A 25-year-old woman sought a second opinion following initial assessment of a lump in the right breast, which was erroneously diagnosed as a sebaceous cyst. No preliminary investigations such as breast imaging had been undertaken, and the patient was scheduled for excision of the lump under local anesthetic as a day case. At the time of her attendance for surgery it was noted that the breast lesion was clinically more ominous than a simple sebaceous cyst and formal breast assessment was arranged. The lump had been present for approximately two months and had progressively increased in size. There was no fluctuation in size with the menstrual cycle, and no associated nipple discharge. The patient had no previous history of breast problems and no family history of breast or ovarian carcinoma. She was nulliparous and had used the oral contraceptive pill continuously since the age of 18 years. The patient's general health was otherwise good, and she reported no unusual cough, back pain, or weight loss. Interestingly, she had been treated for a Wilm's tumor of the right kidney at the age of four years and received adjuvant treatment with both radiotherapy and chemotherapy. There was no evidence of any disease recurrence at a recent routine follow-up.

Aims and background: Rarely are conclusions from clinical trials summarized in international consensus conferences and promptly transferred to patient care. The adjuvant therapy for colorectal cancer used in daily clinical practice in Italy is described and compared with the recommendations of the 1990 NIH Consensus Conference.Patients and methods: We audited prescriptions of adjuvant systemic therapies for Italian colorectal cancer patients in 82 centers during a fixed one-week period.Results: Among 434 patients receiving adjuvant chemotherapy there were 139 (42.5%) colon cancer patients with N- and 169 (51.7%) with N+ regional nodal involvement. Treatment at academic centers, a young age, T4 and a low total number of lymph nodes removed at surgery were the factors potentially justifying the decision for adjuvant chemotherapy in stage II colon cancer patients. The most common chemotherapy used was a bolus of 5-fluorouraci/fiolinic acid for 6 months (75.8%). Adjuvant radiotherapy was not administered to 37 (38.5%) of 96 patients with stage II and III rectal cancer.Conclusions: The study shows that a substantial proportion of patients on adjuvant treatment at a certain time point in a large enough sample of Italian centers are stage II (potential over-treatment) and that an under-treatment of stage II and III rectal cancer patients (lack of radiotherapy) occurs too often in daily clinical practice in this country.

BACKGROUND:This multicenter phase II study evaluated feasibility, clinical efficacy, toxicity and pharmacokinetics of the combination of pegylated liposomal doxorubicin (PLD) and vinorelbine (VNR) in patients with platinum-paclitaxel pretreated recurrent ovarian cancer.PATIENTS AND METHODS:All patients received prior treatment with platinum and paclitaxel. Thirty-two heavily pretreated (median number of chemotherapy regimens two, range one to six) ovarian cancer patients received treatment with PLD 30 mg/m(2) and VNR 30 mg/m(2) every three weeks for six cycles. Ten patients entered the pharmacokinetic study, five receiving the PLD-VNR and five the VNR-PLD sequence.RESULTS:In 30 patients evaluated for response and toxicity, the overall response rate was 37% and 10% of patients achieved stable disease. Median time to progression and overall survival were 5.5 months (range 1-10) and 9 months (range 2-16), respectively. Toxicity was generally mild and reversible. VNR AUC(tot) and plasma levels were considerably higher in the PLD-VNR sequence.CONCLUSIONS:The PLD-VNR regimen exhibits significant activity in heavily pretreated patients, is well tolerated and is associated with encouraging survival. Preliminary pharmacokinetic results suggest the PLD-VNR sequence for further clinical applications. This regimen should be considered as a treatment option in patients with chemotherapy-resistant ovarian cancer.

