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Since the first cancer chemotherapy use, efforts have been made in identifying drugs with an antitumor specific action, but cancer is a very complex situation to be cured with a single agent, and to increase drugs selective cytotoxicity new agent combinations, or innovative cellular cycle related schedule, or the use of pro-drugs have been developed. Notwithstanding some relevant improvements in results, chemotherapy remains often a palliative approach. The improved knowledge of the biology of cancer, and of molecular mechanisms and specific targets, has recently modified the approach to various tumors. In particular, the identification of a single and specific genetic alteration in some tumors such as myeloid chronic leukaemia or gastrointestinal stromal tumors (GIST) led to the development of imatinib, a "target" drug with a multikinase inhibitor activity towards the specific genetic alteration; this unique opportunity is not applicable to other tumors, because usually tumors have multiple genetic alterations with very complex molecular pathways. The development of drugs with a multitarget action is probably the best approach to the majority of human cancers, but other possibility are the combination of multiple agents, each with known selective activity towards a specific molecular target, or the choice of a chemotherapic drug in combination with one or more molecularly targeted drugs. The knowledge of the multiple and extremely complex molecular pathways of the neoplastic cells will hopefully drive oncologic science towards a more "exact" science, with the use of "personalized" treatment in each cancer patient.

Although the relationship between psyche and cancer dates back many centuries, and several studies were conducted on this topic during the last decades, the role of psychological factors in the development of cancer is still controversial. Although a lot of factors have been considered, attention has been focused mainly on stress, which has been evaluated also in experimental models. Generally, the results of case-control studies have been contradictory, and at times more stressfull events have been recorded in patients with benign tumors than in those with cancer. On the contrary, a higher incidence of stress-related cancers has not been documented in cohort studies. Since cancer is a genetic disease, it is difficult to hypothesize that psychological factors may permanently alter nucleotide sequence giving rise to multiple mutations needed for cancer development. At present, there is no sufficient evidence to affirm that psychological factors may contribute without doubt to cancer development.

Adjuvant treatment in hormone-receptor positive, HER2-negative early breast cancer is controversial. Chemotherapy benefit in this subset of patients is generally small, and a wide variability exists among dif-ferent subgroups of patients, depending on various patient and tumor characteristics. To select subsets of patients who will really benefit from chemotherapy, one of the possible strategy is based on multigene expression analysis. This approach is providing deeper insights into the biological heterogeneity of breast cancer, allowing to further sub-divide hormone-receptor positive tumors into groups, with different clinical behavior and response to treatments. Among less expensive and better validated methods, high levels of Ki67, a routinely assessed immunohistochemical marker of cell proliferation, can suggest the use of chemotherapy in this subset of patients. Generally, regimen used should include a taxane. In fact, retrospective analyses of clinical trials suggest that anthracyclines may be less active in hormone-receptor positive HER2-negative patients, while several other trials and meta-analyses involving taxanes, showed a benefit in terms of risk of relapse and death reduction. Among taxanes, docetaxel should be preferred because of a better therapeutic index, and a higher activity in comparison to paclitaxel. At present, reliable and accurate evaluation of histopathological and immunohistochemical factors may allow the choice of omitting adjuvant chemotherapy in patients with low risk hormone receptor positive HER2-negative breast cancer. Uncertainty still exists about chemotherapy benefit for a substantial proportion of women of this subgroup. Nevertheless, the addition of taxanes, mainly docetaxel, to anthracyclines, seems to overcome the relative chemoresistance of hormone-receptor positive tumors, providing a benefit in disease free survival and overall survival.

Adjuvant treatment of early breast cancer has changed considerably in recent years, and the majority of patients are currently treated with the most active single agents in this setting. As a result, the decisions regarding the treatment of patients with metastatic breast cancer have become more difficult. In patients who have not received chemotherapy for early-stage breast cancer or were treated with CMF, many choices are available, including regimens containing anthracyclines or taxanes. Patients who received anthracyclines in the adjuvant setting, may sometimes be re-treated with these agents, and the inclusion of a taxane is frequently the most reasonable choice. Among taxanes, docetaxel should be preferred because it is the most active single agent, and has a synergistic action with several other drugs, when used in combination. Taxanes can be used also in selected patients who had received these agents as adjuvant treatment. In particular, docetaxel did not show complete cross-resistance with paclitaxel, whereas weekly paclitaxel is only minimally effective in patients resistant to docetaxel. Retreatment with trastuzumab combined with chemotherapeutic agents might be a reasonable option in patients who had received adjuvant chemotherapy with trastuzumab. Nevertheless, another recent option is the combination of chemotherapy with lapatinib. Currently, novel target agents are being developed, with the potential to improve survival in patients with metastatic breast cancer. Arguably, the future for treatment of these patients appears to be the combination of effective single agents, such as docetaxel, with novel biologic therapies.

