Randomized phase III trial of adjuvant epirubicin followed by cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) versus CMF followed by epirubicin in patients with node-negative or 1-3 node-positive rapidly proliferating breast cancer.

Adjuvant cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) have proven highly effective in rapidly proliferating breast cancer (RPBC). It has also been seen that sequential administration of doxorubicin and CMF is superior to their alternation, especially in indolent tumors. In a phase III study, we evaluated whether adjuvant epirubicin (E) followed by CMF is superior to the inverse sequence in RPBC. Patients with node-negative or 1-3 node-positive RPBC (Thymidine Labeling Index > 3% or histological grade 3 or S-phase > 10% or Ki67 > 20%) were randomized to receive E (100 mg/m(2) i.v. d1, q21 days for 4 cycles) followed by CMF (600, 40, 600 mg/m(2) i.v. d1 and 8, q28 days for 4 cycles) (E â†’ CMF) or CMF followed by E (CMF â†’ E) or CMF for 6 cycles. From November 1997 to December 2004, 1066 patients were enrolled: E â†’ CMF 440, CMF â†’ E 438, and CMF 188. At a median follow-up of 69 months, 5-year OS was 91% (95% CI 88-94) for E â†’ CMF and 93% (95% CI 90-95) for CMF â†’ E, with adjusted hazard ratio of 0.88 (95% CI 0.58-1.35), and DFS was 80% in both arms, with adjusted hazard ratio of 0.99 (95% CI 0.73-1.33, Cox model). Adverse events were similar, apart from a higher rate of neutropenia in the CMF â†’ E arm. No important differences in clinical outcome were observed between the two different sequences, making both a valid option in early breast cancer. Further molecular characterization of the tumors might help to identify subgroups achieving higher benefit from either sequence.

HER-2 expression and cell proliferation: prognostic markers in patients with node-negative breast cancer.

PURPOSE: We analyzed the clinical relevance of HER-2 expression, widely investigated in breast cancer but with contradictory results, in the largest case series of node-negative breast cancer patients investigated to date. PATIENTS AND METHODS: The pure prognostic value of HER-2 expression was investigated in 529 patients treated with locoregional therapy alone until early relapse. Proliferative activity was evaluated as [3H]thymidine labeling index and HER-2 expression by immunohistochemistry. All biologic determinations were conducted within the context of an intra- and interlaboratory National Quality Control Program. RESULTS: HER-2 expression was not related to relapse-free survival in the overall series but was a significant discriminant of prognosis in the subgroup of patients with rapidly proliferating tumors. Six-year rate of relapse was 40% for patients with highly (> or =30%) positive tumors and 26% for those with weakly HER-2-expressing tumors (P =.039). CONCLUSION: HER-2 expression in association with proliferative activity identifies a subgroup of node-negative breast cancer patients with the worst prognosis, who are candidates for specific intensive adjuvant therapy.

Time to progression in metastatic breast cancer patients treated with epirubicin is not improved by the addition of either cisplatin or lonidamine: final results of a phase III study with a factorial design.

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.

AIDS-related non-Hodgkin's lymphoma: clinico-pathological characteristics and therapeutic strategies (review).

High-grade B-cell non-Hodgkin's lymphoma (NHL), a diagnostic disease for the acquired immunodeficiency syndrome (AIDS), is a late manifestation of HIV infection and is generally related to severe lymphopenia. We reviewed the main clinico-pathological features of this disease and analysed its pathogenetic mechanisms with potential therapeutic implications.

Current status and future potential role of exemestane in the treatment of early and advanced breast cancer (Review).

Exemestane is a new oral steroidal aromatase inactivator, active in postmenopausal women with hormonal sensitive breast carcinoma. This drug, at a dosage of 25 mg once daily, was shown to suppress in vivo aromatase activity by 97.9%, with a subsequent reduction superior to 85% of circulating oestrogen level. It exhibits definite antitumor activity at a relatively low daily dose, and is highly potent, highly selective, and well-tolerated. Moreover, for postmenopausal women with metastatic breast cancer, exemestane demonstrated a higher activity and lower toxicity profile when compared to megestrol acetate and tamoxifen in second- and first-line therapy, respectively. New data on exemestane are forthcoming both in the adjuvant and neoadjuvant setting, which could improve the management of early breast cancer in the future.

