Effects of exemestane and tamoxifen on bone health within the Tamoxifen Exemestane Adjuvant Multicentre (TEAM) trial: results of a German, 12-month, prospective, randomised substudy.

BACKGROUND: Adjuvant treatment of hormone receptor-positive breast cancer in postmenopausal women with aromatase inhibitors may be associated with increased bone loss. PATIENTS AND METHODS: Two hundred patients were randomised to receive exemestane or tamoxifen as adjuvant treatment of hormone receptor-positive breast cancer. Bone mineral density (BMD) was assessed by dual-energy X-ray absorptiometry at baseline and after 6 and 12 months treatment. RESULTS: One hundred and sixty-one patients were assessable. Tamoxifen treatment resulted in a 0.5% increase from baseline in BMD at the spine, which was maintained at 12 months. Exemestane-treated patients experienced a 2.6% decrease from baseline in BMD at the spine at 6 months and a further 0.2% decrease at 12 months. There were significant differences in the changes in BMD between tamoxifen and exemestane at 6 and 12 months (P = 0.0026 and P = 0.0008, respectively). The mean changes in BMD from baseline at the total hip were also significantly different between exemestane and tamoxifen at 6 and 12 months (P = 0.0009 and P = 0.04, respectively). There was no difference between tamoxifen and exemestane in mean changes in BMD from baseline at the femoral neck. CONCLUSIONS: Exemestane treatment resulted in an increase in bone loss at 6 months; bone loss stabilised after 6- to 12-month treatment.

Improved quality of life after long-term treatment with the bisphosphonate ibandronate in patients with metastatic bone disease due to breast cancer.

Bone metastases occur in most women with advanced breast cancer and can lead to considerable morbidity and a rapid deterioration in the patient's quality of life. It was the aim of the present study to assess changes in quality of life and bone pain due to intravenous (i.v.) ibandronate, a potent third-generation bisphosphonate. In a phase III randomised, double-blind, placebo-controlled trial in patients with bone metastases due to breast cancer, 466 women were randomised to receive placebo, 2 mg ibandronate or 6 mg ibandronate for up to 96 weeks. Treatment was administered i.v. at 3- or 4-weekly intervals. Clinical endpoints included the incidence of adverse events, quality of life (assessed using the European Organisation for the Research and Treatment of Cancer (EORTC) Quality of Life Scale - Core 30 questionnaire (QLQ-C30)), and bone pain (assessed on a 5-point scale from 0=none to 4=intolerable). Ibandronate was generally well tolerated. Compared with baseline measurements, the bone pain score was increased at the last assessment in both the placebo and 2 mg ibandronate groups, but was significantly reduced in the patients receiving 6 mg ibandronate (-0.28+/-1.11, P < 0.001). A significant improvement in quality of life was demonstrated for patients treated with ibandronate (P < 0.05) for all global health status. Overall, at the last assessment, the 6 mg ibandronate group showed significantly better functioning compared with placebo (P = 0.004), and had significantly better scores on the domains of physical, emotional, and social functioning, and in global health status (P < 0.05). Significant improvements in the symptoms of fatigue and pain were also observed in the 6 mg ibandronate group. I.v. ibandronate treatment leads to significant improvements in quality of life, and is an effective and well-tolerated palliative treatment in patients with bone metastases due to breast cancer.

Intravenous ibandronate reduces the incidence of skeletal complications in patients with breast cancer and bone metastases.

BACKGROUND: This phase III study compared the efficacy of the new potent bisphosphonate, ibandronate, with placebo as intravenous (i.v.) therapy in metastatic bone disease due to breast cancer. PATIENTS AND METHODS: A total of 466 patients were randomised to receive placebo (n = 158), or 2 mg (n = 154) or 6 mg (n = 154) ibandronate every 3-4 weeks for up to 2 years. The primary efficacy parameter was the number of 12-week periods with new bone complications, expressed as the skeletal morbidity period rate (SMPR). Bone pain, analgesic use and safety were evaluated monthly. Results SMPR was lower in both ibandronate groups compared with the placebo group; the difference was statistically significant for the ibandronate 6 mg group (P = 0.004 versus placebo). Consistent with the SMPR, ibandronate 6 mg significantly reduced the number of new bone events (by 38%) and increased time to first new bone event. Patients on ibandronate 6 mg also experienced decreased bone pain scores and analgesic use. Treatment with ibandronate was well tolerated. CONCLUSIONS: These results indicate that 6 mg i.v. ibandronate is effective and safe in the treatment of bone metastases from breast cancer.

