Corrado Ficorella

Cardiovascular toxicity following sunitinib therapy in metastatic renal cell carcinoma: a multicenter analysis

BACKGROUND Recent data have shown that cardiotoxicity represents a potentially important side-effect in patients treated with sunitinib. We reviewed cardiac adverse events in patients with metastatic renal cell carcinoma (RCC) who underwent treatment with this agent. PATIENTS AND METHODS The medical records of 175 patients with metastatic RCC treated with sunitinib at eight Italian institutions were retrospectively reviewed. Alterations in left ventricular ejection fraction (LVEF) and blood pressure were evaluated. Patients with preexisting cardiac risk factors were specifically scrutinized for increased expression of cardiac changes. RESULTS Grade 3 hypertension was seen in 17 patients (9.7%); in 12 of these 17, hypertension developed after receiving the third sunitinib cycle. Among these 17 patients, 12 (70.6%) also experienced left ventricular systolic (LVEF) dysfunction; in all, 33 of the 175 patients (18.9%) developed some degree of cardiac abnormality, of which 12 were classified as grade 3 LVEF dysfunction and/or congestive heart failure (CHF) (6.9%). Significant univariate associations for predictors of CHF were history of hypertension (P = 0.008), history of coronary heart disease (P = 0.0005) and prior treatment with an angiotensin-converting enzyme inhibitor (P = 0.04). Multivariate analysis suggested that a history of coronary artery disease [odds ratio (OR) 18, 95% confidence interval (CI) 4-160, P = 0.005] and hypertension (OR 3, 95% CI 1.5-80, P = 0.04) was the only significant independent predictors of CHF. CONCLUSIONS Patients undergoing sunitinib, especially those with a previous history of hypertension and coronary heart disease, are at increased risk for cardiovascular events and should be monitored for exacerbations of their hypertension and for evidence of LVEF dysfunction during treatment.

Phase II Study of Sorafenib in Patients With Sunitinib-Refractory Metastatic Renal Cell Cancer

PURPOSE No previous prospective trials have been reported with sorafenib in patients with sunitinib-refractory metastatic renal cell cancer (MRCC). We conducted a multicenter study to determine the activity and tolerability of sorafenib as second-line therapy after sunitinib progression in MRCC. PATIENTS AND METHODS Between January 2006 and September 2008, 52 patients were enrolled onto this single-arm phase II study. All patients received sorafenib 400 mg orally twice a day until disease progression or intolerable toxicity. The primary end point was objective response rate (complete or partial response) evaluated every 8 weeks by use of the Response Evaluation Criteria in Solid Tumors; secondary end points were toxicity, time to progression (TTP), and overall survival (OS). RESULTS All patients were included in response and safety analyses. Partial responses were observed in 9.6% of patients (five of 52 patients; 95% CI, 5% to 17%) after two cycles. Grade 1 to 2 fatigue, diarrhea, nausea/vomiting, rash, and neutropenia were the most common side effects, noted in 16 (30.8%), 19 (36.5%), 20 (38.5%), 19 (36.5%), and 20 patients (38.5%), respectively. The most common grade 3 toxicity was diarrhea, noted in six patients (11.5%). Median TTP was 16 weeks (range, 8 to 40 weeks), and median OS was 32 weeks (range, 16 to 64 weeks). CONCLUSION Although well tolerated, sorafenib shows limited efficacy in sunitinib-refractory MRCC. Further randomized trials comparing sorafenib with other drugs that target different biologic pathways are needed to define the best second-line treatment option in these patients.

Weekly administration of paclitaxel: theoretical and clinical basis

The rationale for weekly administration of paclitaxel, which acts on microtubules to arrest mitosis, is that more frequent delivery of moderate doses may achieve greater efficacy than standard doses every 3 weeks, through more sustained exposure of dividing tumor cells to its cytotoxic effects. This dose-dense approach to treatment may inhibit tumor regrowth between cycles and limit the emergence of malignant cell populations resistant to chemotherapy. More frequent exposure to paclitaxel may also enhance its apoptotic and antiangiogenic effects. Paclitaxel activity is considered to be independent of p53 status, in contrast to anticancer drugs that produce lesions on DNA, which achieve a better response if p53 is functional. Weekly therapy also has advantages in terms of improving paclitaxel therapeutic index. Clinical studies show that weekly paclitaxel is effective and that toxicity is acceptable. The response rates of single-agent paclitaxel varied from 21 to 86% in breast cancer, from 20% to 65% in ovarian cancer and from 30% to 56% in non-small cell lung cancer.

Acupuncture in the treatment of menopause-related symptoms in women taking tamoxifen.

Fifteen patients were enrolled in a pilot study to evaluate the safety and efficacy of acupuncture for the treatment of menopausal symptoms in tamoxifen-treated patients. Patients were evaluated before treatment and after one, three and six months with the Greene Menopause Index and were treated according to the traditional Chinese medicine. Anxiety, depression, somatic and vasomotor symptoms were improved by the treatment; libido was not modified. Acupuncture seems to be safe and effective for the treatment of menopausal symptoms in women with previous breast cancer taking tamoxifen. Confirmatory studies with a larger number of patients and with a placebo-treated group are warranted.

