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Cancer care involves many ethical issues. The need for more patient-centered healthcare together with the improved empowerment of every person diagnosed with cancer have been transposed by the Italian Association of Medical Oncology (AIOM) and eventually translated in the Ragusa statement. This position paper describes the philosophy that lies beneath this document and its fundamental principles.

For decades Western medicine has followed a biomedical model based on linear thinking and an individualized, disease-oriented doctor-patient relationship. Today this framework must be replaced by a biopsychosocial model based on complexity theory and a person-oriented medical team-patient relationship, taking into account the psychological and social determinants of health and disease. However, the new model is already proving no longer adequate or appropriate, and current events are urging us to develop an ecological model in which the medical team takes into account both individual illness and population health as a whole, since we are all part of the biosphere. In recent years, the rising costs of cancer treatment have raised a serious issue of economic sustainability. As the population of our planet, we now need to rapidly address this issue, and everyone of us must try to reduce their ecological footprint, measured as CO2 production. Medical oncologists need to reduce the ecological footprint of their professional activity by lowering the consumption of economic resources and avoiding environmental damage as much as possible. This new paradigm is endorsed by the Italian College of Hospital Medical Oncology Directors (CIPOMO). A working group of this organization has drafted the "Green Oncology Position Paper": a proposal of Italian medical oncology (in accordance with international guidelines) that oncologists, while aiming for the same end results, make a commitment toward the more appropriate management of health care and the careful use of resources in order to protect the environment and the ecosphere during the daily exercise of their professional activities.

Aims and Background: Metronomic chemotherapy refers to the administration of low doses of cytotoxic agents over a prolonged period of time with no or only short drug-free intervals. It is designed to overcome acquired tumor resistance to chemotherapy and reduce neo-angiogenesis despite a lower toxicity than with standard chemotherapy. The role of metronomic chemotherapy remains controversial, and its optimal therapeutic use has not yet been defined., Methods and Study Design: The present survey was designed as a short questionnaire and was sent to the medical oncologists registered with Medikey, a national database listing all the Italian oncology specialists linked with the Italian Council of Medical Oncology Hospital Consultants (Collegio Italiano Primari Oncologi Medici Ospedalieri, CIPOMO) and the Italian Association of Medical Oncology (Associazione Italiana di Oncologia Medica, AIOM). The questionnaire was completed on a voluntary basis and it was totally anonymous., Results: The questionnaire was sent to 3,289 oncologists, and 191 (5.8%) actively participated in the survey. Seventy-two percent of responders declared that they had administered a regimen of metronomic chemotherapy at least once. Metronomic chemotherapy is commonly used in advanced breast cancer patients, and in most cases it was prescribed after failure of at least two lines of treatment. Oral agents such as cyclophosphamide, capecitabine, methotrexate and vinorelbine were the most commonly prescribed drugs. Nearly 60% of responders was believed to have significantly less toxicity with metronomic chemotherapy than with standard chemotherapy., Conclusions: The sample of oncologists who participated in the survey is small but it appears to be representative of the Italian medical oncology community. The answers to the questionnaire indicate a significant interest in metronomic chemotherapy, which is apparently widely prescribed. This is the first large national survey on the use of metronomic chemotherapy. Considering the results, larger research on metronomic chemotherapy is strongly warranted.

Aims and Background: Triple-negative breast cancer, defined by a lack of expression of estrogen, progesterone and HER-2 receptors, accounts for 15% of all types of breast cancer. The subtype mainly includes a molecularly distinct subgroup, the basal-like subtype (accounting for 75% of all cases). We attempt to define triple-negative breast cancer and compare it with basal-like disease, review the molecular, pathologic and clinical features of triple-negative disease, provide an overview of a retrospective subset analysis of clinical trials, and outline ongoing therapeutic trials and possible paths for future research., Methods: We collected data regarding classification, molecular and clinical features and treatment, drawn from the existing literature, including abstracts and verbal accounts. By the term "basal-like", we defined all cases where gene expression array or more sophisticated immunophenotypes are used for identification. When the analysis is restricted to clinical assay (immunohistochemistry), we refer to "triple-negative"., Results: Basal-like breast cancer expresses genes characteristic of basal epithelial cells, which include high-molecular weight basal cytokeratins (CK5/6, CK14, CK17), vimentin, p-cadherin, alpha B crystalline, caveolins 1 and 2 and EGFR. The expression of basal markers (basal cytokeratins and EGFR) is related to a worse prognosis and identifies a clinically distinct subgroup within the triple-negative breast cancer. BRCA1 mutations are present in 11% of triple-negative tumors and even more rare is BRCA2 deficiency. BR-CA1-associated breast cancers types are typically characterized by a high rate of DNA aberrations and defective DNA repair pathways (the so-called "BRCAness"). The use of regimens based on DNA-damaging agents, such as anthracyclines, platinum derivatives and cyclophosphamide seems a sensible option for this breast cancer subtypes. Clinical data support a strong sensitivity to primary chemotherapy with pathologic response rates ranging from 27-45% (with anthracyclines and taxanes) to more than 60% with platinum-based triplets. However, based on retrospective data, major response to chemotherapy does not carry better survival ("triple-negative paradox"). There is no specific targeted therapy in the armamentarium: ongoing trials include anti-angiogenic agents, anti-EGFR and EGFR-TK inhibitors, epothilones and PARP inhibitors., Conclusions: A specific systemic regimen cannot yet be recommended. Moreover, only a few data are available on which treatment selection can be based. Use of the existing cytotoxic agents can be optimized for this patient subgroup by investigating the proliferative signals and the suitability of these signals as therapeutic targets, besides assessing the BRCA1-pathway in this subgroup as regards treatment. A greater understanding of the pathologic and molecular characteristics of this phenotype may lead to customized treatment for these patients.