Single-agent gemcitabine: an active and better tolerated alternative to standard cisplatin-based chemotherapy in locally advanced or metastatic non-small cell lung cancer.

This randomized study was designed to determine the response rates, survival and toxicities of single-agent gemcitabine (GEMZAR) and a combination of cisplatin/etoposide in chemonaive patients with non-resectable, locally advanced or metastatic non-small cell lung cancer (NSCLC). Gemcitabine 1000 mg/m2 was given as a 30-min intravenous infusion on days 1, 8, 15 of a 28-day cycle, cisplatin 100 mg/m2 on day 1, and etoposide 100 mg/m2 on days 1 (following cisplatin), 2 and 3. Major eligibility criteria included histologically confirmed non-small cell lung cancer, measurable disease, Zubrod performance status 0-2, no prior chemotherapy, no prior radiation of the measured lesion, and no CNS metastases. One hundred and forty-seven patients were enrolled, 72 in the gemcitabine and 75 in the cisplatin/etoposide arm. Patient characteristics were well-matched across both arms. Sixty-seven gemcitabine and 72 cisplatin/etoposide patients were qualified for efficacy analysis. There were no complete responses, but 12 partial responses in the gemcitabine arm and 11 in the cisplatin/etoposide arm, for protocol-qualified response but 12 partial responses in the gemcitabine arm and 11 in the cisplatin/etoposide arm, for protocol-qualified response rates of 17.9% (95%, CI: 9.6-29.2%,) and 15.3% (95% CI: 7.9-25.7%,), respectively. Median survival times were 6.6 months (95% CI: 4.9-7.3 months) for gemcitabine and 7.6 months (95% CI: 5.4-9.3 months) for cisplatin/etoposide. The 1-year survival probability estimate was 26% for gemcitabine and 24% for cisplatin/etoposide. There were no statistically significant between-group differences in time-to-event measures, but patients in the gemcitabine arm had a greater probability of achieving a tumour response after 2 months (probability estimate: 8 vs. 0%,) and of the response lasting at least 6 months (73 vs. 45%,). Clinical and haematologic toxicity was more pronounced in the cisplatin/etoposide arm. Quality-of-life measures indicated a significant worsening of symptomatology in the cisplatin/etoposide arm for hair loss, nausea and vomiting, and appetite loss. This randomized study provides further evidence that single-agent gemcitabine is an active and effective therapy for patients with non-resectable. locally advanced or metastatic NSCLC and good performance status, and that it is better tolerated than the combination cisplatin/ etoposide.

Radiotherapy in stage IIA and IIB testicular seminoma with reduced portals: a prospective multicenter study.

PURPOSE: A prospective multicenter study was carried out to estimate the treatment outcome of radiotherapy in Stage II seminoma after the application of modern staging and radiotherapy techniques. The lower margin of the iliac field was positioned on the upper rim of the acetabulum to reduce the amount of scattered irradiation to the remaining testicle. METHODS AND MATERIALS: The study was carried out in 25 centers in Germany. Patients with pure seminoma, negative AFP-values, and retroperitoneal lymph node metastases of less than 5 cm in diameter were entered into the study. All patients received a ventrodorsal opposed field irradiation of the para-aortic and the ipsilateral iliac lymph nodes. The fields extended from the top of the 11th thoracic vertebra to the top of the acetabulum. Patients in Stage IIA (lymph nodes <2 cm ) received 30 Gy, and patients with Stage IIB (lymph nodes between 2 and 5 cm) 36 Gy total dose. RESULTS: 39 patients in Stage IIA and 19 patients in Stage IIB were evaluated. After a median observation time of 37 months all patients are alive and disease free. Recurrence free survival in stage IIA was 100%. Two patients in Stage IIB experienced a recurrence 10 and 17 months after the end of radiotherapy. The actuarial recurrence free survival estimate in Stage IIB was 94.1% for 1 year and 87.4% for 2 years. One recurrence in Stage IIB occurred in the mediastinum, one in the mediastinum, and one the lung. Both patients could be salvaged by chemotherapy. There were no pelvic recurrences. The treatment was well tolerated, with nausea being the most common side effect (56.9% Grade 1, 15.5% Grade 2, and 8.6% Grade 3). Diarrhea occurred in 15.5% (Grade 1), 15.5% (Grade 2), and 5.2% (Grade 3) of the patients. CONCLUSIONS: The outcome of para-aortic and ipsilateral iliac irradiation in Stage IIA/B testicular seminoma is excellent with the currently available staging methods and treatment facilities. The treatment is well tolerated. The lower margin of the iliacal field can be placed at the acetabulum.

