Use of adjuvant chemotherapy (CT) and radiotherapy (RT) in incompletely resected (R1) early stage Non-Small Cell Lung Cancer (NSCLC): a European survey conducted by the European Society for Medical Oncology (ESMO) young oncologists committee.

BACKGROUND: Early stage Non-Small Cell Lung Cancer (NSCLC) is potentially curable with surgery. ESMO guidelines recommend cisplatin-based adjuvant chemotherapy (CT) for completely resected stage II-III NSCLC. There is limited evidence for the use of adjuvant CT and/or radiotherapy (RT) in incompletely resected (R1) early stage NSCLC. MATERIALS AND METHODS: A European survey of thoracic oncologists was conducted to evaluate use of adjuvant CT and RT for R1-resected NSCLC and to identify factors influencing treatment decisions. Demographics and information on clinical stage, regimens, cycles planned, radiotherapy sites, multidisciplinary management and discussion about inconclusive evidence with the patient were collected. Univariate and multivariate analyses were performed. RESULTS: 768 surveys were collected from 41 European countries. 82.9% of participants were medical oncologists; 49.3% ESMO members; 37.1% based in University Hospitals; 32.6% practicing oncology for over 15 years and 81.4% active in research. 91.4% of participants prescribed adjuvant CT and mostly cisplatin/vinorelbine (81.2%) or cisplatin/gemcitabine (42.9%). 85% discussed limited clinical evidence with the patient. In the univariate analysis, a statistically significant association with CT prescription was found for medical oncology specialty (p<0.001), ESMO membership (p<0.001), activity in clinical research (p=0.002) and increased frequency of ESMO guidelines consultation (p for trend <0.001). 48.3% of participants prescribed adjuvant RT and its prescription were associated with radiation oncology specialty (p<0.001), not being an ESMO member (p<0.001), years practicing specialty (p for trend=0.001), workload of lung cancer patients (p for trend=0.027) and decreased frequency in consulting ESMO guidelines (p<0.001). In the multivariate analysis, medical oncology and radiation oncology were the best discriminator for prescription of adjuvant CT and RT, respectively. CONCLUSION: This survey demonstrates that adjuvant CT and RT are commonly used in clinical practice for R1-resected NSCLC despite limited evidence. Prospective trials are necessary to clarify optimal management in this setting.

Phase I trial of pemetrexed in combination with cetuximab and concurrent radiotherapy in patients with head and neck cancer.

BACKGROUND: We studied the combination of pemetrexed, a multi-targeted antifolate, and cetuximab, an mAb against the epidermal growth factor receptor, with radiotherapy in poor prognosis head and neck cancer. PATIENTS AND METHODS: Patients received pemetrexed on days 1, 22, and 43 on a dose-escalation scheme with starting level (0) 350 mg/m(2) (level -1, 200 mg/m(2); level +1, 500 mg/m(2)) with concurrent radiotherapy (2 Gy/day) and cetuximab in two separate cohorts, not previously irradiated (A) and previously irradiated (B), who received 70 and 60-66 Gy, respectively. Genetic polymorphisms of thymidylate synthase and methylenetetrahydrofolate reductase were evaluated. RESULTS: Thirty-two patients were enrolled. The maximum tolerated dose of pemetrexed was 500 mg/m(2) in cohort A and 350 mg/m(2) in cohort B. Prophylactic antibiotics were required. In cohort A, two dose-limiting toxicities (DLTs) occurred (febrile neutropenia), one each at levels 0 and +1. In cohort B, two DLTs occurred at level +1 (febrile neutropenia; death from perforated duodenal ulcer and sepsis). Grade 3 mucositis was common. No association of gene polymorphisms with toxicity or efficacy was evident. CONCLUSION: The addition of pemetrexed 500 mg/m(2) to cetuximab and radiotherapy is recommended for further study in not previously irradiated patients.

Empowering induction therapy for locally advanced head and neck cancer.

Induction therapy followed by definitive chemoradiotherapy (CRT) has emerged as an option for the treatment of patients with locally advanced squamous cell carcinoma of the head and neck. In this setting, the most studied induction regimen is docetaxel, cisplatin, and 5-fluorouracil (TPF). However, the role of induction therapy remains to be fully validated by studies comparing TPF followed by CRT versus CRT alone. Novel combination regimens that incorporate molecularly targeted agents are increasingly being evaluated in the induction therapy setting. Promising results were shown in phase II trials in which the anti-epidermal growth factor receptor monoclonal antibody cetuximab was added to induction therapy with TPF, docetaxel/cisplatin, or paclitaxel/carboplatin, and in some of these studies, to subsequent CRT. Several issues remain to be addressed, including identifying which patients are most likely to benefit from induction therapy, determining how to optimally incorporate targeted agents into induction therapy and subsequent CRT, and evaluating biomarkers that could be used to select patients for induction therapy containing molecularly targeted agents.