Altered p16INK4a and Fhit expression in carcinogenesis and progression of human oral cancer.

To further characterize the biological and clinical role of molecular alterations involved in oral squamous carcinogenesis, the immunohistochemical expression level of two tumor suppressor genes, fragile histidine triad and p16INK4a, in non-carcinomatous squamous epithelia and head and neck squamous cell carcinoma was determined. In addition, human papillomavirus infection determined by PCR assay and the use of alcohol and cigarettes were evaluated. In this study 28 non-carcinomatous squamous epithelia and 57 head and neck squamous cell carcinoma were considered. The expression levels of fragile histidine triad were lower in head and neck squamous cell carcinoma than in non-carcinomatous squamous epithelia. In contrast, p16INK4a is expressed in malignant lesions (51% of the cases analyzed), but not in non-carcinomatous squamous epithelia. No correlation between gene expression alterations of the two tumor suppressors was observed. PCR analysis showed that HPV DNA was present in 5 of the 57 malignant lesions analyzed (8.8%). None of the factors described above, despite changes in gene expression and HPV infection, appears to be associated with alcohol use and/or tobacco smoking and clinical outcome. Our data showed that fragile histidine triad and p16INK4a expression are altered in malignant lesions. Most likely, the decreasing levels of fragile histidine triad is directly involved in cancer development, while the accumulation of p16INK4a in head and neck squamous cell carcinoma may be the consequence of loss of functional tumor suppressor retinoblastoma pathway.

A phase I study of capecitabine in combination with vinorelbine in advanced breast cancer.

A phase I study was conducted in order to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of the combination of vinorelbine and capecitabine in patients affected with metastatic breast cancer. Eighteen patients with histologically confirmed advanced breast cancer, who had failed =1 prior chemotherapy regimen, were enrolled. The median age was 56 years (range, 39-70 years). All but 1 had previously received a combination of anthracyclines and taxanes; performance status (Eastern Cooperative Oncology Group) was 0/1 or 2 in 13 and 5 patients, respectively. Vinorelbine was administered at a fixed dosage of 25 mg/m2 on days 1 and 8 every 3 weeks. Capecitabine was administered orally, at an escalated dose ranging from 1400 mg/m2 to 2250 mg/m2 for 14 consecutive days starting on day 1 of the cycle, divided into 2 daily doses delivered half an hour after eating at 12-hour intervals. Three patients were treated at each dose level: if 1 patient developed a DLT, an additional 3 patients were treated at the same dose level. If 2 additional patients experienced DLT, no further escalation was allowed and the previous dose level was declared MTD. Dose-limiting toxicity was reached at 2250 mg/m2 of capecitabine with 3 out of 3 patients experiencing grade 4 neutropenia plus grade 3 diarrhea and grade 3 oral mucositis in 1 patient). Thus, MTD was defined at 2000 mg/m2 capecitabine. Other observed grade 2 side effects were: 1 patient with neutropenia, 1 with hand-foot syndrome, 2 with mucositis, 1 with cutaneous rash, and 1 with thrombocytopenia. With regard to response rate, we observed 1 complete response (5.5%), 6 partial responses (33%), and 4 disease stabilizations (22%). The median time to progression was 12 weeks and the median survival 41 weeks. The MTD of capecitabine in combination with vinorelbine at 25 mg/m2 dosage on days 1 and 8 of a 3-week schedule is 2000 mg/m2/day for 14 consecutive days. Moreover, this regimen showed interesting activity with 61% overall disease control (complete plus partial response plus disease stabilization) in patients pretreated with anthracyclines and taxanes warranting further investigations in a large, multicenter phase II study.