A randomized study of gemcitabine monotherapy versus etoposide/cisplatin in the treatment of locally advanced or metastatic non-small cell lung cancer.

This randomized, multinational, multicenter study was designed to determine the response rate of gemcitabine monotherapy and cisplatin/etoposide combination therapy in chemotherapy-naive patients with advanced, recurrent, and/or metastatic non-small cell lung cancer (stage IIIA [if inoperable], IIIB, or IV). One group of patients received gemcitabine 1,000 mg/m2 intravenously once a week for 3 weeks (days 1, 8, and 15) followed by a 1-week rest period. The second group received cisplatin 100 mg/m2 intravenously on day 1 of each 28-day cycle in combination with etoposide 100 mg/m2, administered on days 1, 2, and 3 following the cisplatin infusion. Each patient was allowed to remain on study up to a maximum of six cycles. The planned interim analysis was based on the 117 patients in the study, 116 of whom were randomized up until November 20, 1995. The efficacy analysis was performed on the 107 patients who had data from a minimum of two cycles, whereas the safety analysis was based on data from all 116 randomized patients. In the gemcitabine arm there were 10 of 52 (19%) partial responders; in the cisplatin/etoposide arm there were four (7%) of 54 partial responders. There was a statistically significant difference in the response rates between the two arms, with a 95% confidence interval of 0.6% to 32.1% (P = .040). The median time to progressive disease was 4.2 months for gemcitabine patients and 3.7 months for cisplatin/etoposide patients. There was significantly more alopecia and nausea and vomiting in the cisplatin/etoposide arm compared with the gemcitabine arm, as well as two cases of neutropenic sepsis in the cisplatin/etoposide arm. These data indicate that single-agent gemcitabine is at least as effective as the combination of cisplatin/etoposide in the treatment of advanced non-small cell lung cancer and has an improved safety profile.

Single-agent gemcitabine versus cisplatin-etoposide: early results of a randomised phase II study in locally advanced or metastatic non-small-cell lung cancer.

BACKGROUND: This randomised study was designed to determine the response rate survival and toxicity of single-agent gemcitabine and cisplatin-etoposide in chemo-naïve patients with locally advanced or metastatic non-small-cell lung cancer. PATIENTS AND METHODS: Gemcitabine 1,000 mg/m2 was given as a 30 min intravenous infusion on days 1, 8, 15 of a 28-day cycle, cisplatin 100 mg/m2 on day 1, and etoposide 100 mg/m2 on days 1 (following cisplatin), 2 and 3. Major eligibility criteria included histologically confirmed non-small-cell lung cancer, measurable disease, Zubrod PS 0-2; no prior chemotherapy, no prior radiation of the measured lesion, and no CNS metastases. RESULTS: 146 patients were enrolled, 71 patients on gemcitabine and 75 patients on cisplatin-etoposide. Patient characteristics were well matched across both arms. Sixty-six gemcitabine patients and 72 cisplatin-etoposide patients were evaluable. Partial responses were seen in 12 gemcitabine patients (18.2%; 95% CI: 9.8-30) and 11 cisplatin-etoposide patients (15.3%; 95% CI: 7.9-25.7). Early indications show no statistical differences between the two treatments with respect to time to disease progression or survival. Haematological and laboratory toxicity were moderate and manageable. However, hospitalisation because of neutropenic fever was required for 6 (8%) cisplatin-etoposide patients but not for any gemcitabine patients. Non-haematological toxicity was more pronounced with significant differences in nausea and vomiting (grade 3 and 4: 11% gemcitabine vs. 29% cisplatin-etoposide; despite the allowance for 5-HT3 antiemetics during the first cycle of cisplatin-etoposide), and alopecia (grade 3 and 4:3% gemcitabine vs. 62% cisplatin-etoposide). CONCLUSIONS: In this randomised study, single-agent gemcitabine was at least as active but better tolerated than the combination cisplatin-etoposide.

Simultaneous radiochemotherapy with paclitaxel in non-small cell lung cancer: a clinical phase I study.

Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) is one of the most active single agents available for the treatment of non-small cell lung cancer (NSCLC), with reported response rates of 21% to 24%. Its observed radiosensitizing effect is attributed to its interruption of cell development at the G2/M phase of the cell cycle, when cells are most sensitive to the killing effects of ionizing radiation. This phase I study of paclitaxel and simultaneous radiation therapy in patients with previously untreated, locally advanced inoperable stage IIIA/B NSCLC was designed to determine the maximum tolerated paclitaxel dose, to define the safety and toxicity of this combined modality, and to obtain preliminary data on its activity. Patients received a fixed dose of radiotherapy (1.8 Gy/d, 5 days a week, in shrinking-field technique, for a total dose of 59.4 Gy) and concomitant chemotherapy with a 3-hour infusion of paclitaxel once weekly on day 1, initially at a dose of 45 mg/m2, for 3 weeks. This dose remained constant during study levels 1 to 3, with the number of weeks of treatment increasing to 5 and 7 at levels 2 and 3, respectively. At dose level 4, the paclitaxel dose was increased to 55 mg/m2 over 7 weeks. Of 22 NSCLC patients who entered the study, 18 are evaluable for toxicity and response. Responses included one complete and 10 partial remissions; the other seven patients had minimal improvement. The therapy was well tolerated; no severe adverse events were associated with paclitaxel or radiotherapy. This combined modality appears to be a practicable and effective treatment for NSCLC. The maximum tolerated paclitaxel dose has not yet been reached, and dose escalation is planned.

[Treatment results after supraglottic partial resection of the larynx in carcinoma of the laryngeal entrance, the base of the tongue and hypopharynx. 2. Radiotherapy and late results after combined surgical-radiological treatment]. / Behandlungsresultate nach supraglottischer Kehlkopfteilresektion bei Karzinomen des Larynxeingangs, des Zungengrundes und des Hypopharynx. 2. Teil: Bestrahlungstherapie und Spätresultate nach chirurgisch-radiologischer Kombinationsbehandlung.

110 Patients were followed-up after supraglottic laryngectomy: The 3-year survival rate was 74%. The overall 5-year survival rate was 49%. For the cases of T3-tumours from these of the entrance of the larynx the 5-year survival rate was about 73%. For the T4-tumours the 5-year survival rate was only about 22%. Better results are not possible at the present even if other kinds of therapy are used.

Prospective multicenter trial for the response-adapted treatment of high-grade malignant non-Hodgkin's lymphomas: updated results of the COP-BLAM/IMVP-16 protocol with randomized adjuvant radiotherapy.

In a prospective multicenter trial the efficiency of the response-adapted COP-BLAM/IMVP-16 protocol to induce complete remissions (CR) in high-grade malignant non-Hodgkin's lymphomas as well as the prognostic relevance of adjuvant radiotherapy were investigated. From 1986-1989, 548 patients (median age 56 years) with stage II-IV (Ann Arbor) disease were treated with five cycles of COP-BLAM followed by two cycles of IMVP-16. If only a partial remission was obtained at the time of first restaging (RS) after three cycles (delayed response), treatment was switched to IMVP-16 (two to five courses) immediately. Patients achieving CR by the second RS after chemotherapy were randomized to adjuvant radiotherapy or observation. Responses to chemotherapy were 63% CR in patients completing the second RS (N = 350) or 72% if patients achieving late CR by consolidating radiotherapy are added; responses were 58% or 65% if all deaths prior to the second RS are included (N = 50). Overall and relapse-free survival were 71% and 68% at one year and 63% and 61% at two years. Multivariate risk factor analysis proved the early (by first RS) CR response to possess predominant prognostic relevance for survival. A significant advantage of adjuvant radiotherapy over no further treatment for duration of CR is not yet discernible. These results emphasize the importance of a rapidly achieved CR, thus contributing to the design of future trials.

[Primary curative radiotherapy of small vocal cord cancers. A long-term study with 2 to 14 year follow-up]. / Die primär kurative Strahlentherapie kleiner Stimmbandkarzinome. Eine Langzeitstudie mit Verlaufsbeobachtungen über 2 bis 14 Jahre.

Therapeutic results in 92 glottic carcinomas, stage Tis, T1 and T2 are reported. After primary irradiation the patients were followed up for between 5 and 14 years. The five- to ten-year survival probability was about 98%. The functional effects of this method and the surgical alternative are discussed.