Quality of life in metastatic breast cancer patients under chemotherapy or supportive care: a single-institution comparative study.

The aim of the present study was to evaluate quality of life (QoL) parameters in patients with metastatic breast cancer (MBC) and assess the potential differences between patients receiving chemotherapy and those undergoing supportive care interventions. In total, 210 women with MBC were enrolled in this prospective, randomized, single-institution study. The primary outcome of the trial was QoL assessment, using the self-administered European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30, version 3) and Quality of Life Questionnaire Breast 23 (QLQ-BR23) questionnaires. Quality of life was found to be statistically better (P = 0.008) in MBC patients receiving chemotherapy than those under only supportive care. Statistically significant differences in favour of chemotherapy were also found in functioning subscales, symptom single-item questions and sexual functioning. Our findings suggest that chemotherapy in MBC patients with good performance status is the more rational therapeutic approach in terms of QoL improvement.

Multiple cutaneous acral metastases in a woman with breast adenocarcinoma treated with pegylated liposomal doxorubicin: incidental or aetiological association?

This paper reports the case of a 45-year-old female with histologically documented, multiple cutaneous metastases in the palmar and plantar surface of the fingers and toes originating from a breast adenocarcinoma after treatment with a docetaxel and pegylated liposomal doxorubicin regimen. The rarity of such a metastatic pattern from breast cancer and the eventual association with the chemotherapy administered are thoroughly discussed.

Novel biological agents for the treatment of hormone-refractory prostate cancer (HRPC).

Hormone-refractory prostate cancer (HRPC) is an inevitable evolution of prostate carcinogenesis, through which the normal dependence on hormones for growth and survival is bypassed. Although advances in terms of symptoms palliation and quality of life improvement have been addressed with current treatment options, innovative approaches are needed to improve survival rates. A thorough understanding of HRPC-associated molecular pathways and mechanisms of resistance are a prerequisite for novel potential therapeutic interventions. Preclinical and early clinical studies are ongoing to evaluate new therapies that target specific molecular entities. Agents under development include growth factor receptor inhibitors, small molecules targeting signal transduction pathways, apoptosis and cell-cycle regulators, angiogenesis and metastasis inhibitors, differentiation agents, telomerase inactivators, and epigenetic therapeutics. Incorporation of these agents into existing treatment regimens will guide us in the development of a multidisciplinary treatment strategy of HRPC. This article critically reviews published data on new biological agents that are being tested in HRPC clinical trials, highlights ongoing research and considers the future perspectives of this new class of agents.

Simultaneous endometrioid ovarian and uterine carcinoma diagnosed after an in vitro fertilization procedure--case report and review of the literature.

BACKGROUND: The presence of simultaneous carcinomas involving both the ovary and uterus is relatively uncommon, while the possible link between fertility drugs and carcinogenesis still remains controversial. CASE: The case of a 40-year-old patient with simultaneous aggressive endometrioid carcinoma of the ovary and uterus a few months after the sixth attempt of in vitro fertilization is presented. The patient had de novo lung disease at surgery and diffuse metastatic spread to adjacent bone, subcutaneous tissue and the central nervous system (CNS) soon after a spectacular response to the primary paclitaxel/carboplatinum chemotherapy and while on maintenance and second-line chemotherapy, respectively. CONCLUSION: The fulminating course of our patient might in part be attributed to the existence of advanced disease at presentation. Definite conclusions about the possible association with the previously performed assisted reproduction cannot be drawn but close clinical surveillance of such patients before, during and after infertility treatment is strongly warranted.

In vivo synergism between docetaxel and gemcitabine in patients with metastatic breast cancer: general concepts and future perspectives.

The docetaxel and gemcitabine combination is an active regimen as salvage therapy in taxane-resistant or taxane-refractory patients with metastatic breast cancer (MBC). We recently conducted a phase II study administering this combination to patients with MBC after docetaxel failure, with remarkably high response rates that could be attributed to an in vivo synergism between the two drugs. Women with MBC who were refractory or resistant to docetaxel monotherapy as first- or second-line treatment were recruited. Patients with progressive or stable disease after receiving a minimum of four cycles of docetaxel received gemcitabine 900 mg/m(2) on days 1 and 8 plus docetaxel 100 mg/m(2)on day 8, every 3 weeks. Forty-six percent of patients responded (three complete responses, 20 partial responses), while 28% had stable disease and 26% had progressive disease. Median duration of response was 6.07 +/- 2.43 months. Neutropenia was the only grade 4 toxicity, and reported in seven patients. Other grade 3 toxicities included neutropenia (12 patients), thrombocytopenia (seven patients), and anemia (one patient), while nonhematologic toxicities were easily manageable. These data outline the importance of a rational combination of existing, active chemotherapeutic agents for MBC, and broadens our perspectives for more effective combination regimens in various solid tumors in the future.