Percutaneous computed tomography-guided lung biopsies: preliminary results using an augmented reality navigation system.

AIMS AND BACKGROUND: "Augmented reality" is a technique to create a composite view by augmenting the real intervention field, visualized by the doctor, with additional information coming from a virtual volume generated using computed tomography (CT), magnetic resonance or ultrasound images previously acquired from the same patient. In the present study we verified the accuracy and validated the clinical use of an augmented reality navigation system produced to perform percutaneous CT-guided lung biopsies. METHODS: One hundred and eighty consecutive patients with solitary parenchymal lung lesions, enrolled using a nonrandom enrollment system, underwent percutaneous CT-guided aspiration and core biopsy using a traditional technique (group C, 90 patients) and navigation system assistance (group S, 90 patients). For each patient we recorded the largest lesion diameter, procedure time, overall number of CT scans, radiation dose, and complications. The entire experimental project was evaluated and approved by the local institutional review board (ethics committee). RESULTS: Each procedure was concluded successfully and a pathological diagnosis was reached in 96% of cases in group S and 90% of cases in group C. Procedure time, overall number of CT scans and incident x-ray radiation dose (CTDIvol) were significantly reduced in navigation system-assisted procedures (P <0.001; z = 5.64) compared with traditional CT-guided procedures. The percentage of procedural complications was 14% in group S and 17% in group C. CONCLUSION: The augmented reality navigation system used in this study was a highly safe, technically reliable and effective support tool in percutaneous CT-guided lung biopsy, allowing to shorten the procedure time and reduce the incident x-ray radiation dose to patients and the rate of insufficient specimens. Furthermore, it has the potential to increase the number of procedures executed in the allocated time without increasing the number of complications.

Impact of postoperative radiation therapy on survival in patients with complete resection and stage I, II, or IIIA non-small-cell lung cancer treated with adjuvant chemotherapy: the adjuvant Navelbine International Trialist Association (ANITA) Randomized Trial.

PURPOSE: To study the impact of postoperative radiation therapy (PORT) on survival in the Adjuvant Navelbine International Trialist Association (ANITA) randomized study of adjuvant chemotherapy. METHODS AND MATERIALS: ANITA is a randomized trial of adjuvant cisplatin and vinorelbine chemotherapy vs. observation in completely resected non-small-cell lung carcinoma (NSCLC) Stages IB to IIIA. Use of PORT was recommended for pN+ disease but was not randomized or mandatory. Each center decided whether to use PORT before initiation of the study. We describe here the survival of patients with and without PORT within each treatment group of ANITA. No statistical comparison of survival was performed because this was an unplanned subgroup analysis. RESULTS: Overall, 232 of 840 patients received PORT (33.3% in the observation arm and 21.6% in the chemotherapy arm). In univariate analysis, PORT had a deleterious effect on the overall population survival. Patients with pN1 disease had an improved survival from PORT in the observation arm (median survival [MS] 25.9 vs. 50.2 months), whereas PORT had a detrimental effect in the chemotherapy group (MS 93.6 months and 46.6 months). In contrast, survival was improved in patients with pN2 disease who received PORT, both in the chemotherapy (MS 23.8 vs. 47.4 months) and observation arm (median 12.7 vs. 22.7 months). CONCLUSION: This retrospective evaluation suggests a positive effect of PORT in pN2 disease and a negative effect on pN1 disease when patients received adjuvant chemotherapy. The results support further evaluation of PORT in prospectively randomized studies in completely resected pN2 NSCLC.

Lack of benefit of maintenance paclitaxel in first-line chemotherapy in metastatic breast cancer.

