First-line avelumab for patients with PD-L1-positive metastatic or locally advanced urothelial cancer who are unfit for cisplatin.

BACKGROUND: Cisplatin-based chemotherapy is the most recommended treatment for metastatic urothelial cancer (mUC). However, about 50% of patients are considered to be cisplatin ineligible. Anti-programmed cell death protein 1/programmed death-ligand 1 (PD-L1) therapies have, nevertheless, increased the options available to clinicians and are especially valuable for treating these patients. This study therefore tested the activity and safety of avelumab as first-line therapy for mUC. PATIENTS AND METHODS: Patients with mUC who were ineligible for cisplatin-based chemotherapy were screened centrally for PD-L1 expression and only those with a tumour proportion score ≥ 5% were enrolled in the trial. The primary endpoint was 1-year overall survival (OS), and the secondary endpoints were median OS, median progression-free survival, overall response rate, duration of the response, safety and tolerability. All the survival rates were estimated with the Kaplan-Meier product-limit methodology and compared across groups using the log-rank test. RESULTS: A total of 198 patients were screened, with 71 (35.9%) whose PD-L1 expression was ≥5% enrolled in the study. The median age was 75 years, bladder cancer was the primary tumour in 73.2% of cases and 25.3% had liver metastases. The main reasons for the cisplatin ineligibility were a low rate of creatinine clearance (<60 ml/min), present in 70.4% of patients, and an Eastern Cooperative Oncology Group performance status of 2, which affected 31%. The median OS was 10.0 months (95% confidence interval 5.5-14.5 months) and 43% of patients were alive at 1 year. A complete response was achieved in 8.5% of cases, and 15.5% had a partial response. Adverse any-grade and high-grade events occurred in 49.3% and 8.5% of patients, respectively. A grade 3 infusion reaction was the only high-grade treatment-related adverse event. No treatment-related deaths were reported. CONCLUSIONS: This ARIES trial confirmed the activity and safety of avelumab for treating mUC, adding a new therapy option to the armamentarium of checkpoint inhibitors already approved for platinum-ineligible, locally advanced/mUC.

Everolimus and exemestane in long survival hormone receptor positive male breast cancer: case report.

BACKGROUND: Male breast cancer is a rare event, accounting for approximately 1% of all breast carcinomas. Although men with breast cancer had poorer survival when compared with women, data on prognosis principally derive from retrospective studies and from extrapolation of female breast cancer series. We reported the case of a very long survival patient. CASE PRESENTATION: A caucasian 42-year-old man underwent radical mastectomy with axillary dissection for breast cancer in 1993. Pathologic stage was pT4pN0M0 infiltrating ductal carcinoma of right breast without lymph nodes metastases. Biological characterization was not available. He received adjuvant treatment with chemotherapy, six cycles of cyclophosphamide, methotrexate and fluorouracil, then endocrine therapy with tamoxifen for 5 years and complementary radiotherapy. Then he began clinical-instrumental follow up. In May 1996, a computed tomography scan showed multiple lung metastases. Hereafter he received several oncologic treatment including seven chemotherapy and five endocrine therapy lines with two re-challenge of endocrine therapy. In October 2007 further lung progression was showed and a biopsy was performed to characterize the disease. Histological examination confirmed breast cancer metastases, immunohistochemistry showed positive staining for estrogen receptor, negative for progesterone receptor and human epithelial growth factor receptor 2, proliferative index was 21%. In April 2013, bone disease progression was evident and he received radiant treatment to sacral spine. In May 2014 an off-label treatment with exemestane and everolimus combination was approved by Ethics Committee of the Marche Region. The patient received treatment for 3 months with evident clinical benefit to subcutaneous lesions of the chest wall that were not visible nor palpable on physical examination after 1 month of treatment. CONCLUSION: That is the case of long survival male breast cancer patient with luminal B subtype and no BRCA mutations. He achieved higher progression free survival with endocrine therapy creating the rationale for last line treatment with everolimus and exemestane combination. Attending conclusive results from ongoing studies, everolimus and exemestane should not be used routinely in male metastatic breast cancer patients, but taking into account for selected cases. At the best of our knowledge, this is the first case of male beast cancer treated with exemestane and everolimus combination.

Phosphorylated mTOR is associated to androgen receptor expression in early triple-negative breast cancer.