Phase II study of pegylated liposomal doxorubicin (Caelyx) and docetaxel as first-line treatment in metastatic breast cancer.

BACKGROUND: The aim of this study was to determine the activity and safety of pegylated liposomal doxorubicin (PLD; Caelyx) and docetaxel combination as first-line treatment in patients with metastatic breast cancer (MBC). PATIENTS AND METHODS: Forty-four patients with a median age of 63 years were treated with PLD 30 mg/m(2) (day 1) and docetaxel 75 mg/m(2) (day 2) every 3 weeks for six cycles. Recombinant human Granulocyte Colony-Stimulating Factor (rhG-CSF) could be used in patients with grade > or =3 neutropenia after the first cycle. RESULTS: Forty-two of 44 patients were assessable for response. The response rate (RR) was 64.3% (95% confidence interval 49.8% to 78.8%). Six patients (14.3%) achieved complete response (complete disappearance of all measurable and assessable disease lasting at least 4 weeks, no new lesions, no disease-related symptoms), partial response was observed in 21 patients (50%) > or =50% decrease of measureable disease lasting at least 4 weeks, no progression of assessable disease, no new lesions, no disease-related symptoms), eight patients had stable disease and seven patients progressive disease. Median disease-free and overall survival were not reached, but were in excess of 17 months (range 6-17 months). Twenty of the patients had received previous adjuvant chemotherapy (10 with epirubicin-containing regimen with a median cumulative dose of 400 mg/m(2)). Grade > or =3 neutropenia occurred in 18.4% and neutropenic fever in 9% of patients. Palmar-plantar erythrodysesthesia was observed in four patients. Dose reduction was necessary in seven patients. Two patients discontinued treatment: one due to prolonged grade 3-4 neutropenia and one due to neurotoxicity. No treatment-related deaths occurred. CONCLUSIONS: The combination of PLD and docetaxel achieved high RRs with acceptable toxicity as first-line treatment in MBC.

Differential expression of retinoic acid receptor beta (RARbeta) and the AP-1 transcription factor in normal, premalignant and malignant human laryngeal tissues.

The anticancer effects of retinoids are mainly mediated by their nuclear receptors. Recent studies have demonstrated that retinoic acid receptor beta (RARbeta) plays a pivotal role from the early stages of laryngeal carcinogenesis; however, the exact mechanism of this detrimental effect has not yet been elucidated. One of the best-documented actions of retinoid receptors is the transrepression of activator protein-1 (AP-1) transcription factor activity, although this complex interplay has not been clarified. The present report is the first systematic morphological evaluation of the cross-talk of RARbeta and AP-1 transcription factor in a large series of human laryngeal tissues containing normal epithelium, premalignant lesions (hyperplasia and/or dysplasia) and squamous cell carcinoma. Immunohistochemical methodology was performed on formalin-fixed, paraffin-embedded sections by using a panel of monoclonal and polyclonal antibodies against RARbeta and the AP-1 components c-Jun, p-c-Jun (phosphorylated, active c-Jun) and c-Fos proteins. Their expression was screened and compared in 154 patients with various laryngeal histological entities. Nuclear expression of RARbeta, c-Jun, p-c-Jun and c-Fos was detected in 81 (89.2%), 48 (52.8%), 66 (72.6%) and 73 (80.3%), respectively, out of 91 specimens with normal-appearing laryngeal epithelium; in 86 (87.8%), 94 (95.9%), 94 (95.9%) and 94 (95.9%), respectively, out of 98 specimens with hyperplastic laryngeal epithelium; in 58 (56.8%), 92 (90.2%), 96 (94.1%) and 96 (94.1%), respectively, out of 102 specimens with dysplastic laryngeal epithelium; in 10 (22.3%), 41 (91.2%), 44 (97.8%) and 41 (91.2%), respectively, out of 45 specimens with well-differentiated squamous cell carcinoma; in 13 (30.3%), 37 (86%), 39 (90.7%) and 41 (95.3%), respectively, out of 43 specimens with moderately-differentiated squamous cell carcinoma; and in 8 (66.7%), 10 (83.3%), 12 (100%) and 12 (100%), respectively, out of 12 specimens with poorly-differentiated squamous cell laryngeal carcinoma. Statistical analysis and correlation of the intensity of nuclear immunostaining of the studied proteins among the various histological entities revealed statistically significant results. The progressive upregulation of the AP-1 transcription factor constituents and downregulation of the RARbeta protein detected from the onset of laryngeal tumorigenesis suggests an important role for the immediate-early AP-1/RARbeta on/off "switch" in the process of laryngeal carcinogenesis.