Concomitant chemoradiotherapy is the most effective treatment of unresectable head and neck cancer. Docetaxel and carboplatin are two active drugs that potentiate radiotherapy. Thirty patients (median age = 56 years; median Eastern Cooperative Oncology Group performance status = 1) received radiotherapy (70 Gy, 2 Gy/d, 5 d/wk) concurrent with carboplatin AUC 0.3 to 0.5 on day 1-5, weeks 1, 3, 5, 7, and docetaxel 15 to 25 mg/m(2) on day 4 of weeks 2, 4, and 6. Site of unresectable squamous cell carcinoma was as follows: oropharynx, 41%; hypopharynx, 27%; oral cavity, 16%; and larynx, 16%. Stage was III in 13% and IV in 87%. In 11 patients, pharmacokinetic parameters were evaluated. Acute G4 toxicity was as follows: neutropenia, 20%; mucositis, 33%. We had the following acute G3 toxicities: mucositis, 40%; neutropenia, 37%; dermatitis, 23%; and anemia, 13%. The maximum tolerated dosage was area under the curve 0.5 for carboplatin and 20 mg/m(2) for docetaxel. Median radiotherapy dose was 69 Gy, and 175 out of 210 courses (83%) were administered. At the end of the treatment, we had 20 complete responses (CR) (67%), 9 partial responses (30%), and 1 no change (3%). After radial neck dissection, 2 patients achieved a CR (overall CR = 73%). After a median follow-up of 2.5 years, we had a 3-year local progression-free survival of 85%, failure-free survival of 69%, and overall survival of 60%. A significant increase Of C-max of carboplatin concentration was noted at the beginning of weeks 3, 5, and 7. Total plasma platinum raises during each course of 5 days of carboplatin without reaching a steady state. Carboplatin, docetaxel, and concomitant conventional radiotherapy is a feasible and effective treatment of unresectable head and neck cancer. The concurrent administration of two drugs does not alter pharmacokinetic drug behavior compared with single-agent data.

Controversies exist regarding the classification of the emetogenic potential of chemotherapeutic agents such as taxanes, gemcitabine and irinotecan and the antiemetic prophylaxis for acute emesis to be administered. Instead, no prophylaxis for delayed emesis has been suggested. A prospective, observational study was carried out in 103 Italian oncological centers to evaluate the prescriptions of antiemetics and the incidence of nausea and vomiting in patients submitted to these chemotherapy agents. Two hundred and nine patients treated with taxanes, 300 with gemcitabine and 93 with irinotecan were evaluated. For the prophylaxis of acute emesis a 5-HT3 antagonist alone or in combination with a corticosteroid was administered to 86.6% of patients receiving taxanes, to 59.3% of those receiving gemcitabine and to 96.8% of those submitted to irinotecan. 20% to 40% of patients received antiemetic prophylaxis for delayed emesis. In taxane-treated patients the incidence of acute vomiting and nausea was 6.2% and 27.3%, respectively, while in gemcitabine- and irinotecan-treated patients it was 6.0/33.4% and 17.9/58.9%, respectively. In conclusion, the study showed that almost all patients received prophylaxis for acute emesis and that there is overprescription of 5-HT3 antagonists. The incidence of acute emesis is low; therefore, randomized clinical trials are necessary to verify the utility of prophylaxis and to find the best antiemetic treatment.

Surgery is the treatment of choice for major and minor salivary gland malignancies. Herein, the role of radiation and medical treatment in the multidisciplinary management of salivary gland tumours is discussed. Neutron irradiation and hyperfractionated external beam mega voltage irradiation improve local control. Combination of three dimensional conformal radiotherapy and intensive-modulated radiation therapy provide better local tumour delineation, better field design to encompass the tumour allowing dose escalation to target while sparing the surrounding normal tissue. Cisplatin-based chemotherapy provides a response rate > or = 45%, in a palliative setting. Concomitant chemo-radiotherapy could improve local control. Recent studies evaluated the expression of molecular targets in salivary gland carcinomas (c-kit = 53-90%, EGFR = 25-85%, c-erb-B2 = 11-58%, p53 = 11-67%, H ras = 18%); these targets are very important since new targeted drugs are now available. Anti-androgen therapy might have a role in the management of patients with ductal carcinoma. These new targeted drugs could be integrated with chemotherapy and radiotherapy in the treatment of locally advanced/metastatic salivary gland malignancies.