PURPOSE: This randomized study compared maintenance paclitaxel with control in metastatic breast cancer patients not experiencing progression after first-line anthracycline/paclitaxel combination chemotherapy. METHODS: Between April 1998 and October 2003, 459 metastatic breast cancer patients received first-line combination chemotherapy with epirubicin or doxorubicin plus paclitaxel. Of these, 255 who had a response or stable disease were then randomly assigned onto the Maintenance Paclitaxel 1 (MANTA1) study, comparing eight courses of maintenance paclitaxel versus control (ie, no additional chemotherapy administration). The primary end point was progression-free survival. RESULTS: The study was prematurely concluded after a futility analysis, which was performed on 215 of the 238 patients randomly assigned within December 2002. Of these, 109 patients were assigned to maintenance paclitaxel and 106 were assigned to stopping chemotherapy. No significant difference in median progression-free survival was observed (8.0 months for maintenance paclitaxel and 9.0 months for control). There was no significant difference in median survival time (28.0 v 29.0 months). When the Bayesian method for monitoring clinical trials was applied to these data, even under an enthusiastic prior distribution, in the posterior distribution there was only an 8.6% chance of observing a 3-month improvement in median progression-free survival in the group receiving maintenance paclitaxel. After these results study accrual was closed. CONCLUSION: Compared with control, the administration of additional courses of paclitaxel in patients who achieve disease control after six to eight courses of first-line anthracycline plus paclitaxel combination chemotherapy does not improve progression-free survival.

Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): a randomised controlled trial.

BACKGROUND: Whether adjuvant chemotherapy improves survival of patients with non-small-cell lung cancer (NSCLC) is not known. We aimed to compare the effect of adjuvant vinorelbine plus cisplatin versus observation on survival in patients with completely resected NSCLC. METHODS: 840 patients with stage IB-IIIA NSCLC from 101 centres in 14 countries were randomly assigned to observation (n=433) or to 30 mg/m(2) vinorelbine plus 100 mg/m(2) cisplatin (n=407). Postoperative radiotherapy was not mandatory and was undertaken according to every centre's policy. The primary endpoint was overall survival. Analysis was by intention to treat. This trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN95053737. FINDINGS: 367 patients in the chemotherapy group and 431 in the control group received their assigned treatment. 301 (36%) patients had stage IB disease, 203 (24%) had stage II disease, and 325 (39%) had stage IIIA disease. Tolerance to chemotherapy mainly included neutropenia in 335 (92%) patients and febrile neutropenia in 34 (9%); seven (2%) toxic deaths were also recorded. Compliance was greater with cisplatin than with vinorelbine (median dose intensity 89% [range 17-108] vs 59% [17-100]). After a median follow-up of 76 months (range 43-116), median survival was 65.7 months (95% CI 47.9-88.5) in the chemotherapy group and 43.7 (35.7-52.3) months in the observation group. Adjusted risk for death was significantly reduced in patients assigned chemotherapy compared with controls (hazard ratio 0.80 [95% CI 0.66-0.96]; p=0.017). Overall survival at 5 years with chemotherapy improved by 8.6%, which was maintained at 7 years (8.4%). INTERPRETATION: Adjuvant vinorelbine plus cisplatin extends survival in patients with completely resected NSCLC, better defining indication of adjuvant chemotherapy.

Present status and perspectives in the treatment of hormone-refractory prostate cancer.

The cornerstone in the treatment of de novo or recurrent metastatic prostate cancer is androgen deprivation. Unfortunately, nearly all patients will develop androgen-independent ('hormone-refractory') disease with progressive clinical deterioration and ultimately death. Chemotherapy has been shown to palliate symptoms of hormone-refractory disease but not to improve survival. Recently, two large phase III trials have demonstrated an overall survival advantage for patients treated with docetaxel-based regimens as compared to the best standard of care. Indeed, investigations into the pathophysiology of this malignancy, novel biological agents, skeletal protectants and radiopharmaceuticals are expanding the clinician's armamentarium and improving the patient's outcome.

3p microsatellite alterations in exhaled breath condensate from patients with non-small cell lung cancer.

