Efficacy and safety of Everolimus and Exemestane in hormone-receptor positive (HR+) human-epidermal-growth-factor negative (HER2-) advanced breast cancer patients: New insights beyond clinical trials. The EVA study.

BACKGROUND: The BOLERO-2 trial reported efficacy and safety of Everolimus (EVE) and Exemestane (EXE) combination in HR+ advanced breast cancer (ABC) patients. The BALLET trial further evaluated the safety of EVE-EXE in HR+ ABC patients, without reporting efficacy data. Aim of the EVA real-life study was to collect data of efficacy and safety of EVE-EXE combination in the clinical setting, as well as exploring efficacy according to EVE Dose-Intensity (DI) and to previous treatment with Fulvestrant. PATIENTS AND METHODS: This study aimed to describe the outcome of ABC pts treated with EVE-EXE combination in terms of median duration of EVE treatment and ORR in a real-life setting. RESULTS: From July 2013 to December 2015, the EVA study enrolled 404 pts. Median age was 61 years (33-83). Main metastatic sites were: bone (69.1%), soft tissue (34.7%) and viscera (33.2%). Median number of previous treatments was 2 (1-7). 43.3% of the pts had received Fulvestrant. Median exposure to EVE was 31.0 weeks (15.4-58.3) in the whole population. No difference was observed in terms of EVE exposure duration according to DI (p for trend = 0.27) or type of previous treatments (p = 0.33). ORR and Disease Control Rate (DCR) were observed in 31.6% and 60.7% of the patients, respectively, with the lowest ORRs confined in CHT pre-treated patients or in those who received the lowest DI of EVE. Grade 3-4 adverse events (AEs) were reported in 37.9% of the patients. Main AEs were: stomatitis (11.2%), non-infectious pneumonitis - NIP (3.8%), anaemia (3.8%) and fatigue (3.2%). CONCLUSIONS: The EVA study provided new insights in the use of EVE-EVE combination in HR+ ABC pts many years after the publication of the pivotal trial. The combination is safe and the best response could be obtained in patients receiving the full dose of EVE and/or after hormone-therapy as Fulvestrant in ABC.

Therapeutic implications of resistance to molecular therapies in metastatic colorectal cancer.

Metastatic colorectal cancer (mCRC) patients carrying KRAS mutated tumors do not benefit from epidermal growth factor receptor (EGFR)-targeted cetuximab- or panitumumab-based therapies. Indeed, the mutational status of KRAS is currently a validated predictive biomarker employed to select mCRC patients for EGFR targeted drugs. When patients fail standard 5-fluorouracil-, oxaliplatin-, irinotecan- and bevacizumab-based therapies, EGFR-targeted salvage therapy can be prescribed only for those individuals with KRAS wild-type cancer. Thus, clinicians are now facing the urgent issue of better understanding the biology of KRAS mutant disease, in order to devise novel effective therapies in such defined genetic setting. In addition to KRAS, recent data point out that BRAF and PIK3CA exon 20 mutations hamper response to EGFR-targeted treatment in mCRC, potentially excluding from treatment also patients with these molecular alterations in their tumor. This review will focus on current knowledge regarding the molecular landscape of mCRC including and beyond KRAS, and will summarize novel rationally-developed combinatorial regimens that are being evaluated in early clinical trials.

Phase II study of cetuximab in combination with cisplatin and docetaxel in patients with untreated advanced gastric or gastro-oesophageal junction adenocarcinoma (DOCETUX study).