The purpose of this study was to evaluate pharmacokinetic parameters, efficacy, and toxicity of a combination of docetaxel (DTX) and vinorelbine (VNB) in recurrent heavily pretreated squamous cell head and neck cancer. Twenty-nine patients previously treated with concomitant chemoradiotherapy (n = 14), surgery plus radiotherapy (n = 13), surgery + concomitant chemoradiotherapy (n = 1) and radiotherapy alone (n = 1) were enrolled; 9 patients had received I or more courses of palliative chemotherapy. Twenty-one patients had a local-regional recurrence, and 8 patients had metastases. The doses were 80 mg/m(2) for DTX and 20 mg/m(2) for VNB on day I every 21 days for a maximum of 6 cycles. Pharmacokinetic evaluations were performed on 24 patients; in a group of 12 patients, VNB; administration immediately followed DTX infusion (schedule A), and in 12 patients VNB administration was immediately followed by DTX infusion (schedule 13). Twenty-nine patients received a total of 137 cycles (median per patient, 5). Neutropenia was the most frequent and severe side effect (grade IV in 79%; grade III in 21%). Grade IV (7%) and III (14%) infections were observed in the first 12 patients; ciprofloxacin prophylaxis in the following 17 patients reduced the severe toxicity to 0%. The overall response rate was 49%, which included 3 of 29 complete responses (10%) and 11 of 29 partial responses (38%). Median complete and partial response durations were 20+ and 5.5 months, respectively. Overall median survival was 10 months (range, 2-30+). The mean values of area under the curve, mean residence time (MRT), and C-max of VNB, were significantly lower for schedule A than for schedule B. The mean values of VNB clearance were significantly higher for schedule A than for schedule B. Neutrophil count at the nadir was much lower for patients receiving schedule B. The DTX-VNB combination is effective in heavily pretreated patients with a short-lasting manageable toxicity. Pharmacokinetic evaluations suggested that the sequence DTX --> VNB is safer than the sequence VNB --> DTX.

Background:The elderly (>70 years of age) represent a specific group of patients (pts) in which advanced age often causes problems such as impaired organ function, greater frequency of comorbility and reduced tolerability to anticancer treatments.Patients and methods: Between December 2001 and February 2003, 27 pts with colorectal cancer (15 male, 12 female) were treated with CT.All pts had a PS 0-2 (ECOG): PS 0 = 10 pts; PS 1 = 14 pts; PS 2 = 3 pts.The median age was 76 years (range 70-85).Patients were divided into four groups: 11 pts received adjuvant CT with 5-fluorouracil (5-FU) and folinic acid (Mayo regimen); 5 of these, also received neoadjuvant combined radio-chemotherapeutic treatment with 5-FU continuous infusion.5 pts received first-line CT for metastatic disease with irinotecan (CPT11), alone or combined with 5-FU (FOLFIRI regimen); oxaliplatin (OHP), alone or combined with 5-FU (FOLFOX regimen) and uracil/tegafur (UFT).4 pts received second-line CT with OHP or UFT.7 pts received third line CT with Mitomycin C, Capecitabine or UFT.Results: On the whole toxicity was mild and consisted in: asthenia G3:70%, anorexia G2: 40%, nausea G2: 62%, diarrhoea G2: 18%, mucositis G2: 22%, handfoot syndrome G2: 11%, leukopenia G2: 25%,-neurosensory toxicity G2: 40% treated with OHP, hair loss G2: 14%, anemia G1: 66% .To maintain dose-intensity, leukopenia and anemia were managed with G-CSF and Eritropoietin respectively.Moreover, with use of the best supportive care (antiemetic drugs, corticosteroids, antidiarrhoeals, fluid therapy i.v., nutritional support, antifungine and anti-H2 drugs) no pts developed malnutrition.All pts with ECOG PS 0 remain at their initial PS; 57% (8/14) of pts with baseline PS 1, reached PS 0, and 66% (2/3) of pts with baseline PS 2, reached PS 1. Conclusions: In our experience we conclude, that elderly pts with colorectal cancer can be safely treated with CT, but they require a careful evaluation and surveillance of clinical status with better integration of supportive care.