The significance of phosphorylated mTOR (p-mTOR) expression is unknown in triple-negative breast carcinoma (TNBC). The aims of the present study were to assess the expression of p-mTOR in early TNBC and to evaluate possible correlations between androgen receptor (AR) expression, clinicopathological parameters and disease outcome. Between January 2009 and December 2013, all consecutive patients who were diagnosed and completed the treatment of invasive TNBC at our institution were eligible for this analysis. Patients with stage IV disease were excluded. The evaluation of p-mTOR immunohistochemical staining was semi-quantitatively considering both the percentage of positive tumor cells (range, 0-100%) and staining intensity (range, 0-3+). Ninety-eight TNBC patients were included. Approximately 33% of cases were p-mTOR positive and there was no association between positive immunostaining for p-mTOR and DFS (p=0.74) and OS (p=0.81). p-mTOR positivity was associated with small tumor size (p=0.03) and AR expression (p=0.04). High expression of p-mTOR may drive tumor proliferation in almost one third of TNBC. The biological association between mTOR activation and AR pathway suggests that there may exist a subgroup of TNBC in which the combination of both AR antagonism and mTOR inhibition should have a synergistic effect on cell growth and tumor progression.

Biology, prognosis and response to therapy of breast carcinomas according to HER2 score.

BACKGROUND: The standardization of the HER2 score and recent changes in therapeutic modalities points to the need for a reevaluation of the role of HER2 in recently diagnosed breast carcinoma. PATIENTS AND METHODS: A multicenter, retrospective study of 1794 primary breast carcinomas diagnosed in Italy in 2000/2001 and scored in HER2 four categories according to immunohistochemistry was conducted. RESULTS: Ductal histotype, vascular invasion, grade, MIB1 positivity, estrogen and progesterone receptor expression differed significantly in HER2 3+ tumors compared with the other categories. HER2 2+ tumors almost showed values intermediate between those of the negative and the 3+ subgroups. The characteristics of HER2 1+ tumors were found to be in between those of HER2 0 and 2+ tumors. With a median follow-up of 54 months, HER2 3+ status was associated with higher relapse rates in node-positive and node-negative subgroups, while HER2 2+ only in node positive. Analysis of relapses according to type of therapy provided evidence of responsiveness of HER2-positive tumors to chemotherapy, especially taxanes. CONCLUSIONS: The present prognostic significance of HER2 is correlated to receptor expression level and points to the need to consider HER2 2+ and HER2 3+ tumors as distinct diseases with different outcomes and specific features.

Vinorelbine plus trastuzumab combination as first-line therapy for HER 2-positive metastatic breast cancer patients: an international phase II trial.

The aim of this international phase II trial was to determine the efficacy and safety profile of weekly vinorelbine plus trastuzumab as first-line chemotherapy for women with HER 2-overexpressing metastatic breast cancer. Sixty-nine patients with tumours overexpressing HER 2 received vinorelbine: 30 mg m-2 week-1 and trastuzumab: 4 mg kg-1 on day 1 as a loading dose followed by 2 mg kg-1 week-1 starting on day 8. Sixty-two patients were evaluable for response and 69 patients were evaluable for toxicity. The overall response rate was 62.9%. The median time to response was 8.4 weeks, the median duration of response was 17.5 months, the median progression-free survival was 9.9 months (95% CI, 5.6-12.1) and the one-year progression-free survival was 39.1%. The median survival for all patients was 23.7 months (95% CI, 18.4-32.6). This regimen was safe: grade 3-4 neutropenia were observed over 17.7% of courses in 83.8% of patients, with only two episodes of febrile neutropenia (0.1%) in two patients (2.9%). Only one patient discontinued treatment due to grade 3 symptomatic cardiac dysfunction that resolved with therapy. Vinorelbine plus trastuzumab is one of the most active treatment regimens for patients with HER 2-positive metastatic breast cancer and demonstrates a very favourable safety profile allowing prolonged treatment with long-term survival. This study has been presented in part at the following conferences: The San Antonio Breast Cancer Symposium, San Antonio, TX, USA, 2003; The American Society of Clinical Oncology, Orlando, FL, USA, 2005.

Low dose-intensity docetaxel in the treatment of pre-treated elderly patients with metastatic breast cancer.