BACKGROUND: The conventional treatment options for advanced gastric patients remain unsatisfactory in terms of response rate, response duration, toxicity, and overall survival benefit. The purpose of this phase II study was to evaluate the activity and safety of cetuximab combined with cisplatin and docetaxel as a first-line treatment for advanced gastric or gastro-oesophageal junction adenocarcinoma. METHODS: Untreated patients with histologically confirmed advanced gastric or gastro-oesophageal adenocarcinoma received cetuximab at an initial dose of 400 mg m(-2) i.v. followed by weekly doses of 250 mg m(-2), cisplatin 75 mg m(-2) i.v. on day 1, docetaxel 75 mg m(-2) i.v. on day 1, every 3 weeks, for a maximum of 6 cycles, and then cetuximab maintenance treatment was allowed in patients with a complete response, partial response, or stable disease. RESULTS: Seventy-two patients (stomach 81.9% and gastro-oesophageal junction 18.1%; locally advanced disease 4.2%; and metastatic disease 95.8%) were enrolled. The ORR was 41.2% (95% CI, 29.5-52.9). Median time to progression was 5 months (95% CI, 3.7-5.4). Median survival time was 9 months (95% CI, 7-11). The most frequent grades 3-4 toxicity was neutropenia (44.4%). No toxic death was observed. CONCLUSIONS: The addition of cetuximab to the cisplatin/docetaxel regimen improved the ORR of the cisplatin/docetaxel doublet in the first-line treatment of advanced gastric and gastro-oesophageal junction adenocarcinoma, but this combination did not improve the TTP and OS. The toxicity of cisplatin/docetaxel chemotherapy was not affected by the addition of cetuximab.

Laparoscopic resection for rectal adenocarcinoma.

AIMS: Laparoscopic surgery for rectal cancer is still under discussion, but there is evidence that minimal access surgery can be feasible and safe also in this field. The aim of this study was to confirm that laparoscopic resection for rectal cancer can afford good results in terms of recurrence rate and survival. PATIENTS AND METHODS: Since June 1998 through December 2007 as many as 252 patients underwent laparoscopic resection for rectal cancer. Laparoscopic anterior resection (LAR) was performed in 209 and laparoscopic abdominoperineal resection (LAPR) in 43. Neoadjuvant radiochemotherapy (nCRT) was administered in 48 patients with mid-low rectal cancer stage II and III with evidence of nodal involvement in preoperative work up. RESULTS: Patients who received nCRT showed a significant longer duration of surgery compared to patients who did not (p=0.004). Conversion to laparotomy was needed in 24 cases, (21 LAR and three LAPR) but no patient receiving nCRT needed conversion. Postoperative surgical complications occurred in 38 patients, 20 of which were represented by anastomotic leak after LAR. Six patients died postoperatively, in half the cases for surgery related causes. Downstaging after nCRT was seen in 40 patients, and complete histological response was observed in six cases. The mean number of lymph nodes harvested was 12, also in patients receiving nCRT. The mean follow-up was 48+/-33 months (range 0.1-120.4), and 10 patients experienced local recurrence. Cumulative 5 year survival was 73.7%. CONCLUSION: Laparoscopic resection for rectal cancer is feasible and safe, with morbidity and long-term results quite acceptable also in patients receiving neoadjuvant treatment.

First-line single-agent cetuximab in patients with advanced colorectal cancer.

BACKGROUND: The anti-epidermal growth factor receptor (EGFR) antibody cetuximab is active in heavily pretreated patients with metastatic colorectal cancer (mCRC) both in monotherapy and in combination with chemotherapy (CT). This study assesses the antitumor activity of single-agent cetuximab in CT-naive patients. PATIENTS AND METHODS: Phase II clinical trial was used. Patients were EGFR positive by immunohistochemistry and were not candidate for radical surgery, even in the case of substantial tumor shrinkage. Cetuximab was administered weekly. RESULTS: Thirty-nine patients were treated and evaluated. The most common adverse event was skin toxicity (89% any grade; 48% grade 1; 31% grade 2; 10% grade 3). One patient had a complete response and three obtained partial responses (10% overall response rate). Thirteen patients had stable disease (34%). Twenty-two patients experienced progressive disease (56%). Overall median time to progression (TTP) was 2 months, and the responders individual TTP was 12, 9, 9, and 6 months. CONCLUSIONS: Even in chemo-naive patients, cetuximab as single agent is active only in a small fraction of mCRC, similarly to what has been reported for heavily pretreated patients. The extent of benefit when response occurs is, however, such that it is mandatory to intensify the search for the predictive markers of response to cetuximab therapy.