The fundamental imperative of adjuvant treatment of early breast cancer is to improve long-term survival and minimize toxicity. The inclusion of docetaxel in adjuvant chemotherapy regimens has improved patient survival in comparison to anthracycline-containing regimens, even if the incidence of acute side effects has increased in some studies. However, late or persistent toxic effects are becoming more important due to an increasing proportion of patients remaining disease free after treatment for early breast cancer. Several studies have recently reported that docetaxel-containing regimens without anthracyclines are equally active, and have no apparent cardiotoxicity. At present, docetaxel-based combinations represent an appropriate choice in the adjuvant treatment of HER2-negative breast cancer, and several studies are ongoing aiming at a better evaluation of the efficacy of this agent in order to optimize its role.

The development of taxanes in cancer chemotherapy required several decades of research mainly because of the difficulty related to supply and formulation of paclitaxel. Lesser difficulty was encountered in the development of docetaxel, which initially took place in breast cancer. In this disease, docetaxel showed a significant activity, probably superior to that of paclitaxel. In the first-generation studies in patients with early breast cancer, comparing anthracycline-based regimens with regimens containing anthracyclines and taxanes, docetaxel significantly improved survival independently from schedule, either sequential or concurrent. The aim of current second-generation studies, comparing taxanes in all study arms, is to answer several questions, including the best administration schedule and the best taxane to be used. Currently, the use of docetaxel in the adjuvant chemotherapy of breast cancer represents one of the most important achievements in the treatment of this disease. However, since further improvement in therapeutic results are needed, it is likely that in the future docetaxel will be used in combination with molecular targeted agents.

Purpose: To determine wether primary CEF is effective in locally advanced breast cancer, as measured by response, local recurrences, disease free survival (DFS) and overall survival (OS)., Material and Methods: From 1990 to 1998, 62 patients with stage III disease were enrolled into a prospective study at Regina Elena Institute for Cancer Research, Rome. Inflammatory breast cancer (IBC) was included. Patients received three 21 days cycles of chemotherapy that consisted in epirubicin 50 mg/m2, cyclophosphamide 400 mg/m2, and fluorouracil 500 mg/m2 i.v. on days 1 and 8. G-CSF (300 microg) was given subcutaneously every other day from day 5 to day 17. After primary chemotherapy, whenever possible, mastectomy or conservative surgery was performed. Subsequently responding patients received the same regimen, while non responders were given a non cross resistant chemotherapy. In case of conservative surgery or initial T4 tumor radiation therapy was performed at the end of adjuvant chemotherapy. ER positive patients received tamoxifen 20 mg/d for five years., Results: Seven IIIA patients had a median OS of 43 months (C.I. 95%, 31-55) and DFS of 42 months (C.I. 95%, 16-68), while 15 IBC patients had a median OS of 52 months (C.I. 95%, 52-79) and DFS of 27 months (C.I. 95%, 14-39). Forty IIIB non inflammatory breast cancer patients had a median DFS of 87 months (C.I. 95%, 1-175); median OS was not reached. Ten-year OS was 28.6% for stage IIIA, 50.6% for stage IIIB and 36% for IBC., Conclusion: Primary CEF appear to be an effective treatment. In our study we obtained a good local control and interesting long term data of disease free and overall survival.

Breast cancer (BC) is the most common malignancy and the second most common cause of cancer-related death in Western European and North American women. Neoadjuvant chemotherapy may be used in the management of both BC patients with locally advanced disease, and those with earlier stage and operable tumors. Data from recently phase III trials and worldwide consensus conference document the benefit of adjuvant chemotherapy in improving disease free survival and overall survival for patients diagnosed with invasive BC > 1 cm. When BC cells metastasize to distant organs, the disease is incurable, but chemotherapy may offer these patients a significant palliation.

Purpose: We have evaluated whether tumor markers can be used to assess response to systemic chemotherapy. We analyzed the relationship between the response to chemotherapy based on serial imaging and on change in serum tumor marker level of CEA Ca 19-9 and Ca 125., Patients and Methods: The levels of serum CEA, Ca 19.9 and Ca 125 were measured before and after 6 and 12 week systemic chemotherapy in twenty-five elderly patients age 68-80 (median age 71) with advanced gastric cancer. We evaluated the relationship between the change in serum tumor markers level and response assessment by imaging studies throughout the treatment course., Results: There was a significant correlation between the assessment of response by tumor markers and by imaging studies. The survival time of responders assessed by tumor markers was significantly longer than that of non-responders., Conclusions: The serum levels tumor markers may be used as a mean of monitoring treatment in elderly patients, when in a imaging study it is difficult, to assess response to chemotherapy and in predicting the prognosis of patients with advanced gastric cancer.