Tapentadol in cancer pain management: a prospective open-label study

Abstract Objectives: The aim of this prospective, open-label study was to evaluate the efficacy and tolerability of tapentadol (TP) in the management of cancer pain. Methods: A 4 weeks’ prospective study was carried out in 50 opioid-naive cancer patients with moderate–severe pain. Each patient initially received twice-daily doses of slow-release TP 50 mg. Doses were then managed to maintain adequate relief or dose-limiting toxicity, on the basis of the clinical response. The following parameters were recorded at weekly intervals for 4 weeks: pain and opioid-related adverse effects, quality of life measured with the Spitzer score, TP escalation index percent (TPEI%) and TP escalation index in mg (TPEImg), calculated at the end of the study, pain mechanisms, and PainDETECT at baseline. Results: Of 50 patients, 39 completed the entire study and 11 discontinued the treatment for different reasons. Pain intensity significantly decreased from baseline to all the week intervals (p < 0.0005), and adverse effects did not changed significantly, while quality of life improved. TP escalation indexes were low and no relationship was found with age, gender, and pain mechanisms. Conclusion: Tapentalol started in doses of 100 mg/day was well-tolerated and effective in opioid-naive patients with cancer pain, regardless of the pain mechanism. It can be considered as a flexible drug to be used in patients with moderate–severe pain. Limitations: This was an open-label study for exploratory purposes. Data should be confirmed in controlled studies with a larger number of patients.

Combined targeting of epidermal growth factor receptor and MDM2 by gefitinib and antisense MDM2 cooperatively inhibit hormone-independent prostate cancer.

Purpose: The epidermal growth factor receptor (EGFR) may play a relevant role in the progression, hormone therapy resistance, and prognosis of prostate cancer patients. Also MDM2, a negative p53 regulator that interacts with retinoblastoma (Rb), E2F, p19arf and the ras-mitogen-activated protein kinase(MAPK) cascade plays an important role in prostate cancer progression and prognosis. On the basis of the EGFR and MDM2 role in integrating signaling pathways critical for prostate cancer progression, we investigated whether their selective combined blockade may have a cooperative antitumor effect in prostate cancer. For this purpose, we have used the EGFR tyrosine kinase inhibitor gefitinib (ZD1839, Iressa) and a second generation hybrid oligonucleotide antisense MDM2 (AS-MDM2), respectively. Experimental Design: Gefitinib and AS-MDM2 were administered to hormone-refractory and hormone-dependent human prostate cancer cells in vitro and to mice bearing tumor xenografts, evaluating the effects on growth, apoptosis, and protein expression, in vitro and in vivo. Results: We demonstrated that the combination of gefitinib and AS-MDM2 synergistically inhibits the growth of hormone-independent prostate cancer cells in vitro. This effect is accompanied by the inhibition of MDM2, phosphorylated Akt (pAkt), phosphorylated MAPK (pMAPK), and vascular endothelial growth factor (VEGF) expression and by Rb hypophosphorylation. The combination of the two agents in nude mice bearing the same hormone-independent tumors caused a potent cooperative antitumor effect. Tumor samples analysis confirmed the inhibition of MDM2, pAkt, pMAPK, VEGF, and basic fibroblast growth factor expression. Conclusions: This study shows that EGFR and MDM2 play a critical role in the growth of prostate cancer, especially hormone-dependent, and that their combined blockade by gefitinib and AS-MDM2 causes a cooperative antitumor effect, supporting the clinical development of this therapeutic strategy.

Prophylactic options in patients with 5-fluorouracil-associated cardiotoxicity

At present, the various mechanisms involved in 5-fluorouracil (5-FU)-correlated cardiotoxicity remain to be elucidated and a universally accepted prophylaxis or treatment for this specific toxicity is not available. Although it may improve time to progression, survival and clinical benefit, a 5-FU-based regimen usually has to be discontinued if a patient experiences cardiotoxicity. Here, we describe our experience with three cases of 5-FU-associated cardiotoxicity. The angina-like pain that appeared approximately 95 h after beginning 5-FU therapy was apparently independent of the drugs administration modality. In the two patients receiving 5-FU 12-h flat continuous infusion from 22.00 to 10.00 h (5-FU 12-h c.i.) in combination with other drugs, the dose of 5-FU was reduced by 10–20% and patients received prophylactic transepidermal nitroglycerin. In the third patient, 5-FU administration modality was changed and prophylactic therapy was not given. By taking these precautions, the patients no longer complained of anginal pain and none of them discontinued chemotherapy.

Gabapentin in the treatment of hiccups in patients with advanced cancer: a 5-year experience.

