Integration of Homeopathy and Complementary Medicine in the Tuscan Public Health System and the Experience of the Homeopathic Clinic of the Lucca Hospital.

INTRODUCTION: The healthcare programs of the Region of Tuscany (Italy) have started the process of integration of some types of complementary medicine (CM), including homeopathy, which began in 1996. The Homeopathic Clinic of Lucca was opened in 1998, followed by the Homeopathic Clinic for Women in 2003, and the Clinic for CM and Diet in Oncology in 2013. METHODS: Observational longitudinal studies conducted on 5,877 patients (3,937 in the general clinic, 1,606 in the women's clinic and 334 in oncology) were consecutively examined from 2003 to 2016. The Outcome in Relation to Impact on Daily Living (ORIDL) was generally used to assess outcomes. RESULTS: Comparing the clinical conditions before and after homeopathic treatment, improvement was observed in 88.8% of general medicine patients with follow-up (45.1%); in particular, 68.1% of the patients had a major improvement in or resolution (ORIDL +2, +3, +4) of their condition. In women, an improvement was obtained in 74.1% cases and a major improvement in 61.2%. In cancer patients with homeopathic and integrative treatment, a significant improvement was observed for all the symptoms during anti-cancer therapy, particularly for hot flashes, nausea, depression, asthenia, and anxiety. CONCLUSIONS: These results suggest that homeopathy can effectively be integrated with allopathic medicine and that the Tuscan experience could provide a useful reference for developing national and European regulations on the use of CM and homeopathy in public healthcare.

Phase I study of PF-03446962, a fully human monoclonal antibody against activin receptor-like kinase-1, in patients with hepatocellular carcinoma.

BACKGROUND: This expansion cohort of a multicenter, dose-escalation, phase I study (NCT00557856) evaluated safety, tolerability, antitumor activity, pharmacokinetics, and pharmacodynamic effects of the anti-activin receptor-like kinase-1 (ALK-1) monoclonal antibody PF-03446962 in advanced hepatocellular carcinoma (HCC). PATIENTS AND METHODS: Patients with HCC and disease progression after prior antiangiogenic therapy or intolerance to treatment received PF-03446962 7 mg/kg intravenously biweekly, as recommended in the dose-escalation part of the study. RESULTS: Twenty-four patients received PF-03446962. The most frequent treatment-related adverse events (AEs) were thrombocytopenia (33.3%), asthenia (29.2), and chills (16.7%). Two patients experienced treatment-related telangiectasia, suggesting an in vivo knockout of ALK-1 function through ALK-1 pathway inhibition. Overall, treatment-related grade 3-4 AEs were reported in eight patients (33.3%). Treatment-related grade 3-4 thrombocytopenia was noted in four patients. No complete or partial responses were reported. Twelve (50%) patients achieved stable disease, which lasted ≥12 weeks in seven (29.2%) patients. The median time to progression was 3 months. Biomarker analyses showed higher mean tumor expression of c-tumor mesenchymal-epithelial transition factor and higher mean serum levels of bone morphogenetic protein-9 in patients with disease control (DC) for ≥12 weeks versus patients with disease progression. Conversely, lower mean serum transforming growth factor-ß and vascular endothelial growth factor receptor-3 levels were detected in patients with DC versus patients with progression. CONCLUSIONS: The observed safety, tolerability, pharmacokinetic profile, and clinical activity support further evaluation of PF-03446962 in patients with HCC and other solid malignancies, as single agent or in combination with other antiangiogenic, chemotherapeutic, or immunotherapeutic agents. TRIAL REGISTRATION NUMBER: NCT00557856.

The choice of whether to participate in a phase I clinical trial: increasing the awareness of patients with cancer. An exploratory study.