Evidence for in vivo synergism between docetaxel and gemcitabine in patients with metastatic breast cancer.

BACKGROUND: The docetaxel and gemcitabine combination is active as salvage therapy in taxane-resistant/refractory patients with metastatic breast cancer (MBC). We conducted a phase II study to determine if this activity is due to an in vivo synergistic effect. PATIENTS AND METHODS: Women with measurable MBC, who were refractory or resistant to docetaxel monotherapy as first- or second-line treatment, were enrolled. Patients with progressive disease (PD) or stable disease (SD) after receiving at least four cycles of docetaxel received gemcitabine 900 mg/m(2) on days 1 and 8 plus docetaxel 100 mg/m(2 )on day 8, every 3 weeks. Granulocyte colony-stimulating factor could be used prophylactically in patients who experienced grade 3/4 neutropenia after the first cycle. RESULTS: Between January 1999 and March 2002, 173 courses of docetaxel and gemcitabine were administered to 50 patients. The median number of metastatic sites was two (range one to three). Forty-six percent of patients responded (three complete responses, 20 partial responses), whereas 28% had SD and 26% had PD. The median duration of response was 6.1 +/- 2.4 months. The median time to disease progression was 7.5 months (range 1-25) and the overall median survival was 15 months (range 3-57). Neutropenia was the only National Cancer Institute Common Toxicity Criteria grade 4 toxicity (in seven patients). Hematological grade 3 toxicities included neutropenia in 12 patients, thrombocytopenia in seven and anemia in one, while non-hematological toxicities were mild and manageable. CONCLUSIONS: The high overall response rate of the docetaxel plus gemcitabine combination after docetaxel failure in patients with MBC can be attributed to an in vivo synergism between the two drugs. These data warrant confirmation in a randomized study.

The status of chemoprevention in the current cancer therapeutic armamentarium.

Cancer mortality nowadays remains unacceptably high despite immense advances in the understanding of the mechanisms of carcinogenesis, in bringing potent new drugs to the clinic and in treating several rare forms of cancer. Many scientists suggest that overall cancer mortality statistics are unlikely to change in a fundamental way until there has been a re-orientation of emphasis in cancer research that will direct greater resources towards prevention of disease development, rather that treatment of end-stage disease. Cancer chemoprevention represents a rather new rational approach in the management of cancer. Although the results of chemoprevention clinical trials will appear in the near future, the current preclinical and initial clinical published data outline the significant future perspective of cancer chemoprevention.

Hepatocellular carcinoma metastasis in the pituitary gland: case report and review of the literature.

Symptomatic pituitary metastases are uncommon and have been reported mainly in autopsy series. Although all types of malignancies can metastasize to the pituitary gland, a review of the literature has indicated that lung and breast carcinomas are the most frequent primary tumors while hepatocellular carcinoma metastasis has only recently been described. A 59-year-old man with abdominal pain and fever was admitted to our hospital. Hepatosplenomegaly was present without signs of ascites. Laboratory tests showed only abnormal hepatic biochemistry while the radiological studies revealed a solid mass occupying the left hepatic lobe. The patient underwent excision of the left hepatic lobe and was closely followed-up. Six months later he readmitted with headache and visual disturbances. MRI revealed a solid mass in the sella region pressing the optic chiasma. Transsphenoidal excision of the pituitary mass was followed and the histological examination of the tumor was compatible with hepatocellular carcinoma. Symptomatic pituitary metastases are uncommon and may be difficult to differentiate from pituitary adenomas. The present case emphasizes on the capricious nature of hepatocellular carcinoma and on the importance of the individualized therapeutic approach.

Asymptomatic adult cystic lymphangioma of the spleen: case report and review of the literature.

In the present report we describe a case of an asymptomatic splenic cystic lymphangioma in a 43 year-old female. Only a few cases of this benign tumor have been reported in adult patients so far. Clinical examination revealed a tender mass in the upper left quadrant of the abdomen. Abdominal ultrasound and CT-scan revealed a large well-defined splenic cystic mass surrounded by multiple peripheral cysts, all divided by thin septa. MRI confirmed these findings and excluded the possibility of malignant degeneration. Histologic examination permitted the accurate diagnosis to be made. Different imaging findings of this tumor have been described but only a few reports have focused on the value of MRI imaging.