All-trans retinoic acid (ATRA) inhibits proliferation of cancer. However, the effects of ATRA on scattering and invasion of pancreatic cancer cells remain unknown. Also, the effects of ATRA on c-Met expression in pancreatic cancer have never been addressed so far. The effects of ATRA on a pancreatic cancer cell line, Capan-1, were determined by proliferation assay, scattering assay and invasion assay. In addition, the expression of c-Met in pancreatic cancer cell lines treated with ATRA was investigated by real-time PCR and western blotting. The growth-inhibitory effect of ATRA was found when the cells were cultured with 5 μM ATRA for 3 days. In cell scattering assay, ATRA-treated pancreatic cancer cells were found to spread out from their colonies. In invasion assay, cells treated with ATRA invaded the matrigel more than vehicle-treated cells. The expression of c-Met was up-regulated both in the mRNA and protein levels after the treatment of ATRA. The highest expression was found at 48 h after the treatment. ATRA induced scattering and invasion of pancreatic cancer cells, although it inhibited proliferation of those cells. In addition, ATRA also increased the protein level of c-Met. These findings may indicate that the use of retinoic acid as an anti-cancer therapeutic drug needs some additional treatments to control cell invasion or scattering.

Tree rings reveal climatic variations through years, but also the effect of solar activity in influencing the climate on a large scale. In order to investigate the role of solar cycles on climatic variability and to analyse their influences on tree growth, we focused on tree-ring chronologies of Araucaria angustifolia and Araucaria araucana in four study areas: Irati and Curitiba in Brazil, Caviahue in Chile, and Tolhuaca in Argentina. We obtained an average tree-ring chronology of 218, 117, 439, and 849 years for these areas, respectively. Particularly, the older chronologies also included the period of the Maunder and Dalton minima. To identify periodicities and trends observable in tree growth, the time series were analysed using spectral, wavelet and cross-wavelet techniques. Analysis based on the Multitaper method of annual growth rates identified 2 cycles with periodicities of 11 (Schwebe cycle) and 5.5 years (second harmonic of Schwebe cycle). In the Chilean and Argentinian sites, significant agreement between the time series of tree rings and the 11-year solar cycle was found during the periods of maximum solar activity. Results also showed oscillation with periods of 2–7 years, probably induced by local environmental variations, and possibly also related to the El-Niño events. Moreover, the Morlet complex wavelet analysis was applied to study the most relevant variability factors affecting tree-ring time series. Finally, we applied the cross-wavelet spectral analysis to evaluate the time lags between tree-ring and sunspot-number time series, as well as for the interaction between tree rings, the Southern Oscillation Index (SOI) and temperature and precipitation. Trees sampled in Chile and Argentina showed more evident responses of fluctuations in tree-ring time series to the variations of short and long periodicities in comparison with the Brazilian ones. These results provided new evidence on the solar activity-climate pattern-tree ring connections over centuries.

OBJECTIVES:To evaluate the pharmacokinetic parameters, efficacy and toxicity of a combination of gemcitabine (GEM) and vinorelbine (VNB) in recurrent heavily pre-treated squamous cell head and neck carcinoma.MATERIALS AND METHODS:Twenty-four patients previously treated with concomitant chemo-radiotherapy (n = 13), surgery plus radiotherapy (n = 10) and surgery + concomitant chemo-radiotherapy (n = 1) were enrolled; 7 patients had received one or more courses of palliative chemotherapy. Twenty patients had a local-regional recurrence and 4 patients had metastases. The doses were 1200 mg/m2 for GEM and 30 mg/m2 for VNB on days 1 and 8 every 21 days; a maximum of 6 cycles was allowed. Pharmacokinetic investigations were performed on 9 patients receiving GEM and VNB. As a PK control, a second group of 5 patients was given GEM as single agent, at the same doses and with the same i.v. infusion length.RESULTS:Twenty-four patients received a total of 135 cycles (median per patient, 5). Neutropenia was the most frequent side-effect (92% of patients; grade 3-4 in 50%). The overall response rate was 25% which included 1 of 24 complete responses (4%) and 4 of 24 partial responses (21%). Responses were observed only in patients with good prognostic characteristics. The median response duration was 5.5 months (2-16 months) and the overall median survival was 9 months (range, 2-25+). Vinorelbine serum levels showed no evidence of any pharmacokinetic interaction with GEM; most of all, no rebound in VNB disposition can be produced by GEM pre-administration.CONCLUSION:The GEM-VNB combination has a palliative role in patients with favourable characteristics; the results seem no better than those observed with VNB alone. Moreover, this drug association does not alter the pharmacokinetic profile of both drugs, also compared to GEM monotherapy.