OBJECTIVE: In a previous study, we found that patients who were offered the possibility of participation in a clinical trial had unexpressed concerns and fears that prevented them from making free or fully knowledgeable choices about their trial participation. In a selected population of patients who were offered participation in a phase I trial, we prospectively investigated whether a face-to-face discussion about their unexpressed fears might lead to a more conscious decision about whether to accept/refuse participation in the trial. METHODS: After the presentation of the trial, a questionnaire was administered to assess the presence of specific fears. Before the patients decided whether to participate in the trial, they discussed any fears that they had; finally, the impact of the discussion on the patients' choice to participate was evaluated. RESULTS: The majority (86%) of the patients thought that physicians conduct clinical trials for scientific interest, 13% felt exploited as 'guinea pigs' and 20% believed they were offered participation because they had no further hope for improvement. These existing fears were not elicited during the trial interview because the patients were themselves unaware of having them (28%) and because of fear of the doctors (3%). The possibility of discussing these fears was felt as an opportunity and made patients feel more conscious (92%) and freer (97%) when making their choice. CONCLUSIONS: Recognising and discussing misconceptions and fears, often unexpressed, make patients freer and more aware when facing the choice of whether or not \to participate in a phase I clinical trial.

Using 3% retinol peeling and cosmeceuticals for the aesthetic wellness of the oncological patient after precautionary endocrine treatment: A case series.

BACKGROUND: Roughness, sagging, and skin rash are common in patients with breast cancer treated with LH-RH analog plus tamoxifen or aromatase inhibitors as adjuvant postsurgical endocrine therapy. The use of topical retinol (vitamin A) has shown to be an efficacious cosmetic treatment. AIMS: Peeling with an advanced retinol peel formulation based on 3% retinol, 4% triethyl citrate, 0.1% aminophil, bisabolol, and 1% vitamin E acetate, in a vehicle in an alcoholic solution has been successfully used to ameliorate skin appearance on subjects with photodamage and in the aged population. We aimed to verify its use during adjuvant chemotherapy. PATIENTS: Four subjects experiencing skin issues during postsurgical adjuvant therapy for their breast cancer received retinol peel at least 6 weeks after stopping their postsurgery therapy as a low invasive aesthetic medical treatment to be used both at the dermatology desk and at home. RESULTS: Retinol peel was effective, safe, and well-tolerated, improving skin brightness and firmness in all the patients, since 4 weeks after the beginning of the treatment. Patients declared to be satisfied with the treatment and their skin appearance letting them feel better for cancer recovery, too. CONCLUSION: These preliminary observations suggest that the use of an advanced retinol peel formulation might improve skin appearance in women experiencing skin damages caused by adjuvant therapy after breast cancer surgery.

Optimizing clinical care in patients with advanced soft tissue sarcoma: a phase II study of a new schedule of high-dose continuous infusion ifosfamide and doxorubicin combination.

BACKGROUND: Ifosfamide and doxorubicin combination is an active regimen for patients with advanced soft tissue sarcomas (STS) but is burdened by high toxicity. A phase II trial was designed to assess the activity of continuous infusion ifosfamide and doxorubicin combination. PATIENTS AND METHODS: Thirty-four chemotherapy-naive patients with advanced STS were treated with ifosfamide (13 g/m(2)/12 days as continuous infusion) and doxorubicin (75 mg/m(2) on day 8) every 28 days with granulocyte colony-stimulating factor. RESULTS: The major toxicity was hematological: grade 3/4 neutropenia, anemia and thrombocytopenia occurred in 63, 30 and 12% of patients, respectively. The disease control rate was 68% and the median time to progression was 7.1 months. Among leiomyosarcomas, 2 partial responses and 4 stable diseases were observed. CONCLUSIONS: Our study confirms that the ifosfamide and doxorubicin combination has a very low non-hematological toxicity profile. This regimen attained a high disease control rate with moderate activity. Further investigation into leiomyosarcoma is warranted.

Expression of gemcitabine- and cisplatin-related genes in non-small-cell lung cancer.

