A randomized, phase 2 study of cetuximab plus cisplatin with or without paclitaxel for the first-line treatment of patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck.

BACKGROUND: B490 (EudraCT# 2011-002564-24) is a randomized, phase 2b, noninferiority study investigating the efficacy and safety of first-line cetuximab plus cisplatin with/without paclitaxel (CetCis versus CetCisPac) in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). PATIENTS AND METHODS: Eligible patients had confirmed R/M SCCHN (oral cavity/oropharynx/larynx/hypopharynx/paranasal sinus) and no prior therapy for R/M disease. Cetuximab was administered on day 1 (2-h infusion, 400 mg/m2), then weekly (1-h infusions, 250 mg/m2). Cisplatin was given as a 1-h infusion (CetCis arm: 100 mg/m2; CetCisPac arm: 75 mg/m2) on day 1 of each cycle for a maximum of six cycles. Paclitaxel was administered as a 3-h infusion (175 mg/m2) on day 1 of each cycle. After six cycles, maintenance cetuximab was administered until disease progression or unacceptable toxicity. The primary end point was progression-free survival (PFS). We assumed a noninferiority margin of 1.40 as compatible with efficacy. RESULTS: A total of 201 patients were randomized 1 : 1 to each regimen; 191 were assessable. PFS with CetCis (median, 6 months) was noninferior to PFS with CetCisPac (median, 7 months) [HR for CetCis versus CetCisPac 0.99; 95% CI: 0.72-1.36, P = 0.906; margin of noninferiority (90% CI of 1.4) not reached]. Median overall survival was 13 versus 11 months (HR = 0.77; 95% CI: 0.53-1.11, P = 0.117). The overall response rates were 41.8% versus 51.7%, respectively (OR = 0.69; 95% CI: 0.38-1.20, P = 0.181). Grade ≥3 adverse event rates were 76% and 73% for CetCis versus CetCisPac, respectively, while grade 4 toxicities were lower in the two-drug versus three-drug arm (14% versus 33%, P = 0.015). No toxic death or sepsis were reported and cardiac events were negligible (1%). CONCLUSION: The two-drug CetCis regimen proved to be noninferior in PFS to a three-drug combination with CetCisPac. The median OS of both regimens is comparable with that observed in EXTREME, while the life-threatening toxicity rate appeared reduced. CLINICAL TRIAL NUMBER: EudraCT# 2011-002564-24.

Real-world experience of abiraterone acetate plus prednisone in chemotherapy-naive patients with metastatic castration-resistant prostate cancer: long-term results of the prospective ABItude study.

BACKGROUND: Limited real-world data exist on the effectiveness and safety of abiraterone acetate plus prednisone (abiraterone hereafter) in the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) naive to chemotherapy. Most of the few available studies had a retrospective design and included a small number of patients. In the interim analysis of the ABItude study, abiraterone showed good clinical effectiveness and safety profile in the chemotherapy-naive setting over a median follow-up of 18 months. PATIENTS AND METHODS: We evaluated clinical and patient-reported outcomes (PROs) of chemotherapy-naive mCRPC patients treated with abiraterone as for clinical practice in the Italian, observational, prospective, multicentric ABItude study. mCRPC patients were enrolled at abiraterone start (February 2016-June 2017) and followed up for 3 years; clinical endpoints and PROs, including quality of life (QoL) and pain, were prospectively collected. Kaplan-Meier curves were estimated. RESULTS: Of the 481 patients enrolled, 454 were assessable for final study analyses. At abiraterone start, the median age was 77 years, with 58.6% elderly patients and 69% having at least one comorbidity (57.5% cardiovascular diseases). Visceral metastases were present in 8.4% of patients. Over a median follow-up of 24.8 months, median progression-free survival (any progression reported by the investigators), time to abiraterone discontinuation, and overall survival were, respectively, 17.3 months [95% confidence interval (CI) 14.1-19.4 months], 16.0 months (95% CI 13.1-18.2 months), and 37.3 months (95% CI 36.5 months-not estimable); 64.2% of patients achieved ≥50% reduction in prostate-specific antigen. QoL assessed by Functional Assessment of Cancer Therapy-Prostate, the European Quality of Life 5 Dimensions 3 Level, and European Quality of Life Visual Analog Scale remained stable during treatment. Median time to pain progression according to Brief Pain Inventory data was 31.1 months (95% CI 24.8 months-not estimable). Sixty-two patients (13.1%) had at least one adverse drug reaction (ADR) and 8 (1.7%) one serious ADR. CONCLUSION: With longer follow-up, abiraterone therapy remains safe, well tolerated, and active in a large unselected population.