Ifosfamide (IFO) has demonstrated activity in recurrent/metastatic squamous cell head and neck carcinoma with an overall response rate of 24-26%. Better results are reported for chemotherapy-naive patients; in heavily pretreated cases results are poor and toxicity unacceptable. Cisplatin-IFO combination in stage III-IV is probably more active than IFO alone (ORR = 60-72 vs. 50%) but is indicated in patients who desire aggressive treatment and are physically able to tolerate the drugs. The carboplatin-IFO scheme is better tolerated than the cisplatin-IFO regimen with superimposable clinical results (ORR = 69%; CR = 15%). Carboplatin-taxol-IFO is one of the most active regimens in recurrent (ORR = 59%; CR = 17%) and in locally advanced (ORR = 81%; CR = 31%) head and neck cancer. Its role in the multidisciplinary treatment of advanced head and neck cancer is under investigation. In recurrent/metastatic undifferentiated nasopharygeal carcinoma, IFO combinations have proven to be effective as first- and second-line treatment.

The aim of this study was to evaluate the pharmacokinetic parameters, efficacy and toxicity of a docetaxel and vinorelbine combination in metastatic breast cancer patients previously treated with anthracycline. A population of 40 patients was analyzed; 30 patients (75%) had visceral metastases as the dominant site of disease, including 20 patients (50%) with liver metastases. Three or more organs were involved in 43% of patients. All patients had received prior anthracycline therapy. Five patients (12%) had primary resistant disease, 10 patients (25%) secondary resistant disease and 25 patients (63%) had progressive metastatic breast cancer after first-line chemotherapy. Docetaxel and vinorelbine were given at 80 mg/m(2) and 20 mg/m(2) i.v., respectively, on day 1 every 3 weeks. After a median of 5 cycles, it was found that 5 patients had a complete remission (13%), 19 a partial remission (48%), 9 had stable disease (22%) and 7 had progressive disease (17%). Response rates in patients with visceral and liver metastases were 57% and 50%, respectively. After a median follow-up of 24 months ( 13 - 36), median time to progression was 8.5 months and median overall survival 17 months. Grade 4 neutropenia was observed in 78% of courses ( febrile neutropenia in 9%). Possible pharmacokinetic interactions were studied in 23 patients by administering docetaxel immediately followed by vinorelbine ( protocol A) or vinorelbine followed by docetaxel ( protocol B). Patients in protocol B had significantly higher vinorelbine plasma levels and more pronounced neutropenia. Docetaxel plus vinorelbine is an effective combination in anthracycline resistant/relapsed metastatic breast cancer. The administration sequence docetaxel --> vinorelbine is safer than the reverse order.

Background Recurrent undifferentiated nasopharyngeal carcinoma is a chemosensitive disease. Few third-line treatments have been reported. Methods Twelve patients (9 males, 3 females; median age 50 years, range, 20-62) with recurrent undifferentiated nasopharyngeal carcinoma were treated with carboplatin AUC 5.5 + paclitaxel (175 mg/m2, 3-hr infusion) on day 1 every 3 weeks. All patients had been previously treated for recurrent disease with a first-line cisplatin-based chemotherapy and a second-line therapy with low-dose continous infusion 5-fluorouracil. Results Overall, 54 courses were given (median, 5; range, 2-6). Three patients (25%) obtained a partial response lasting 6, 10 and 26+ months, 1 (8.3%) a minimal response lasting 6 months, and 3 (25%) no change with a median duration of 5 months. The median survival time was 14 months for patients who had a partial or minimal response or no change, and 5 months for nonresponders. Median overall survival was 9.5 months (3-30+). The treatment was well tolerated, and toxicity was manageable. Conclusions The combination has a good pallitive role as third-line chemotherapy in recurrent undifferentiated nasopharyngeal cancer.