Cetuximab for treatment of metastatic colorectal cancer.

In the past decade the median overall survival of patients with metastatic colorectal cancer has increased from 12 to more than 20 months, mostly due to the new chemotherapeutic agents, irinotecan and oxaliplatin. Most recently, targeted therapies, that inhibit specific cancer pathways and molecules, have shown promising results in the treatment of patients with metastatic colorectal cancer and other solid tumors. One of the most studied targets for anticancer therapy is the epidermal growth factor receptor (EGFR), which is overexpressed in a variety of malignancies. Cetuximab, an anti-EGFR chimeric monoclonal antibody, has shown clinically meaningful antitumor activity in patients with metastatic colorectal cancer in several clinical trials. Efforts of physicians and researchers are currently directed towards the identification of predictive factors (clinical or molecular) of clinical outcome, with the aim of both optimizing the therapeutic index and dealing with increasing costs of these new compounds.

New clinical trials for the treatment of neuroendocrine tumors.

In oncology there is an increasing interest in neuroendocrine tumors, whose incidence is generally considered low, although in a recent analysis of 5,468 cases there was an increase in the proportion of pulmonary and gastric carcinoids and a decrease in the appendiceal carcinoids. However carcinoid tumors are indolent and their diagnosis is often difficult to carry out, so the true incidence may be higher. Surgery remains the treatment of choice and it should always be considered in patients with neuroendocrine tumors although a complete cure is difficult to obtain. Cytotoxic chemotherapy is the medical treatment for highly proliferating neuroendocrine tumors, but it has showed a modest benefit. Somatostatin analogues, octreotide and lanreotide are the standard hormonal treatment for neuroendocrine tumors. Recently, two trials on lanreotide and octreotide have been published, and it is worth noting that in each trial a long-acting formulation has been used: for lanreotide a prolonged-release formulation (PR) which allows an injection of 30 mg every 2 weeks, and for octreotide a long-acting release formulation (LAR) which allows an injection of 10, 20 or 30 mg every 28 days. The results of each trial are very promising. However, there are methodological and clinical aspects which make it difficult to carry out new trials for studying neuroendocrine tumors. The increasing number of biological markers deserve further investigations before their wide use in clinical practice.

Chemoradiotherapy as preoperative treatment in locally advanced unresectable pancreatic cancer patients: results of a feasibility study.

PURPOSE: The combination of radiotherapy and fluorouracil (5-FU) in patients with locally unresectable pancreatic carcinoma has led to a significant increase in survival in comparison with radiotherapy alone. Doxifluridine (5-DFUR) is an orally active fluoropyrimidine, and its cytotoxic metabolite (5-FU) may concentrate in areas of high tumor vascularization. This trial was carried out with the aims of improving locoregional control and making lesions resectable in patients with unresectable pancreatic cancer. METHODS: 5-DFUR was given at a dose of 500 mg/m2 b.i.d. by way of mouth for 4 days every other week for a total of four courses, with leucovorin 25 mg b.i.d. orally being given 2 hours before each 5-DFUR administration. External beam RT was administered at a dose of 1000 cGy per week for 3 weeks, followed by a 2-week break and then by 1000 cGy per week for a further 2 weeks (a total dose of 5000 cGy). The patients were restaged 4 weeks after the end of treatment and explored for resection in cases of partial response (PR). RESULTS: A total of 32 patients were treated between 1992 and 1997. Ab initio unresectability was shown by laparotomy (16 cases) or computed tomography (16 cases), and was due to vascular invasion in 27 patients, massive regional nodal metastases in nine, and both in four. The median age was 63 years (range 36-71); performance status (PS) (ECOG): 0-1 = 28 and PS 2 = 4. All the patients had measurable disease and were evaluable for response. There were seven PR (22%), 10 SD (31%), and 15 PD (47%). All of the responders underwent surgical exploration, and radical resection was possible in 5. Three of these patients are still disease-free with a follow-up of 18, 27, and 65 months; the other two cases relapsed 11 and 14 months after surgery. The median survival time was 9 months for the entire group, and 1-year survival rate was 31%. The treatment was never stopped because of toxicity. There were no CTC-NCI grade 3 or 4 toxic events; grade 1-2 diarrhea was observed in 10 cases. CONCLUSIONS: This preoperative regimen was feasible and led to a successful surgical resection in 16% of otherwise inoperable cases. The median survival was comparable with the results obtained after 5-FU infusion plus radiotherapy. The resectability rate, and the benefit in terms of survival in the resected patients, make these results worthy of confirmation by larger studies.