The aim of this study was to investigate the influence of histology and site of analysis (primary tumor versus lymph node) on the expression of genes involved in gemcitabine and cisplatin activity in non-small-cell lung cancer (NSCLC). Excision repair cross-complementing-1 (ERCC1), human equilibrative nucleoside transporter-1 (hENT1), deoxycytidine kinase (dCK), 5'-nucleotidase (5'-NT), cytidine deaminase (CDA) and ribonucleotide-reductase regulatory subunits (RRM1 and RRM2) were analyzed by quantitative-reverse transcription-PCR in 88 microdissected samples from 69 chemonaive patients. The results showed different patterns of expression for all studied genes, suggesting a possible stratification of the patients. No difference was observed between primary tumor and lymph node metastasis, as well as in adenocarcinoma and squamous-cell carcinoma specimens, while we found a correlation between the CDA-A79C polymorphism and gene expression levels. These data suggest a similar genetic susceptibility to gemcitabine-cisplatin regimens for squamous cell and adenocarcinoma and support the use of both lymph node and primary tumor for the expression profiling of NSCLC.

Clinical and pharmacological phase I evaluation of Exherin (ADH-1), a selective anti-N-cadherin peptide in patients with N-cadherin-expressing solid tumours.

BACKGROUND: Upregulation of N-cadherin promotes dysregulated cell growth, motility, invasiveness, plus maintenance of vascular stability and is associated with cancer progression in several human tumour types. N-cadherin is expressed also on tumour cells and the anti-N-cadherin cyclic pentapeptide ADH-1, tested in the present study, can exert a direct antitumour effect. PATIENTS AND METHODS: Adult patients with advanced solid malignancies expressing N-cadherin on tumour biopsies carried out in the previous 12 months received escalating i.v. doses of ADH-1 given weekly (initially for 3 of 4 weeks, then every week). Plasma pharmacokinetics (PK) was studied at cycle 1. Blood flow changes were assessed after first dosing in all patients treated in the initial regimen. RESULTS: In all, 129 patients were screened, 65 (50%) were N-cadherin positive, and 30 were enrolled. The doses ranged from 150 to 2400 mg/m(2); no maximum tolerated dose was reached. Treatment was well tolerated with asthenia as the most frequent adverse event. Two patients with ovarian cancer showed prolonged disease stabilisation while one patient with fallopian tube carcinoma achieved a mixed response. PK was linear in the range of doses tested. CONCLUSION: ADH-1 is the first anti-N-cadherin compound tested in humans. In N-cadherin-positive patients, ADH-1 showed an acceptable toxicity profile, linear PK and hints of antitumour activity in gynaecological cancers.

Efficacy and tolerability of 4-hydroxyandrostenedione (4-OHA) as first-line treatment in postmenopausal patients with breast cancer after adjuvant therapy.

Aromatase inhibitors are known to be effective in the treatment of advanced postmenopausal breast cancer. To assess the efficacy of the aromatase inhibitor 4-hydroxyandrostenedione (4-OHA) as first-line treatment in patients who were either resistant to or had relapsed after adjuvant therapy, 50 eligible patients received intramuscular 4-OHA either 250 mg or 500 mg fortnightly until disease progression or severe adverse events. Of the 43 patients evaluable for clinical response (UICC criteria), 15 (36%) showed objective response (CR+PR), 6 (14%) stable disease (SD). In relation to disease site, objective responses were obtained in 55% of cases with soft tissue metastases (16/29); in 33% with visceral metastases (8/24), and in 24% with bone involvement (5/21). In relation to previous adjuvant treatment, there were eight objective responses among the 17 patients treated with chemotherapy (47%), and seven objective responses among the 24 treated with tamoxifen (29%). The treatment was well tolerated. These results support the hypothesis that adjuvant therapy, whether hormonal or chemotherapy, may make patients less responsive to subsequent treatment.

Pre-operative chemotherapy and radiotherapy in breast cancer.