PURPOSE:To investigate the value of the addition of either cisplatin (CDDP) or lonidamine (LND) to epirubicin (EPI) in the first-line treatment of advanced breast cancer.PATIENTS AND METHODS:Three hundred seventy-one metastatic breast cancer patients with no prior systemic chemotherapy for advanced disease were randomized to receive either EPI alone (60 mg/m(2) on days 1 and 2 every 21 days), EPI and CDDP (30 mg/m(2) on days 1 and 2 every 21 days), EPI and LND (450 mg orally daily, given continuously), or EPI, CDDP, and LND. Time to progression, response rates, side effects, and survival were compared according to the 2 x 2 factorial design of this study.RESULTS:The groups were well balanced with respect to prognostic factors. Time to progression did not differ in the comparison between CDDP arms and non-CDDP arms (median, 10.9 months v 9.4 months, respectively; P =.10) or between that of LND arms and non-LND arms (median, 10.8 months v 9.9 months, respectively; P =.47), nor did overall survival. The response rate did not significantly differ in the comparison between LND arms and non-LND arms (62.9% v 54.0%, P =.08). No difference in treatment activity was observed between CDDP arms and non-CDDP arms. Toxicity was significantly higher in the CDDP arms, leading to CDDP dose adjustment in 40% of cases. The most frequent side effects were of a hematologic and gastrointestinal nature. The addition of LND produced more myalgias and fatigue.CONCLUSION:Neither CDDP nor LND was able to significantly improve the time to progression obtained by EPI. CDDP, however, significantly worsened the drug's tolerability.

Aims and background Undifferentiated carcinoma of the parotid gland is a poor-prognosis lesion. Results in unresectable lesions, treated with radiotherapy alone, are very disappointing. Methods Six patients with T3-4 N0-1 inoperable lesions were treated with conventional radiotherapy (64-70 Gy, 2 Gy per fraction 5 times a week) and concomitant cisplatin (100 mg/m2, days 1, 22 and 43). Four weeks after radiotherapy, adjuvant chemotherapy (cisplatin, 80 mg/m2, day 1, + VP16, 100 mg/m2, days 1, 3 and 5, q = 3 weeks, for 3 cycles) was given. Results A median dose of 66 Gy (range, 64-70 Gy) was delivered, and all patients recived 3 courses of cisplatin during radiotherapy. Five of 6 patients recived all three chemotherapeutic adjuvant courses. Two months after the end of treatment, 3 CR (50%), 2 PR (33%) and 1 NC (16%) was observed. Median CR and PR duration was 26+ and 10 months, respectively. Median overall survival was 18 months. No severe acute or late toxicity was observed. Conclusions Concomitant chemoradiotherapy followed by adjuvant chemotherapy in advanced unresectable undifferentiated parotid carcinoma is feasibile and well tolerated. The high percentage of long-lasting CR is encouraging.

Background. We have shown that rIL-2 administration in recurrent head and neck cancers induces a tumor-specific T-lymphocyte reactivity and tumor regression; in a pilot study we have shown a safe and effective administration of rIL2 after cisplatin + 5-fluorouracil. Long-term results are not known.Methods. Thirty patients with recurrent/persistent head and neck cancer were treated with cisplatin (100 mg/m(2)) d.1,5-fluorouracil (1 gr/m(2)/d c.i. 96 h), and SQ rIL-2 (4.5 M IU day 8 to 12 and 15 to 19) every 3 weeks.Results. The overall response rate was 53.3% (95% CI; 34.4-72.3%): 26.6% complete response (CR) (8 patients) and 26.6% partial response (PR) (8 patients); 6 patients had SD (20%), 8 had PD (26.6%). The median follow-up was 36 months (range, 28-44). The median CR duration is 16.2 months (8.5-39+); the median survival duration of this group has not been reached. The median PR duration was 7.2 months (3-10); the median survival was 13.3 months (10-26). The median overall survival was 14 months.Conclusions. The most impressive finding is the very long survival of CRs patients. This outcome has been reported in other cancer patients with a CR after IL-2 therapy. (C) 2001 John Wiley 8 Sons, Inc.