We evaluated the efficacy and toxicity profile of single-agent docetaxel administered in daily clinical practice at low-dose regimen in 37 pre-treated elderly patients with metastatic breast cancer previously exposed to chemotherapy. Docetaxel was employed by physician's preference according to a weekly (8 patients, 25-30 mg/m2 every 7 days), bi-weekly (19 patients, 40-50 mg/m2 every 14 days), or tri-weekly (10 patients, 75-100 mg/m2 every 21-28 days) schedule. The median age of patients was 70 yrs, and most of them (84%) had a good PS; visceral metastases were found in 26 patients. Twenty-five patients were pre-treated by two or more chemotherapy lines. Anthracycline or anthracycline/paclitaxel therapy was previously employed in 25 patients (67%). Median delivered dose-intensity of docetaxel was 21 mg/m2/week (range 11-32), without significant differences between the regimens used. Thirty-three patients were evaluable for response. Eight (24%) patients had objective responses (2 complete and 6 partial) to docetaxel, with a median duration of response of 18 months; 14 (42%) patients had stable disease lasting more than 6 months (median 10 months). Median overall time to progression was 6 months. Median overall survival was 16 months, with 1- and 2-year survival rates of 64% and 34%, respectively. Grade 3/4 toxicities were rare: leucopenia in 18% of patients, neutropenia in 13%, emesis in 8%, diarrhea in 5%, and mucositis in 5%. Severe fatigue was recorded in 4 patients. In conclusion, docetaxel, even when administered at low dose-intensity, demonstrated good disease control and toxicity profile. This approach provides an excellent alternative for pre-treated elderly patients with advanced breast cancer.

[Paraneoplastic syndromes: a review]. / Le sindromi paraneoplastiche: revisione critica della letteratura.

Modern oncology often obtains good results against earlier neoplasms, whilst it's still in difficulties against the advanced ones. The knowledge of paraneoplastic syndromes is crucial both to cure patients and to do an earlier diagnosis. When we recognize a paraneoplastic syndrome that comes before the clinic beginning of a neoplasm, perhaps we save a life. This review discusses all the main paraneoplastic syndromes, focusing mainly on their clinical aspect and reminding the most commonly associated cancers.

Raltitrexed plus oxaliplatin (TOMOX) as first-line chemotherapy for metastatic colorectal cancer. A phase II study of the Italian Group for the Study of Gastrointestinal Tract Carcinomas (GISCAD).

BACKGROUND: To evaluate the safety and efficacy of the novel raltitrexed/oxaliplatin combination (TOMOX) as first-line chemotherapy for patients with advanced colorectal cancer. MATERIALS AND METHODS: Previously untreated patients with metastatic colorectal cancer received raltitrexed 3 mg/m2 plus oxaliplatin 100 mg/m2, both intravenously, on day 1 every 3 weeks. Patients were re-evaluated after every third cycle and chemotherapy was continued up to tolerance or disease progression. RESULTS: Fifty-eight patients from 13 Italian Group for the Study of Gastrointestinal Tract Carcinomas (GISCAD) centers were accrued from September 1999 to November 2000. According to the intention-to-treat analysis from 58 patients, the overall response rate was 50% [95% confidence interval (CI) 38% to 62%], with three complete responses and 26 partial responses. The median overall survival (44 patients currently alive) was >9 months and the median time to disease progression was 6.5 months (range 1-15 months). The main hematological toxicity was grade III/IV neutropenia, which occurred in 17% of patients, while anemia and thrombocytopenia were uncommon. Grade III/IV non-hematological toxicities were transient transaminitis (17% of patients); asthenia (16% of patients); neurotoxicity (10% of patients) and diarrhea (7% of patients). No toxic death was observed, one patient with grade IV asthenia after the first cycle refused chemotherapy. CONCLUSIONS: The results of this study suggest that the TOMOX combination is an effective and well tolerated regimen for the treatment of advanced colorectal cancer. Its ease of administration and patient tolerance warrant further investigation as an alternative to fluoropyrimidine-based regimens with repeated and prolonged fluorouracil infusions.

A phase II study of weekly docetaxel as salvage chemotherapy for advanced gastric cancer.

BACKGROUND: Docetaxel has shown some activity in advanced gastric cancer. Recent phase I studies found low hematologic toxicity and a favourable toxicity profile when docetaxel was administered on a weekly schedule. In this study, we explored the activity of weekly docetaxel in patients with advanced gastric cancer who failed first-line chemotherapy. MATERIALS AND METHODS: Patients with stable or progressing disease after first-line chemotherapy received 36 mg/m2 weekly docetaxel. One cycle consisted of six administrations followed by a two-weeks rest, patients were re-evaluated at week eight. The optimal two-stage design was adopted for early stopping of the trial if responses were one or less in 21 patients (< 20% response rate with alpha and beta error probabilities 0.05 and 0.010 respectively). RESULTS: Twenty-one patients have been enrolled and they are fully evaluable for response and toxicity. One patient achieved partial response, 8 patients had stable disease and 12 patients progressed. Median overall survival from the onset of salvage chemotherapy was 3.5 months. Hematologic toxicity was observed in two patients who experienced grade III leukopenia. Beginning from the third week of treatment, most of the patients (90%) showed grade II asthenia which resulted the commonest side-effect. CONCLUSIONS: This schedule of weekly docetaxel did not show significant activity in pretreated patients with advanced gastric cancer.