Primary systemic treatment of breast cancer with cytotoxics yields a high response rate and allows conservative surgical procedures in bulky tumours. In order to maximise local control of disease, two innovations were introduced in a pilot study. The first was to identify the good responders after three cycles of chemotherapy and to treat them with three additional cycles. The second was to also give this group of patients a full dose of radiotherapy before surgery with the aim of verifying the rate of pathological complete remissions in view of a possible treatment of breast primary with chemoradiotherapy only. Patients were treated with doxorubicin 60 mg/m2 and cyclophosphamide, 600 mg/m2 both intravenously on day 1, every 21 days for three courses. Partial or complete responders received three more courses followed by radiotherapy (50 Gy plus a 10 Gy boost). The others underwent immediate surgery. A total of 32 patients (median age, 50 years; range 28-69 years); performance status, 0-1; T2 22, T3 8, T4 2) were enrolled and were evaluable for response and side-effects. 9 patients had only three cycles of chemotherapy due to absence of response and 23 patients had six cycles of chemotherapy. Overall, 7 patients had a complete remission, 16 a partial remission and 9 had stable disease, for an overall response rate of 72% (95% confidence interval 53-86%). In the group of patients that completed the programme, two complete pathological remissions were observed and 5 patients had only microfoci of tumour. No toxic death or grade III-IV toxicities were observed. Mild or moderate side-effects included mucositis, nausea/vomiting and leucopenia. In conclusion, our results indicate that the addition of radiotherapy to pre-operative chemotherapy did not significantly enhance the incidence of pathological complete remissions. New primary treatment approaches should be explored in this subset of patients in order to improve outcome.

Phase II studies of BBR3464, a novel tri-nuclear platinum complex, in patients with gastric or gastro-oesophageal adenocarcinoma.

BBR3464, a novel tri-nuclear platinum complex, forms long-range DNA adducts and is highly potent when compared with cisplatin in vitro. Preclinical studies demonstrated activity in cisplatin-resistant tumours and tumours with mutated p53 status. Phase I & II clinical studies gave preliminary indications of activity in melanoma, pancreatic, lung and ovarian cancers. The aim of this study was to determine the efficacy and confirm the toxicity of BBR3464 when given either as first- or second-line treatment for advanced disease in patients with gastric and gastro-oesphageal adenocarcinoma. Two multicentre, open label, Gehan design studies were conducted; one study used BBR3464 as first-line and the other as second-line treatment for metastatic or locally advanced disease. Nineteen first-line and 26 second-line patients were enrolled receiving a total of 74 and 53 infusions, respectively. Initially, seven patients in the second-line study received BBR3464 using the planned schedule of 1.1 mg/m2 every 4 weeks; however, 5 of these patients experienced dose-limiting grade 3 or 4 febrile neutropenia; subsequent patients in both studies were treated using the modified schedule of 0.9 mg/m2, every 21 days. In 1 of 17 evaluable, previously untreated patients, regression of multiple skin lesions was noted with stabilisation of lung metastases and maxillary sinus mass, lasting 155 days. In the first-line study, the median time to progression was 85 days [95% Confidence Interval (CI): 42, 127] (2.8 months) and in the second-line study, the median time to progression was 71 days [95% CI: 42, 109] and 38 days [95% CI: 32, 73] in the 1.1 and 0.9 mg/m2 dose level groups, respectively. Toxicity data were available for 45 patients. Neutropenia was the main toxicity seen (G3: 40%, G4: 40%). Febrile neutropenia was observed in six patients (15%) treated with 0.9 mg/m2 compared with five patients (71%) treated with 1.1 mg/m2 BBR3464. Other drug-related toxicities (G3/4) included: anaemia, thrombocytopenia, nausea, vomiting, diarrhoea, mucositis and fatigue. Diarrhoea and nausea/ vomiting were adequately controlled by the use of loperamide and antiemetics, respectively. Recruitment to the second-line study was closed early due to the poor response rate (1/17 evaluable, 6%; 95% CI: 1%, 27%) and short time to progression noted in the first-line study. Further studies with BBR3464 in this tumour type are not recommended.

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.

Prediction of response to primary chemotherapy for operable breast cancer.