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.

Pharmacokinetic evaluation of gemcitabine and 2',2'-difluorodeoxycytidine-5'-triphosphate after prolonged infusion in patients affected by different solid tumors.

BACKGROUND: The study determined pharmacokinetic parameters, toxicity profile and preliminary clinical activity of gemcitabine administered i.v. at different infusion rates in patients with a range of solid tumors. PATIENTS AND METHODS: Twenty patients were enrolled for both pharmacokinetic and clinical studies. Gemcitabine 300 mg/m(2) was administered during 1 h, 2 h or 3 h, and as a conventional dose of 1000 mg/m(2) during 30 min infusion. Administration was on days 1, 8 and 15 every 4 weeks. RESULTS: Patients were randomly assigned to one of the four arms. After 30 min infusion of 1000 mg/m(2) gemcitabine the plasma concentration remained above the saturation level of 10-20 microM, whereas after 1, 2 or 3 h infusion 300 mg/m(2) gemcitabine it remained below the saturation level for most of the time (being in the range 2.5-10 microM). Gemcitabine triphosphate was determined in the four arms in white blood cells; for infusion times from 0.5 to 3 h there was a progressive enhancement of gemcitabine triphosphate levels. In all evaluable patients the toxicity was mild, myelosuppression being the main toxicity. No grade 3 or 4 toxicities occurred. Clinical response was similar in patients receiving 300 mg/m(2) gemcitabine in 2 and 3 h and in the 1000 mg/m(2) arm. CONCLUSIONS: 300 mg/m(2) gemcitabine during 3 h infusion produced the highest accumulation of gemcitabine triphosphate. Thus, to achieve the highest possible gemcitabine triphosphate level, prolonged infusion time would appear to be more important than a high dose administered as a short infusion. However, there was no substantial difference in toxicity or antitumoral activity in the all different patient groups.

Pain management in head and neck cancer patients undergoing chemo-radiotherapy: Clinical practical recommendations.

Pain in head and neck cancer represents a major issue, before, during and after the oncological treatments. The most frequent cause of pain is chemo/radiation related oral mucositis, which involves 80% of the patients and worsens their quality of life inhibiting speaking, eating, drinking or swallowing and sometimes reducing the treatment compliance, the maximum dose intensity and thus the potential efficacy of treatment. Nevertheless pain is still often under estimated and undertreated. An Italian multidisciplinary group of head and neck cancer specialists met with the aim of reaching a consensus on pain management in this setting. The Delphi Appropriateness method was used for the consensus. External expert reviewers evaluated the final statements. The paper contains 30 consensus-reached statements about pain management in HNC patients and offers a review of recent literature in these topics.

Parameters and outcomes in 525 patients operated on for oral squamous cell carcinoma.

PURPOSE: This report analyzed the outcomes of patients undergoing surgery for oral squamous cell carcinoma (OSCC) to identify the value of prognostic factors. MATERIAL AND METHODS: A total of 525 patients were studied who had undergone surgery for oral squamous cell carcinoma (OSCC) between 2000 and 2011, of whom 222 had received postoperative radiation-therapy (PORT) and or chemoradiation-therapy (PORTC). For each patient, personal data, histological findings, treatment and outcome were recorded and analyzed statistically. Survival curves were calculated using the Kaplan-Meier algorithm, and the difference in survival among subgroups was examined. RESULTS: The overall survival (OS) and disease-specific survival (DSS) 5-year survival rate in the 525 patients were respectively 71.38% and 73.18%. The differences in the overall survival and disease-specific 5-year survival were significant (p < 0.05) for age < 40 years, site of origin, N status, staging, grading, osseous medullar infiltration, and perineural invasion. In patients undergoing radiation therapy, only perineural invasion negatively influenced the survival prognosis. In 150 pT1 cases of tongue and floor-of-mouth cancer, an infiltration depth (ID) > 4 mm was statistically correlated with poorer prognosis. CONCLUSIONS: The results demonstrate an improvement in the 5-year OS and DSS rates during the past decade compared with the previous decade. Univariate analysis revealed that age, tumor staging, and lymph node involvement, extracapsular spread, grading, perineurial invasion, infiltration depth, and osseus medullary invasion were associated significantly with overall survival and disease-specific survival.