Aim:To evaluate safety and efficacy of gabapentin in the treatment of severe chronic hiccups in patients with advanced cancer. Methods:Charts of all patients observed in the palliative care unit of a 4-bed hospital and at home by our Home Care Service were reviewed retrospectively.The presence of hiccups was routinely assessed. Patients with severe chronic hiccups were treated with gabapentin (300 mg t.i.d.). Doses of gabapentin were titrated based on the response to treatment.Gabapentin-related adverse effects were recorded. Results:Thirty-seven (3.9%) of 944 in-hospital patients and 6 (4.5%) of 134 patients observed at home presented severe chronic hiccups.We registered an improvement of hiccups, defined as complete resolution of hiccups, in 31 (83.8%) of 37 in-hospital patients and 4 (66.7%) of 6 patients observed at home.Four (10.8%) of the 37 in-hospital patients and 2 (33.3%) of the 6 patients observed at home experienced a reduction of hiccups.In 2 patients (5.4%), we registered a worsening of hiccups.Responses were observed in 32 patients (74.4%) with gabapentin at a dosage of 900 mg/d and in 9 patients (20.93%) at 1200 mg/d.In 2 patients (4.65%), grade 2 sleepiness was observed and in 10 patients (23.25%), grade 1 sleepiness was observed based on the Epworth Sleepiness Scale. Conclusion:The results of the study allow suggesting gabapentin at least as a promising drug in the treatment of severe chronic hiccups in advanced cancer patients.

The Supportive Care Task Force at the University of L’Aquila: 2-years experience

The Supportive Care Task Force (SCTF) was established within the Medical Oncology Department at the University of L’Aquila in May 2002. The missions of the SCTF were to allow systematic evaluation and treatment of symptoms, to warrant continuity of care in all phases of disease and to provide medical oncology residents with training in the treatment of symptoms. A medical oncologist, two senior residents in medical oncology and a registered nurse comprised the SCTF. A psychiatrist, two neurologists, a dietician, and two physiotherapists served as consultants or on a part-time basis. Four beds in two-bedded rooms inside the Medical Oncology Department were reserved to SCTF. A close integration with the physicians of the Medical Oncology Department was realised. The only criterion to admission was the presence of uncontrolled symptoms. Patients were evaluated and monitored with the visual analogue scale for pain and with the Edmonton Symptom Assessment Scale (ESAS). The Palliative Prognostic Score (PaP Score) was employed to assess the prognosis. Non-clinical needs were evaluated with the Need Evaluation Questionnaire (NEQ). Protocols for the treatment of common symptoms were available in written form for consultation by physicians, residents and nurses. From 1 May 2002 to 31 May 2004, we observed 208 patients: 111 women and 97 men. The median age was 64.7 (range 28–90) years. Fifty-four patients (25.9%) were admitted more than once, for a total of 285 admissions. One hundred ninety-nine admissions (69.5%) were for supportive care while 86 admissions (30.5%) were for supportive care and active treatment. The most frequent symptoms were asthenia and anorexia. We registered excellent results regarding the treatment of pain, nausea and dyspnea while psychological symptoms, anorexia and asthenia proved more difficult to treat.Two hundred twenty patients were discharged: 142 (49.8%) home; 76 (26.7%) to the Home Care Service and two (0.7%) to others units of the hospital. Sixty-five (22.8%) died in our unit.

Poker association of weekly alternating 5-fluorouracil, irinotecan, bevacizumab and oxaliplatin (FIr-B/FOx) in first line treatment of metastatic colorectal cancer: a phase II study

BackgroundThis phase II study investigated efficacy and safety of weekly alternating Bevacizumab (BEV)/Irinotecan (CPT-11) or Oxaliplatin (OHP) associated to weekly 5-Fluorouracil (5-FU) in first line treatment of metastatic colorectal carcinoma (MCRC).MethodsSimon two-step design: delta 20% (p0 50%, p1 70%), power 80%, α 5%, β 20%. Projected objective responses (ORR): I step, 8/15 patients (pts); II step 26/43 pts. Schedule: weekly 12 h-timed-flat-infusion/5-FU 900 mg/m2, days 1-2, 8-9, 15-16, 22-23; CPT-11 160 mg/m2 plus BEV 5 mg/kg, days 1,15; OHP at three dose-levels, 60-70-80 mg/m2, days 8, 22; every 4 weeks.ResultsFifty consecutive, unselected pts < 75 years were enrolled: median age 63; young-elderly (yE) 24 (48%); liver metastases (LM) 33 pts, 66% Achieved OHP recommended dose, 80 mg/m2. ORR 82% intent-to-treat and 84% as-treated analysis. Median progression-free survival 12 months. Equivalent efficacy was obtained in yE pts. Liver metastasectomies were performed in 26% of all pts and in 39% of pts with LM. After a median follow-up of 21 months, median overall survival was 28 months. Cumulative G3-4 toxicities per patient: diarrhea 28%, mucositis 6%, neutropenia 10%, hypertension 2%. They were equivalent in yE pts. Limiting toxicity syndromes (LTS), consisting of the dose-limiting toxicity, associated or not to G2 or limiting toxicities: 44% overall, 46% in yE. Multiple versus single site LTS, respectively: overall, 24% versus 20%; yE pts, 37.5% versus 8%.ConclusionPoker combination shows high activity and efficacy in first line treatment of MCRC. It increases liver metastasectomies rate and can be safely administered.Trial registrationOsservatorio Nazionale sulla Sperimentazione Clinica dei Medicinali (OsSC) Agenzia Italiana del Farmaco (AIFA) Numero EudraCT 2007-004946-34