The use of primary systemic cytotoxics leads to a high remission rate in patients with breast cancer. Response was identified as an important variable associated with survival. Thus, features which predict response, are potentially relevant for planning treatments and improving survival. Retrospectively, we investigated several histopathological features (expression of oestrogen and progesterone receptors, Mib1, bcl-2, c-erbB-2, and p53) prior to two programmes of either sequential preoperative chemotherapy (doxorubicin plus cyclophosphamide) and radiotherapy (Group A), or preoperative chemotherapy (5-fluorouracil, folinic acid and vinorelbine) alone (Group B) in patients with operable breast cancer. After three courses, patients with a partial or complete response were given a further three courses, which was followed for patients in Group A by radiotherapy 50 Gy plus a boost of 10 Gy. All patients were submitted to surgery after completion of preoperative treatment and pathology material from 73 patients (median age, 49 years, range, 30-70; performance status, 0-1; 68 T2, 5 T3) was obtained. The overall response rate according to radiological and clinical evaluation was 59% (68% for Group A and 49% for Group B). 12 of 14 patients with p53-positive tumours and 31 of 59 with p53-negative tumours responded (P = 0.04). 6 of 7 patients with elevated c-erbB-2 had a response compared with 37 of 66 patients in the group with c-erbB-2 negative tumours (P = 0.03). Mib1 expression decreased substantially (> or = 50%) in 25 patients during treatment, of whom 20 responded compared with 21 of 48 patients with a lower decrease (P = 0.04). Response was observed in 28 of 37 patients with high baseline Mib1 (> 20%) and in 15 of 36 patients in the low Mib1 group (P = 0.05). Finally, 32 of 44 tumours with low expression of progesterone receptors responded compared with 11 of 29 tumours with high receptors expression (P = 0.05). These markers might be useful for tailoring primary and postsurgical systemic treatments.

Effects of aromatase complex selective inhibition on insulin-like growth factor 1 and insulin-like growth factor binding protein 3 circulating levels in breast cancer.

The aim of our study is to evaluate insulin-like growth factor (IGF) and IGF binding protein (IGFBP)-3 circulating levels in postmenopausal women treated with type I aromatase inhibitor formestane for breast cancer. Sixty-three patients at their first relapse entered the trial and were randomly given formestane at 250 mg or 500 mg i.m. fortnightly. Effects of the endocrine treatment on IGF-1 and IGFBP-3 were measured before and during therapy at scheduled times. IGF-1 and IGFBP-3 seems to slightly increase in both the dose groups, but only IGFBP-3 levels showed statistically significant fluctuation (baseline vs 4 weeks, p=0.01925; baseline vs 10 weeks, p=0.04537). These modifications are unlikely to be related to clinical status because they were observed both in responsive and unresponsive patients. This report demonstrates that hormonal treatments for breast cancer (particularly, aromatase inhibitor administration) can modify growth factor disposition to tumour.

Formestane: an effective first-line endocrine treatment for advanced breast cancer.

Formestane, a new selective aromatase inhibitor devoid of severe side-effects, has been shown to be active in patients with advanced breast cancer. To investigate the clinical activity and endocrinological effects of formestane as a first-line treatment, 52 patients were administered two different doses: 24 received 250 mg formestane and 28 received 500 mg formestane i.m. fortnightly. All of the patients had a performance status of 2 or less (ECOG scale), 34 (65%) had a disease-free interval of at least 2 years and 21 (40%) were both oestrogen-receptor- and progesterone-receptor-positive; 20 patients received hormone and 13, received chemotherapeutical adjuvant treatment. Objective responses were obtained in 8 patients in the 250-mg group (33%; 95% CI: 14%-52%) and in 13 patients in the 500-mg group (46%; 95% CI: 28%-64%). The median response duration in the two groups was respectively 11 and 12 months. E2 serum levels of oestradiol had significantly (P < 0.001) decreased to more than 40% below the baseline value in both groups after 15 days of treatment, and remained unchanged thereafter. Local and systemic tolerability was satisfactory. We conclude that formestane is an effective and well-tolerated agent in previously untreated patients, and that these results should be confirmed by further studies.