Advanced non-small cell lung cancer in the elderly: effective and well tolerated weekly gemcitabine and cisplatin regimen. A pilot study.

BACKGROUND: The frequency of advanced non-small cell lung cancer (NSCLC) increases with age and more effective and less toxic chemotherapy schedules are needed in elderly patients. Cisplatin-based regimens are considered the best treatment for advanced NSCLC, although they produce only a modest advantage in overall survival with considerable toxicity. METHODS: In the present study the activity and toxicity of a weekly gemcitabine and cisplatin schedule was evaluated in a small group of advanced NSCLC patients aged 68 years or more. Treatment consisted of gemcitabine 1000 mg/m2 i.v. and cisplatin 35 mg/m2 i.v., both given weekly on days 1, 8, 15 followed by 1 week of rest. RESULTS: Fifteen previously untreated patients entered the study; their median age was 72 years (range 68-76). One hundred and sixteen weekly administrations were delivered. The median dose-intensity was 614.5 mg/m2 per week for gemcitabine (82%) and 21 mg/m2 per week for cisplatin (80%). All the 15 patients were evaluable for response and toxicity. The overall response rate was 40% [95% CI = 16-68%]. The main toxicity was WHO grade III-IV thrombocytopenia that was recorded in 6 patients (40%). Other major toxicities were very low and no treatment-related deaths were reported. CONCLUSIONS: This schedule appears to be active, to have a favourable toxicity profile and can be considered in advanced NSCLC elderly patients. Of interest, the patients enrolled received high dose intensities of both drugs.

Intensive weekly chemotherapy is not effective in advanced pancreatic cancer patients: a report from the Italian Group for the Study of Digestive Tract Cancer (GISCAD).

Twenty-two patients, with locally advanced unresectable and/or metastatic pancreatic carcinoma, received weekly administration of cisplatin 40 mg m(-2), 5-fluorouracil 500 mg m(-2), epidoxorubicin 35 mg m(-2), 6S stereoisomer of leucovorin 250 mg m(-2) and glutathione 1.5 mg m(-2), supported by a daily administration of lenograstim at a dose of 5 microg kg(-1). Nineteen patients were men and three were women. Median age was 63 years (range 47-70). At study entry, pain was present in 15 out of 22 patients (68%) with a mean value of Scott-Huskisson scale of 27.6+/-23.8, whereas a weight loss >10% was present in 15 patients. After eight weekly treatments, three partial responses were achieved for a response rate of 13% (95% CI 0-26%), five patients had stable disease and 14 progressed on therapy. Pain was present in 9 out of 22 patients (40%) with a mean value of Scott-Huskisson scale of 12.3+/-18.4. Eight patients (36%) (three partial response and five stable disease) had a positive weight change. Toxicity was mild: WHO grade III or IV toxicity was recorded in terms of anaemia in 7 out of 188 cycles (3.7%), of neutropenia in 9 out of 188 cycles (4.7%) and of thrombocytopenia in 3 out of 188 cycles (1.5%). Median survival of all patients was 6 months. The outcome of this intensive chemotherapy regimen does not support its use in pancreatic cancer.

First line chemotherapy in patients with brain metastases from non-small and small cell lung cancer.

In this study we evaluated the role of systemic chemotherapy in 23 previously untreated patients with brain metastases from both non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). In NSCLC group, 2 patients out of 14 had a brain response after treatment (1 complete and 1 partial response). In the group of 9 patients with SCLC, we observed 5 brain responses (3 complete and 2 partial responses). Brain responses were in accordance with extracranial responses although this appeared more clearly in SCLC than in NSCLC patients.

A phase II study of mitomycin C, vindesine and cisplatin combined with alpha interferon in advanced non-small cell lung cancer.