Chromogranin A, neuron specific enolase, carcinoembryonic antigen, and hydroxyindole acetic acid evaluation in patients with neuroendocrine tumors.

BACKGROUND: Chromogranin A (CgA), neuron specific enolase (NSE), carcinoembryonic antigen (CEA), and urinary 5-hydroxyindole-3-acetic acid (5-HIAA) are the markers currently used in the diagnosis, prognosis, and follow-up of patients with neuroendocrine tumors (NETs). The authors examined the role of such biomarkers in a large series of patients with NETs. METHODS: One hundred and twenty-seven patients entered the study. Multiple blood and 24-hour urine specimens were assayed for biomarker quantitation. RESULTS: The accuracy of each marker was assessed in patients with (n = 106) and without (n = 21) disease. CgA proved to be the best marker (specificity of 85.7% and sensitivity of 67.9%). Patients with disease had significantly higher CgA and NSE levels compared with disease free patients (P = 0.00003 and P = 0.00240, respectively). NSE and 5-HIAA determination showed a very high specificity (100%) but a rather low sensitivity (32.9% and 35.1%, respectively). CEA was found to have little diagnostic value (sensitivity of 15.4%). CgA was the most sensitive marker for detecting patients with disseminated disease and 5-HIAA displayed the highest sensitivity in identifying syndromic patients. Tumor marker modifications were studied during follow-up. In particular, rises in CgA were associated with progressive disease in 83.3% of cases and stable CgA was associated with stable disease in 53.8% of cases. The relation between CgA modifications and liver lesions during follow-up also was studied; increases in CgA levels were associated with local progression in 100% of cases and stable marker levels were found in 68.7% of the patients with unchanged lesions. CONCLUSIONS: The results of the current study demonstrate that CgA has the highest accuracy and is the most reliable biomarker reflecting the clinical evolution of NETs.

Integrated treatment with doxifluridine and radiotherapy in recurrent or primary unresectable rectal cancer. A feasibility study.

AIMS AND BACKGROUND: When combined with radiotherapy, fluoropyrimidines have been shown to have synergistic effects on various tumor types. Doxifluridine (5-dFUR) is a 5-fluorouracil (5-FU) prodrug that is transformed into 5-FU in neoplastic tissue, which suggests that it may improve the activity of radiotherapy. The aims of this study were to evaluate the feasibility and efficacy of the combination of radiotherapy and oral 5-dFUR plus l-leucovorin in terms of pathologically complete remissions in locally advanced rectal cancer. METHODS: Eleven patients with locally recurrent (n = 7) or primary unresectable rectal cancer (n = 4) were treated with three cycles of oral l-leucovorin 25 mg/dose followed by 5-dFUR 750 mg/m2 twice daily for four days every 12, in combination with pelvic radiation at a standard dose of 45 Gy over five weeks. The tumor burden was assessed by means of CT and endoscopic ultrasound at baseline and at least four weeks after the end of the treatment and before surgery. RESULTS: Four patients achieved an objective response, 6 disease stabilization and 1 had progressive disease. After a median time of five weeks from the end of treatment 8 patients underwent radical resection and a pathologically complete remission was documented in 2. Seven of these patients are still alive and disease free after a median follow-up of 18 months. The major side effects were grade 3 diarrhea in one case, and grade 1-2 nausea and vomiting in three cases. No significant hematological toxicity was observed. CONCLUSIONS: This combination of radiation and 5-dFUR plus l-leucovorin led to an interesting rate of resectability, with pathological downstaging being documented in two cases. These preliminary results show an encouraging local control of an otherwise unresectable disease. Combined preoperative therapy with oral fluoropyrimidine plus l-leucovorin together with radiation may be an attractive approach in patients with operable rectal cancer.