Aims and Background: Approximately half of metastatic breast cancers expressing estrogen and/or progesterone receptors responds to endocrine therapy, and postoperative adjuvant endocrine therapy provides about a 50% reduction in the development of recurrent disease. A number of publications have focused on the correlation of biomarkers, in particular estrogen and progesterone receptors and HER-2/neu status as well as different gene profiles, multigene assays and genetic polymorphisms with response to hormone therapy. The purpose of this article is to review the literature to identify biological markers predictive of response to tamoxifen and aromatase inhibitors., Methods: A computerized literature search through Medline and ASCO abstract databases was performed, applying the words "endocrine therapy" and "predictive markers" and each of the following: early and metastatic breast cancer, estrogen receptors, progesterone receptors, HER2/neu, multigene assays, polymorphisms. The last search was updated in June 2007. In the examined literature, biological markers were retrospectively assayed to establish whether such variables were predictive for endocrine therapy efficacy., Results: The role of estrogen receptor content as a predictor of response to endocrine treatment was confirmed: benefit from endocrine treatment was directly proportional to estrogen receptor levels. Progesterone receptor status was only a strong time-dependent prognostic value, and it has not yet been validated as a predictive factor of tamoxifen efficacy. Retrospective clinical data from upfront and sequential studies of aromatase inhibitors were discordant regarding the degree of benefit of these drugs over tamoxifen according to progesterone receptor status. HER-2 positivity was associated with a significantly greater risk of endocrine therapy failure in metastatic and neoadjuvant settings. The current generation of genomic assays for tamoxifen sensitivity all contain a combination of prognostic information that it is difficult to integrate into clinical practice., Conclusions: Available clinical data are inconclusive to support preferential use of aromatase inhibitors over tamoxifen in progesterone-receptor-negative and HER-2-positive tumors, but it was also clear that lower estrogen receptors, lower progesterone receptors, and positive HER-2 are associated with lower responsiveness to any type of endocrine therapy. Tumors overexpressing HER-2 are endocrine resistant and they require the blockage of the HER-2 pathway in addition to estrogen deprivation. Recent molecular studies have shown that endocrine responsiveness is to a large extent influenced by estrogen-receptor-related pathways. In the future, the key to the correct tailoring of hormone therapy will probably be the ability to subtype estrogen-receptor-positive breast cancer.

Aims and Background: To compare conventional fractionation (CF) radiation therapy (RT), arm A, versus a split-course accelerated hyperfractionated schedule (S-AHF), arm B, versus CFRT plus concomitant chemotherapy (CT), arm C, in terms of five-year survival and toxicity for squamous cell tumors of the oropharynx., Methods and Study Design: Between January 1993 and June 1998, 192 previously untreated patients with stage III and IV oropharyngeal carcinoma (excluding T1N1 and T2N1) were enrolled in a multicenter randomized phase III trial (ORO 93-01). In arms A and C, 66 to 70 Gy in 33 to 35 fractions was administered five days a week for six and a half to seven weeks. In arm B, the dose delivered was 64 to 67.2 Gy in two fractions of 1.6 Gy every day, five days a week, with a planned two-week split at 38.4 Gy. In arm C the CT regimen consisted of three cycles of carboplatin and 5-fluorouracil (CBDCA 75 mg/m2 on days 1 to 4 and 5-FU 1000 mg/m2 i.v. on days 1 to 4 every 28 days)., Results: No statistically significant difference was found in five-year overall survival (P = 0.39): 21% for arm A, 21% for arm B, and 40% for arm C. Similarly, there was no statistically significant difference in terms of five-year relapse-free survival: 15% for arm A, 17% for arm B, and 36% for arm C. There was a slight trend towards better five-year locoregional control (P = 0.07) for the combined arm: patients without locoregional relapse were 48% in arm C, 21% in arm A and 18% in arm B. Locoregional control was significantly better when arm C was compared with arms A and B combined (P = 0.02; arm A+B 20%; arm C 48%). Distant metastases were fairly balanced in the three arms (A: 14; B: 9; C: 11), with a tendency towards more frequent isolated distant metastasis development in arm C (8 of 11 [72%] versus 7 of 23 [30%] in arms A+B). Five-year second-tumor-free survival was 85%. The 13 second tumors were equally distributed and were mainly correlated with tobacco and alcohol consumption (five lung, two esophagus, two oral cavity, one larynx, one pancreas, one hepatocarcinoma, one myeloma). Arm C showed slightly more G3+ late side effects involving subcutaneous tissues and mucosa, although significant late sequelae were relatively uncommon and the mucosal side effects were mostly transient. The occurrence of persistent G3 xerostomia was comparable in the three treatment arms., Conclusions: The results obtained with the combination of CT and RT compared with RT alone did not reach statistical significance, but combined treatment almost doubled the five-year overall survival, relapse-free survival and locoregional control rate. Patients with advanced squamous cell carcinomas of the oropharynx who are medically suitable for the combined approach should be treated with a combination of radiotherapy and chemotherapy. The occurrence of second tumors is relatively common in these patients and may contribute substantially to the causes of death.