Current role of chemotherapy in exclusive and integrated treatment of malignant tumours of salivary glands.

In the management of salivary glands carcinomas, surgery is the treatment of choice. Post-operative radiotherapy is indicated in cases with high risk of loco-regional relapse. Radiotherapy is also standard treatment in cases that are inoperable at onset. Chemotherapy plays a palliative role. Today, the integration between radiotherapy and chemotherapy, which provides increased local control, represents a significant step forward. This integration is important since 5-year survival in tumours with high grade histology is approximately 50%. Overall incidence of metastases is approximately 25%. Primary locations of metastases are lungs, liver, bone, central nervous system and other organs. In cases of metastatic disease, chemotherapy plays only a palliative role.

Paclitaxel and carboplatin for recurrent salivary gland malignancies.

BACKGROUND: The use of chemotherapy for recurrent salivary gland carcinomas is under investigation. PATIENTS AND METHODS: Fourteen patients (10 males, 4 females; median age 55 years, range 20-70) with recurrent carcinomas of major (9 patients) and minor (5 patients) salivary gland origin (histology: 1 adenocarcinoma, 10 adenoid cystic carcinoma, 2 undifferentiated carcinoma, 1 mucoepidermoid carcinoma) were treated with carboplatin AUC 5.5 + paclitaxel 175 mg/m2 (3-hour infusion) on day 1 (interval = 3 weeks). All patients had been previously treated with surgery + radiotherapy and 8 with a cisplatin combination. One patient had a local lesion, 7 locoregional recurrence and metastases and 6 patients had metastases only. RESULTS: Overall 65 courses were given (median 5; range 2-6). Responses were: PR in 2 patients (14%) lasting 5 and 12 months; 7 NC (50%) with a median duration of 8.5 months (5-12); and 5 PD (36%). The median survival time was 13.5 months for PR/NC patients, 6 months for non responders; median overall survival was 12.5 months (3-17+). CONCLUSION: This combination had a moderate activity; the treatment was well tolerated and toxicity was manageable.

HIV/HCV co-infection: natural history.

HIV and HCV share common transmission pathways, but HCV is more efficiently transmitted through blood than with sexual exposure. Thus HCV coinfection is frequent in HIV seropositives, mainly in those with history of injection drug use and/or transfusion. HIV coinfection increases HCV replication rate, the rate of HCV vertical transmission and accelerates the course of hepatitis C towards cirrhosis and hepatocellular carcinoma. The evidence of an effect of HCV on HIV disease progression is less convincing. The results of several studies suggest that HCV coinfection does not hasten the progression of HIV infection towards AIDS. However two recent studies showed that HCV coinfection is independently associated with a lower restoration of CD4 counts during combination antiretroviral treatment. However this finding should be confirmed by additional studies.

A retrospective study of treatment of cerebral toxoplasmosis in AIDS patients with trimethoprim-sulphamethoxazole.

AIMS OF THE STUDY: a retrospective study was designed to evaluate efficacy and tolerance of trimethoprim-sulphamethoxazole (TMP-SMZ) in AIDS patients with cerebral toxoplasmosis (TE). PATIENTS AND METHODS: we reviewed 471 patients with AIDS, and we analysed 71 AIDS patients with TE, who received intravenous therapy with TMP-SMZ (TMP: 10 mg/kg/day, SMZ: 50 mg/kg/day) for 4 weeks. RESULTS: 35 patients (49.2%) had a complete regression of clinical signs, and a complete resolution of radiological lesions was noted in 41 patients (57.7%). Improvement of clinical signs and radiological lesions were observed in 27 patients (38%), and in nine patients (12.6%), respectively. In contrast, nine patients (12.6%) did not show any clinical change, or worsened. Twenty-two patients (30.9%) suffered from adverse cutaneous reactions, whereas many patients had haematological toxicity. CONCLUSIONS: TMP-SMZ seems to be an efficient therapy for TE in AIDS patients, although further prospective, randomized therapeutic trials are required to confirm these results.

A retrospective study on the efficacy and safety of amphotericin B in a lipid emulsion for the treatment of cryptococcal meningitis in AIDS patients.