Purpose: To evaluate the activity and toxicity of cisplatin (DDP), epirubicin (EPI) and interferon alfa-2a (a-IFN) in patients (pts) with metastatic melanoma., Patients and Methods: Thirty-seven pts with histologically-proven metastatic melanoma were treated with DDP 75 mg/m2 e.v. and EPI 90 mg/m2 e.v. on day 1 + alpha-IFN 9 MUI/die s.c. on days 4 to 8 and 18 to 22. Cycles were repeated every 4 weeks., Results: Characteristics of the patients were the following: median age 55 years (range, 24-75), median WHO performance status 1 (range, 0-2), prior chemotherapy 9, prior immunotherapy 16 (adjuvant/advanced 11/5), sites of disease: soft tissue only 10, lung 22, liver 11, bone 1, brain 3. In 35 evaluable patients we have obtained 3 complete and 10 partial responses, for an overall response rate of 37%. Dose-limiting toxicity was myelosuppression with grade (G) 4 neutropenia in 59.5% of patients and G4 thrombocytopenia in 11% of patients. Other toxicities were generally mild to moderate with nausea and vomiting in 67.5% of patients, flu-like syndrome in 78.5% and fatigue in 48.5% of the patients. Median time to response, median time to progression and survival were 3 (range, 2-6), 7 (range, 2-45+) and 10 months (range, 4-45+), respectively., Conclusion: This combination is active and well tolerated in metastatic melanoma. Toxicity was manageable and has enabled us to conduct this trial on an outpatient basis.

Purpose: To evaluate the activity and toxicity of simultaneous infusion of vinorelbine (VNB) and paclitaxel (T) as first line chemotherapy in advanced breast cancer patients (pts)., Patients and Methods: 33 pts with histologically proven advanced breast cancer were treated with VNB 25 mg/m2 and T 150 mg/m2, both drugs given by i.v. infusion over 3 hours, with cycles repeated every 3 weeks. Granulocyte-colony-stimulating factor (G-CSF), 300 micrograms subcutaneously, was given on days 7 to 12 of each cycle in the first 10 patients., Results: From October 1995 to July 1996, 33 untreated pts entered the study. Characteristics of the pts were the following: median age 53 years (29-71); median WHO performance status 1 (0-3); pre/postmenopausal 8/25; prior adjuvant chemotherapy 16; prior radiotherapy 8; dominant disease sites: soft tissue in 6; bone in 7, viscera in 19; number of metastatic sites: 1 in 18, 2 in 9, 3 in 6 pts. In 31 evaluable pts we observed: 1 CR (3%) and 14 PR (45%), for an overall response rate of 48%. Median time to response was 2 months; median time to progression and median survival were 7 and 22+ months, respectively. Median number of cycles was 6. Myelosuppression was the dose-limiting toxicity, with G 4 neutropenia occurring in 22% of the pts and neutropenic fever in 6% of the pts. Other toxicities were generally mild with nausea in 52% of the pts; mucositis in 15%; constipation in 12%; peripheral neuropathy in 46.5%. Alopecia was universal., Conclusions: Simultaneous infusion of VNB and T is well tolerated and active in untreated patients with advanced breast cancer. Median survival (22+ months) is similar to that reported with anthracycline-containing regimens, although response rate appears to be lower. It is likely that higher response rates may be achieved with a higher dose-intensity.

Purpose: To evaluate efficacy and tolerability of vinorelbine in breast cancer., Design: A review of most significant and recent clinical trials was performed., Results: Vinorelbine as single agent showed 44% and 17.36% of response as 1st and 2nd line treatment, respectively. When combined with other agents, these figures were the following: cisplatin, 73%-75% and 43-64%; mitomycin C, up to 92% and 33%-69%; 5-fluorouracil, 33%-64% and 22%-55%; ifosfamide, 57% and 28%; taxol, 78% and 54%; taxotere, up to 80%; mitoxantrone, 44%-68% and 31%-40%; doxorubicin, 57%-82% and 30%-33%; epirubicin, 22%-78% and 33%. Vinorelbine-epirubicin combination appears to be very active in neoadjuvant setting, with up to 92% response rates., Conclusions: Vinorelbine activity is significant and similar to that of the most active antineoplastic drugs in breast cancer. The most promising combinations appear to be with anthracyclines, taxanes or mitomycin C, even in heavily pretreated patients. Some aspects, such as optimal dose and scheduling and the inclusion in adjuvant programs or in new combination regimens remain to be defined.

Twenty-seven postmenopausal women with advanced breast cancer were treated with the potent LHRH-agonist buserelin. The drug was given s.c. three times daily at a daily dosage of 3 mg the first week and subsequently of 2 mg daily. Although pituitary gonadotropins were suppressed in all cases, no response was observed in 26 evaluable patients. This study does not confirm earlier findings suggesting a role for LHRH-agonists in the treatment of postmenopausal patients with breast cancer.

Forty-five consecutive patients with advanced colorectal cancer were treated with 5-fluorouracil and high dose folinic acid. Among 43 evaluable patients there were 7 objective responses for an overall response rate of 16%. Toxicity was generally mild and rapidly reversible. Compared to those reported with 5-fluorouracil alone, these results failed to demonstrate an increase in response rate in the treatment of advanced colorectal cancer with the combination of 5-fluorouracil and folinic acid.