The still-high mortality for lung cancer urgently requires the availability of new, noninvasive diagnostic tools for use in early diagnosis and screening programs. Recently, exhaled breath condensate (EBC) has been proposed as a useful tool to obtain biological information on lung cancer disease. This study provides, for the first time, evidence that DNA alterations already described in lung cancer are detectable in EBC from patients with non-small cell lung cancer (NSCLC) and in healthy subjects. Thirty patients with histologic evidence of NSCLC and 20 healthy subjects were enrolled in the present study. All subjects had allelotyping analysis of DNA from EBC (EBC-DNA) and from whole blood (WB-DNA) of a selected panel of five microsatellites (D3S2338, D3S1266, D3S1300, D3S1304, D3S1289) located in chromosomal region 3p. Results from healthy subjects and subjects with cancer, and from EBC and WB, were compared. In addition, the relationships with smoking habit and clinicopathologic tumor features were considered. Microsatellite alterations (MAs) were found in 53% of EBC-DNA and in 10% of WB-DNA loci investigated in patients with NSCLC (p < 10(-6)); conversely, MAs were present only in 13% of EBC-DNA and in 2% of WB-DNA informative loci in healthy subjects. In patients with NSCLC, a direct association between number of MAs detected in EBC-DNA and tobacco consumption was observed. We conclude that EBC-DNA is highly sensitive in detecting MA information unique to patients with lung cancer. Furthermore, MA information seems to be directly related with tobacco consumption, and is potentially applicable to screening and early diagnostic programs for patients with NSCLC.

The role of letrozole (Femara(R)) in breast cancer therapy: A clinical review.

Letrozole is a third-generation aromatase inhibitor for use in postmenopausal women with hormonal-sensitive breast cancer. This drug was found to reduce or effectively shrink tumors in a significant number of such patients. It exhibits antitumor activity at a relatively low daily dose, and is highly potent and selective and well tolerated. Results from recent phase III clinical studies have confirmed the efficacy and the key role of this drug in the therapy of advanced breast cancer in postmenopausal women. Moreover, letrozole demonstrated higher activity and lower toxicity compared to tamoxifen in the first-line therapy of postmenopausal women affected with advanced breast cancer. However, it also represents a valid option in second-line therapy after tamoxifen failure. New data on this agent in adjuvant or neoadjuvant treatment also suggest efficacy in the treatment of early breast cancer. This article reviews the clinical data on letrozole in all settings and its future potential in chemoprevention. (c) 2001 Prous Science. All rights reserved.

Radiofrequency ablation of 40 lung neoplasms: preliminary results.

OBJECTIVE: Radiofrequency thermal ablation is a minimally invasive treatment widely used for treatment of liver neoplasms and has also been tested on other types of tumor. Few studies have been published regarding the use of radiofrequency thermal ablation in the treatment of lung neoplasms. This study was performed to evaluate the technical feasibility, the safety, and the efficacy of lung radiofrequency thermal ablation. SUBJECTS AND METHODS: Between February 2002 and March 2003, 18 subjects with unresectable lung neoplasms, four of whom had primary neoplasms and 14 of whom had metastatic neoplasms, underwent lung radiofrequency ablation. The technique was performed percutaneously using a monopolar cooled-tip electrode needle under CT guidance with the patient under general anesthesia. Patients had no more than three nodules with a total diameter of 10 cm and no evidence of extrathoracic disease. A total of 40 nodules were treated in 24 therapeutic sessions. After treatment, patients underwent follow-up every 3 months by CT and nuclear MRI with gadolinium for a median time of 8 months (range, 2-14 months). RESULTS: No evidence of local relapse was discovered in 94.4% of subjects. The treatment was safe and well tolerated. Complications encountered included massive pneumothorax, which occurred in one subject, requiring pleural drainage. Other complications were moderate pneumothorax (also requiring pleural drainage), cough, fever, slight dyspnea, and pain, but these complications were short in duration and successfully treated. CONCLUSION: Radiofrequency thermal ablation is a promising technique in the treatment of patients with lung neoplasms and has been found to be both safe and technically feasible.