Chromogranin A measurement in neuroendocrine tumors.

Neuroendocrine tumors (NETs) are rare neoplasms characterized by a low proliferative index and, in some cases, a favorable prognosis. These tumors often overproduce and release biologically active substances that are responsible for severe syndromes. Tumor marker measurement provides the clinician with useful information for the management of NET patients. The substances released by overproducing tumors are currently used as biomarkers, but there is a need for sensitive markers also for the "biochemically silent" NETs. The most effective and reliable blood marker available today is chromogranin A (CgA). Because of its high sensitivity and specificity, this glycoprotein can be used for the diagnosis, prognosis and followup of NETs. Furthermore, CgA measurement can be used for monitoring those tumors not over-producing or releasing any hormones or biological amines. This paper is a synthetic review on the value of CgA in NET management and reports our experiences with CgA measurement in NET patients.

The minimal effective exemestane dose for endocrine activity in advanced breast cancer.

Phase I studies have demonstrated that exemestane, an irreversible oral aromatase inhibitor, is able to suppress circulating oestrogen levels. In our previous experience, doses ranging from 2.5 to 25 mg induced a similar suppression of oestrogens. The aim of this study was to identify the minimum effective exemestane dose on the basis of endocrine activity. 20 evaluable postmenopausal advanced breast cancer patients were randomly given exemestane 0.5, 1, 2.5 or 5 mg, in double-blind conditions. Oestrone (E1), oestradiol (E2), oestrone sulphate (E1S), gonadotrophins, sex-hormone binding globulin and dehydroepiandrosterone sulphate serum levels were evaluated from the first day of treatment to the 7th, 14th, 28th and 56th day. Serum E1, E2 and E1S levels were suppressed by all doses starting from day 7; the degree of inhibition versus baseline was 25 up to 72% for E1, 30 up to 62% for E2 and 16 up to 52% for E1S, with higher doses achieving greater suppression; these changes were maintained over time. A significant increase in FSH and LH levels was observed for all doses. Treatment tolerability was satisfactory. The endocrine effects of exemestane appear to be dose related and 0.5 and 1 mg are ineffective for adequately suppressing circulating oestrogens.

Doxifluridine in colorectal cancer patients resistant to 5-fluorouracil (5-FU) containing regimens.

Doxifluridine (5-dFUR) is a fluoropyrimidine derivative, which is preferentially converted to 5-fluorouracil (5-FU) within tumour tissues. Although the activity of 5-FU in metastatic colorectal cancer is well recognised, resistance to this agent is frequently observed and remains its major limitation. The aim of this phase II study was to evaluate the activity of oral and i.v. 5-dFUR in metastatic or locally advanced colorectal cancer patients, who had been previously treated with a 5-FU containing regimen in either an adjuvant or metastatic setting. We treated 48 patients who, on the basis of tumour progression during, or within 8 weeks of the discontinuation of 5-FU therapy, were considered 5-FU resistant, 14 of the patients received 5-dFUR 3000 mg/m2 as a 1-h i.v. infusion, combined with L-leucovorin 25 mg/dose on days 1-5, every 3 weeks; the remaining 34 received oral 5-dFUR 1200 mg/m2 for 5 days followed by 5 days off. Oral L-leucovorin 25 mg/dose was administered 2 h before 5-dFUR. On the basis of WHO criteria, 4/14 (29%, 95% CI 4-51) partial responses were noted in the i.v. treated patients, and 4/34 (12%, 95% CI 1-23) in those treated orally. The radiological examinations documenting the response were a CT scan in 4 cases, ultrasound in 2 and NMR in 2. The median response duration was 6 months (range 3-11+), whereas the median time to treatment failure was 4 months (range 2-17). The responses were achieved in cases previously treated with a median of 9250 mg/m2 (range 5500-18,650) of 5-FU. No CTC-NC1 grade 4 toxicity was observed, although grade 3 diarrhoea occurred in 5 of the orally treated and in 3 of the intravenously treated patients. This is the first report documenting the efficacy of 5-dFUR in patients resistant to 5-FU therapy, and suggests that there is an absence of complete cross-resistance between these two fluoropyrimidines.