To evaluate the efficacy and safety of Amphotericin B dissolved in dextrose (Amb) or in a lipid emulsion (Intralipid, Amb-IL) in AIDS patients with cryptococcal meningitis, we conducted a retrospective study in 30 AIDS patients with cryptococcal meningitis. A clinical complete resolution was obtained in 11 patients (55%) treated with Amb, and in six patients (60%) treated with Amb-IL. Intralipid did not decrease the infusion-related adverse effects, in particular nephrotoxicity and anaemia. Our results indicate that Amb-IL formulation is useful in the treatment of cryptococcal meningitis in AIDS patients, but it does not reduce the infusion-related adverse events.

Small cell carcinoma of the esophagus.

Small cell carcinoma of the esophagus (SCEC) is a rare tumor with its particular biologic features, distinct from squamous and glandular carcinoma of esophagus. Although initial symptoms can be similar (with metastatic dissemination and paraneoplastic syndromes at presentation more frequent in SCEC), differences in age and sex distribution, tumor location, radiological and endoscopic findings, clinical course and prognosis have been observed between SCEC and other esophageal malignancies. SCEC should be considered a systemic disease, and by analogy to bronchogenic small cell carcinoma, multimodality approach including chemotherapy is recommended. In patients with limited disease, irradiation or surgery should be offered after induction chemotherapy to manage local disease. However, optimal treatment schedule has not yet been defined. In the future, registration of all SCEC cases and careful analysis of prognostic factors in the larger multi-institutional series could contribute to further progress in treatment outcome.

Combined chemotherapy for recurrent and metastatic nasopharyngeal carcinoma.

Thirty-two patients (24 males, 8 females; median age 54 yrs) with recurrent and/or metastatic undifferentiated carcinoma of the nasopharyngeal type were treated with chemotherapy. Remissions were observed in 17 of 32 (53.2%) with 5 complete (CR) (15.6%) and 12 partial responses (PR) (37.6%). A combination of cisplatin and 5-fluorouracil was the most effective regimen (CR + PR = 83.3%). Objective responses. (CR + PR) were 47% (CR = 11.7%) in schemes without cisplatin and 60% (CR = 20%) in cisplatin-based combinations. The median overall duration of response was 7.2 months. The median overall survival time was 10.3 months: 15.1 months for responders and 5.2 for non-responders. No important toxicity was observed.

Adjuvant therapy with essential fatty acids (EFAs) for primary liver tumors: some hypotheses.

Hepatocarcinoma is responsible for approximately 1 million deaths annually. It is usually discovered at an advanced stage and, if inoperable, has a poor prognosis. New therapies combining chemotherapy, hyperthermia, radiotherapy and immunomodulators have been recently attempted with various levels of success. Once the tumor is detected at an early stage, some possibilities of cure seem to emerge either by intratumoral percutaneous injection (PEI) of alcohol or by chemoembolization and interstitial hyperthermia. When the tumor volume is more than 5 cm, these therapies are less successful and radiotherapy can be used. All the techniques described have some limits; PEI, for instance, does not achieve a complete eradication of lesions > 3 cm and a non-homogenous alcohol distribution within the tumor leads to areas of necrosis. Radiotherapy, even if effective, is limited by dose-related radiation hepatitis. Another important limiting factor is the incomplete response to therapy and tumor recurrence. Essential fatty acids, especially gamma linolenic acid (GLA) and eicosapentaenoic acid (EPA) are discussed here for their ability to control primary tumor proliferation and increase response to chemotherapy, radiotherapy and hyperthermic treatment, thanks to their effects on cellular membranes (increased lipoperoxidation and modification of tumor stroma).

Combined chemotherapy, cryosurgery, and radiotherapy/surgery for oral cancer.

UNLABELLED: One hundred and twelve patients (95 males, 17 females) with untreated squamous-cell carcinoma of the oral cavity underwent a multidisciplinary treatment. FOLLOW-UP: 6-72 months (median 51 months). T1-4N0M0 lesions (tongue, 31 patients; floor, 31 patients; cheek, 17 patients; retromolar, 9 patients) were treated with cryosurgery (T1-2: 1-2 sessions, T3-4: 2-4 sessions) and contemporaneously with (cyclophosphamide, methotrexate, fluorouracil)(CMF) (T1-2:2 courses; T3-4: 3 courses). The patients, 15-20 days after the end of cryo-chemotherapy, underwent TCT (T1: 50 Gy on tumour and lymph nodes; T2-3-4: same with an extra dose of 10-15 Gy on the primary lesion). T1-4N1-3M0 patients (tongue: 8, floor: 13, cheek: 2, retromolar: 1) received the same cryotherapy and chemotherapy, followed by surgery (16 widened suprahyoid dissections, 8 conservative laterocervical dissections, 1 radical neck dissection). Overall actuarial survival at six years was 61.9%: T1-4N0M0 (88 patients) 66.6% (T1-2 76.0%; T3-4 56.9%); T1-4N1-3M0 (24 patients) 44.4% (T1-2 66.6%; T3-4 33.3%). Six-year actuarial survival by site was: tongue (39 patients) 79.2% (N0 85.9%); floor (44 patients) 55.2% (N0 57.1%); cheek (19 patients) 74.2% (N0 68.9%); retromolar (10 patients) 0% (N0 0%). Complete remission was reached four months after treatment by 97 patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Combined chemo-radiotherapy for stage IV undifferentiated nasopharyngeal carcinoma.

