced colorectal cancer is efficacious and safe. In addition to a more favorable safety profile, the 300 mg/m(2) dosage offered improved dose-intensity compared with the initial dosage.

Malignant pericardial mesothelioma. Report of two cases, review of the literature and differential diagnosis.

Malignant pericardial mesothelioma is an uncommon variety of a primary malignant cardio-pericardial tumor and it is a highly lethal and fortunately rare cardiac neoplasm. The presentation of pericardial mesothelioma is aspecific and pathologically mesothelioma is not the most common among primary tumors of the pericardium. It is characterized by atypical solid growth of mesothelium with formation of atypical cavities surrounded by fibrous stroma. Antemortem diagnosis is difficult and distant metastases are extremely rare. Radical surgery can be used to treat localized mesothelioma. The treatment for advanced primary pericardial mesothelioma is usually palliative because the tumor is resistant to radiotherapy and chemotherapy. The prognosis is unfavorable. The median survival from the onset of symptoms is six months. In this paper we report two cases of patients with primary mesothelioma of the pericardium without a definite history of asbestos exposure.

Oral vinorelbine plus cisplatin as first-line chemotherapy in nonsquamous non-small-cell lung cancer: final results of an International randomized phase II study (NAVotrial 01).

BACKGROUND: The combination of oral vinorelbine plus cisplatin has been studied in numerous trials as first-line treatment of patients with non-small cell lung cancer (NSCLC) regardless of histologic subtype. NAVoTrial 01 is the first study that explores this combination specifically in nonsquamous (NS) NSCLC by assessing the feasibility of this doublet (ratio 1:2) in an investigational approach. A reference arm with pemetrexed plus cisplatin was included. Maintenance therapy with single-agent therapy after 4 cycles of combination therapy was included in the study schedules because it reflected a trend in first-line treatment of NSCLC. PATIENTS AND METHODS: Stage IIIB/IV untreated/relapsed patients with NS NSCLC received a 3-week cycle of pemetrexed 500 mg/m(2) and cisplatin 75 mg/m(2) on day 1 (arm A) or oral vinorelbine 80 mg/m(2) on days 1 and 8 (first cycle 60 mg/m(2)) and cisplatin 80 mg/m(2) on day 1 (arm B). After 4 cycles, patients without disease progression received single-agent maintenance treatment with pemetrexed or oral vinorelbine. RESULTS: Overall, 153 patients were randomized (arm A/arm B: 51/102). Disease control rate (%) for arm A was 76.5 (95% confidence interval [CI], 62.5-87.2) and for arm B it was 75.0 (95% CI, 65.3-83.1), Response rates for arm A were 31.4% (95% CI, 19.1-45.9) and for arm B were 24.0% (95% CI, 16.0-33.6). Median progression-free survival for arm A was 4.3 months (95% CI, 3.8-5.6) and for arm B it was 4.2 months (95% CI, 3.6-4.7). Median survival for arm A was 10.8 months (95% CI, 7.0-16.4) and for arm B it was 10.2 months (95% CI, 7.8-11.9). Main grade 3/4 hematologic toxicities were neutropenia 18.3% (arm A) and 44.0% (arm B), whereas febrile neutropenia was reported in 2% of patients in each arm. CONCLUSION: Oral vinorelbine and cisplatin had an efficacy in line with that achieved with a standard treatment such as pemetrexed and cisplatin, coupled with an acceptable safety profile.

Genetic markers for toxicity of adjuvant oxaliplatin and fluoropyrimidines in the phase III TOSCA trial in high-risk colon cancer patients.

We investigated 17 polymorphisms in 11 genes (TS, MTHFR, ERCC1, XRCC1, XRCC3, XPD, GSTT1, GSTP1, GSTM1, ABCC1, ABCC2) for their association with the toxicity of fluoropyrimidines and oxaliplatin in colorectal cancer patients enrolled in a prospective randomized trial of adjuvant chemotherapy. The TOSCA Italian adjuvant trial was conducted in high-risk stage II-III colorectal cancer patients treated with 6 or 3 months of either FOLFOX-4 or XELOX adjuvant chemotherapy. In the concomitant ancillary pharmacogenetic study, the primary endpoint was the association of polymorphisms with grade 3-4 CTCAE toxicity events (grade 2-4 for neurotoxicity). In 517 analyzed patients, grade ≥ 3 neutropenia and grade ≥ 2 neurotoxicity events occurred in 150 (29%) and in 132 patients (24.8%), respectively. Diarrhea grade ≥ 3 events occurred in 34 (6.5%) patients. None of the studied polymorphisms showed clinically relevant association with toxicity. Hopefully, genome-wide association studies will identify new and more promising genetic variants to be tested in future studies.

Lipoplatin treatment in lung and breast cancer.

The introduction of cisplatin in cancer treatment represents an important achievement in the oncologic field. Many types of cancers are now treated with this drug, and in testicular cancer patients major results are reached. Since 1965, other compounds were disovered and among them carboplatin and oxaliplatin are the main Cisplatin analogues showing similar clinical efficacy with a safer toxicity profile. Lipoplatin is a new liposomal cisplatin formulation which seems to have these characteristics. Lipoplatin was shown to be effective in NSCLC both in phase 2 and phase 3 trials, with the same response rate of Cisplatin, a comparable overall survival but less toxicity. A new protocol aiming to elucidate the double capacity of Lipoplatin to act as a chemotherapeutic and angiogenetic agent in triple-negative breast cancer patients is upcoming.