Phase II study of vinorelbine in patients with pretreated advanced ovarian cancer: activity in platinum-resistant disease.

PURPOSE: The aim of the study was to evaluate the activity of vinorelbine (VNLB) in a population of advanced ovarian cancer patients, with particular attention to defining its role in platinum-resistant disease. PATIENTS AND METHODS: Thirty-three patients were recruited and treated with VNLB 25 mg/m2 intravenously (IV) weekly. the median age was 53 years, performance status 0 to 2, and number of previous chemotherapy regimens two (range, one to five). Twenty-four patients were platinum-resistant; the remaining nine either were platinum-sensitive (four cases) or had undetermined sensitivity (five cases). RESULTS: The mean delivered dose-intensity of VNLB was 67% of the planned level, because 60% of the cycles were delayed due to neutropenia or anemia. Four partial responses (PRs) and one complete response (CR) were observed, for an overall response rate of 15% (95% exact confidence interval, 5.1% to 31.9%). All the responses occurred in the subgroup of 24 platinum-resistant cases, in whom the response rate was 21% (95% exact confidence interval, 7.1% to 42.1%). Seven patients became stabilized on VNLB, and 27% of the cases showed a reduction in serum cancer antigen 125 (CA 125) levels. G3/G4 side effects consisted of neutropenia, anemia, and worsening of preexisting peripheral neuropathy. No treatment-related deaths occurred. CONCLUSION: VNLB led to a 21% response rate in the population of heavily pretreated and platinum-resistant ovarian cancer patients. Further studies of VNLB alone or in combination with taxanes are warranted in patients with less pretreatment.

[Multiparameter analysis of the ergometric test. Significance of the failure of systolic blood pressure to decrease during recovery phase as an index of coronary disease]. / Analisi poliparametrica del test ergometrico. Significato del mancato decremento della pressione arteriosa sistolica in fase di recupero come indice di coronaropatia.

Ergometric tests were performed in 27 patients who had previously undergone coronarography following instrumental findings and/or symptoms which seemed highly indicative of ischemic cardiopathy. The aim of the study was to assess the diagnostic importance of the failure of systolic blood pressure to decrease during the third minute of the recovery phase of the test as an index of coronary disease. In particular, as reported by other studies, the ratio between systolic blood pressure at the third minute of recovery and maximum systolic blood pressure during the test was also assessed values above 0.7 were considered pathological. Sixteen out the 27 patients examined showed lesions which were hemodynamically significant, whereas 11 patients were free of lesions and 9 had previous myocardial necrosis. The level of the above ratio in subjects without significant coronary lesions was 0.66 +/- 0.05, whereas it was 0.85 +/- 0.04 (p less than 0.01) in patients with coronary disease. Sensitivity, specificity, and positive and negative prognostic values were respectively 91.6%, 62%, 64.7% and 90.9%. In patients with lesions to the three main arteries both the sensitivity and the specificity were 100%. In the same patients, the ST criteria were 85.7%, 50%, 81.8% and 74.3%.