Undifferentiated nasopharyngeal carcinoma is a chemosensitive lesion, but its role in the management of local advanced disease is under investigation. Twenty-seven untreated stage IV undifferentiated nasopharyngeal carcinoma patients were treated with radiotherapy (median dose, 66.6 Gy, 1.8 Gy/day) and concomitant cisplatin (100 mg/m2 days 1, 22 and 43). After 4 weeks, patients received, every 4 weeks, 3 cycles with cisplatin (80 mg/m2 day 1) + 5-fluorouracil (1,000 mg/m2/day continuous infusion for 96 h). After radiotherapy, we observed 74% complete responses and 26% partial responses; after adjuvant chemotherapy 96% had a complete and 4% a partial response. After a median follow-up of 36 months, 81% of the patients were alive (70% with no evidence of disease). Four-year overall and disease-free survival was 70% and 60%, respectively. Concomitant chemotherapy plus radiotherapy was well tolerated, whereas adjuvant chemotherapy was more toxic. Long-term results were significantly better than those observed with radiotherapy alone.

Small bowel metastasis from squamous cell carcinoma of the larynx. A case report.

Small bowel metastases from squamous cell carcinoma of the head and neck are relatively rare and in some cases asymptomatic. In the case herein reported, small bowel metastasis from a laryngeal carcinoma caused a life-threatening complication. The surgical approach was effective in saving the patient's life. Death occurred for neck tumor progression without abdominal signs of secondary lesions. A review of the previously reported cases is provided.

Cisplatin, epirubicin and 5-fluorouracil combination chemotherapy for recurrent carcinoma of the salivary gland.

Nine patients (5 males, 4 females; median age, 62 years) with recurrent high-grade malignancies of major (7 cases) and minor (2 cases) salivary gland origin (4 adenoid cystic carcinomas, 2 adenocarcinomas, 2 poorly differentiated carcinomas, 1 mixed malignant tumor) were treated with cisplatin (60 mg/m2), epirubicin (50 mg/m2) and 5-fluorouracil (600 mg/m2) (CEF) by intravenous injections on the first day of a 21-day regimen. Previous therapy included surgery (1 case), radiotherapy (1 case), and surgery + radiotherapy (7 cases). There was 1 complete response (11.1%), 3 partial responses (33.3%), 2 unchanged lesions (22.2%) and 3 progressions (33.3%). Patients with local recurrence had a better response. Median remission duration was 7.5 months in CR + PR patients. Median overall survival was 8+ months; 14+ months for responders and 4 months for nonresponders. The major toxic effects were nausea/vomiting and alopecia; myelosuppression was less frequent and usually not severe.

Head and neck metastases of renal cancer after nephrectomy: a report of 2 cases.

Two cases of metachronous metastases of renal cell adenocarcinoma are reported. One case presented a solitary metastasis of the ethmoid-orbit which was resected. The patient has remained well for the following 12 months. The second case presented with a secondary to the tongue and multiple metastases elsewhere. Electrodissection achieved a good palliative result.

Oral and pharyngeal cancer: combined approach for multimodal therapy.

Five-year results in 60 oral and pharyngeal cancer patients treated with combined approach chemoradiotherapy (39 patients) and chemoradiotherapy plus lymph node surgery (21 patients) are reported. Complete remission (CR) was achieved in 16/39 (41%) patients treated with chemoradiotherapy alone, and in 16/21 (76%) patients who had chemoradiotherapy plus surgery. The number of CR was statistically (chi-square test) higher (p less than 0.025) in the second group. The 5-year actuarial survival was 39.7% in the group of patients treated with chemoradiotherapy plus surgery. After 5 years 53% of the patients who reached CR are living free of disease in the first group and 76% in the second group.