AIMS AND BACKGROUND: MVP chemotherapy (mitomycin C, vindesine or vinblastine, cisplatin) is one of the most commonly used regimens for advanced non-small cell lung cancer (NSLCLC). Experimental data suggest a synergistic cytotoxic activity of alpha-interferon (alpha-IFN) when combined with cisplatin, mitomycin C and vinca alkaloids. In an effort to improve MVP chemotherapy activity, we have combined this regimen with alpha-IFN. PATIENTS AND METHODS: Thirty-five patients with advanced NSCLC (19 stage IV) were treated with the MVP regimen (mitomycin C, 8 mg/m2; vindesine, 3 mg/m2, cisplatin, 75 mg/m2, all on day 1) plus alpha-2a-IFN, 3x10(6) U from day 1 to 7. The cycles were repeated every 28 days. RESULTS: There were no complete responses and 18 partial responses, for an overall response rate of 51%. Median time to treatment failure was 6 months (range, 1-18), and the median survival was 9.5 months (range, 1-32). WHO grade 3 toxicity was recorded in up to 8% of patients, flu-like syndrome was a common complaint; one toxic death occurred. CONCLUSIONS: The combination yielded a level of response comparable to that of other cisplatin-based regimens. Larger randomized trials are needed to assess the role of alpha-IFN combined with chemotherapy in advanced NSCLC.

c-erbB-2 and common prognostic factors in breast cancer patients.

We report data on c-erbB-2, hormone receptors, and Ki-67 proliferation associated antigen in ninety-seven unselected breast carcinoma specimens. Immunohistochemical results and clinical data (age, axillary nodal involvement, menopausal status, tumor size) were compared. Positivity for c-erbB-2 staining was detected in the 46% of tumors. There was no correlation among c-erbB-2 status and age, menopausal status, tumor size, lymph nodes involvement or Ki-67 index. An inverse relationship of c-erbB-2 and estrogen and progesterone receptor status was detected, although not statistically significant. Increased levels of c-erbB-2 were observed in 40-50% of all the subsets of patients grouped on the basis of established prognostic factors. These higher levels could lead to the identification of further subsets of patients at higher risk of relapse. However, at present, the role of c-erbB-2 for clinical management of patients with breast cancer remains unclear.

[Biologic aspects and clinical use of granulocyte growth factor]. / Aspetti biologici e impiego clinico del fattore di crescita granulocitario.

Granulocyte colony stimulating factors (G-CSF) has a wide spectrum of action: it stimulates proliferation and differentiation of granulocyte-macrophage progenitors, it promotes the chemotactic activity of monocytes and granulocytes and it develops the antibody-dependent cytotoxicity of neutrophils. In vivo G-CSF induces leucocytosis and it hastens the granulocyte recovery after chemio-radiotherapy. So it has been used in many pathologies: aplastic anaemia, AIDS in treatment with antiviral drugs, myelodysplastic syndromes, acute leukemias and solid tumors. If G-CSF is administered after chemotherapy, both in acute leukemias and in solid tumors, it reduces the duration of neutropenia and the number of febrile episodes so that it is possible to give the whole therapy at the planned dosage with no delay. However G-CSF does not modify the incidence of complete remissions and the overall survival. G-CSF allowed the increase of dose-intensity in chemoresistent neoplasms even if this therapy is always complicated by a heavy extrahaematological toxicity. Moreover G-CSF shortens the total duration of neutropenia after autologous or allogenic bone marrow and peripheral stem cell transplantation even if the appearance of the first neutrophil is not accelerated.

Mitomycin C, 5fluorouracil and folinic acid in combination with alpha 2b interferon for advanced colorectal cancer.

AIMS AND BACKGROUND: This study was conducted to investigate the activity and toxicity of 5fluorouracil folinic acid+mitomycin C combined with alpha 2b interferon in advanced colorectal cancer based upon recent studies suggesting a possible biochemical modulation of 5fluorouracil by interferon. PATIENTS AND METHODS: Between June 1990 and April 1991 25 previously untreated patients with advanced colorectal carcinoma were treated with mitomycin C 10 mg/m2 iv bolus on day 1, 5fluorouracil 375 mg/m2 on days 1 to 4 and folinic acid 200 mg/m2 on days 1 to 4 every 4 weeks, combined with alpha 2b interferon 3 million U day continuously. RESPONSE: Of the 25 patients entered into the study, 20 were evaluable for response as 5 patients withdrew due to toxicity (grade 3-4 thrombocytopenia in 4 cases and fatigue in 1). No complete response was recorded, 6 patients had partial remission (30%; 95% confidence interval, 10% to 50%), 4 experienced no change and 10 showed progressive disease. The toxicity of this regimen was significant, particularly myelosuppression. CONCLUSIONS: This combination showed a significant toxicity and low response rate compared with other 5fluorouracil based regimens in advanced colorectal cancer.