Hormonal-therapy in patients with stage-iv breast-cancer at diagnosis.

The incidence of stage IV breast cancer at diagnosis is low, representing about 8% of all new cases. We report on the results obtained with a new aromatase inhibitor, formestane (500 mg i.m. fortnightly), given as a first treatment to fifteen postmenopausal patients with metastatic breast cancer. The overall response rate was 40%, with one complete remission in a patient with soft tissue and bone lesions and five partial remissions. The drug was well. tolerated and no significant systemic or local side effects were observed. We conclude that first treatment of stage IV breast cancer appears to be feasible with a hormonal drug such as formestane.

Formestane as treatment of advanced breast cancer in elderly women.

AIMS AND BACKGROUND: The number of elderly people is increasing, and the proportion of breast cancer in female cancer patients older than 65 years is 26%. In elderly patients, hormone therapy is widely accepted as the treatment of choice, because of its efficacy and good tolerability compared to chemotherapy. The aim of this study was to evaluate the endocrinologic and clinical activity of formestane (4-hydroxyandrostenedione), a selective aromatase inhibitor, in elderly patients with advanced breast cancer. METHODS: Thirty-five patients older than 65 years, selected from a larger group, were given formestane (250 mg or 500 mg i.m. fortnightly). Patients were evaluable for tumor response after 4 doses of formestane. Blood samples were collected to evaluate E2, FSH, LH, SHBG and DHEAS serum levels at baseline and after 2, 4, 8, 12 and 24 weeks. RESULTS: Thirty patients had PS < or = 1 (ECOG) and only 5 patients had PS = 2. Twenty-six patients were ER positive. Previous hormonal treatment for metastatic disease had been given to 17 patients; only 1 case had received chemotherapy. The overall response rate was 51% (95% C.I. 35-67%) and the median response duration was 9.5 months. Three complete responses were observed on viscera. The best responses were obtained on soft tissues (59%); on bone and viscera the response was respectively 45% and 47%. Local and systemic tolerability was highly satisfactory. Formestane induced prolonged suppression of E2 levels in all of the patients, and a significant reduction in SHBG levels was also observed from month 2 onward. A statistically significant (P = 0.0001) rise in serum FSH was also observed during the therapy. CONCLUSIONS: The study showed that formestane induced a long-lasting suppression of E2 levels and a satisfactory overall response. In our opinion, the drug is an effective and well-tolerated approach in the management of advanced breast cancer in elderly patients.

Phase I/II study of the tumour-targeting human monoclonal antibody-cytokine fusion protein L19-TNF in patients with advanced solid tumours.

PURPOSE: L19-TNF is an armed antibody that selectively targets human TNF to extra domain B-fibronectin on tumour blood vessels. We performed a phase I/II first-in-man trial with L19-TNF monotherapy in metastatic solid cancer patients to study safety and signs of clinical activity. METHODS: Six cohorts of patients were treated with increasing (1.3-13 µg/kg) doses of intravenous L19-TNF on day 1, 3, and 5 of repeated 3-weekly cycles, and 12 colorectal cancer patients were treated at 13 µg/kg. PK, antibody formation, changes in lymphocyte subsets, 5-HIAA plasma levels as well as safety and clinical activity were analysed. RESULTS: Thirty-four patients received at least one L19-TNF dose. The serum half-life of L19-TNF at 13 µg/kg was 33.6 min, and maximum peak serum concentration was 73.14 µg/L. Mild chills, nausea and vomiting but no haemato- or unexpected toxicity were observed. Grade 3 lumbar pain in bone metastasis was the only dose-limiting toxicity found in one patient. Objective tumour responses were not detected. Transient stable disease occurred in 19 of 31 evaluable patients. CONCLUSIONS: Intravenous L19-TNF on day 1, 3, and 5 of a 3-weekly schedule was safe up to 13 µg/kg, but did not result in objective tumour responses. The maximally tolerated dose (MTD) was not reached, allowing for further dose escalation of L19-TNF possibly in combination with chemotherapy.