Zoledronic acid (zoledronate) for postmenopausal women with early breast cancer receiving adjuvant letrozole (ZO-FAST study): final 60-month results.

BACKGROUND: Aromatase inhibitors are the preferred adjuvant endocrine therapy for the majority of postmenopausal women with hormone-responsive early breast cancer. Although generally more effective than tamoxifen, aromatase inhibitor therapy is associated with increased bone loss and fracture risk. PATIENTS AND METHODS: Postmenopausal women receiving adjuvant letrozole (2.5 mg/day for 5 years; N = 1065) were randomly assigned to immediate zoledronic acid (zoledronate) 4 mg every 6 months for 5 years, or delayed zoledronate (initiated for fracture or on-study bone mineral density [BMD] decrease). The primary end point was the change in lumbar spine BMD at 12 months. Lumbar spine and total hip BMD at subsequent follow-up, disease-free survival (DFS), and overall survival were assessed as secondary end points. RESULTS: At 60 months (final analysis), the mean change in lumbar spine BMD was +4.3% with immediate zoledronate and -5.4% with delayed intervention (P < 0.0001). Immediate zoledronate reduced the risk of DFS events by 34% (hazard ratio [HR] = 0.66; P = 0.0375) with fewer local (0.9% versus 2.3%) and distant (5.5% versus 7.7%) recurrences versus delayed zoledronate. In the delayed group, delayed initiation of zoledronate substantially improved DFS versus no zoledronate (HR = 0.46; P = 0.0334). CONCLUSIONS: Immediate zoledronate in postmenopausal women receiving letrozole preserved BMD and is associated with improved DFS compared with letrozole alone. Clinical Trials Registration No NCT00171340.

Prevention of anaemia by early intervention with once weekly epoetin alfa during chemotherapy.

This study compared the effects of early intervention with standard use of epoetin alfa on haemoglobin (Hb) levels and transfusion requirements in cancer patients receiving chemotherapy. Patients with Hb>10 and < or= 12 g/dL were randomised 1:1 to epoetin alfa (40,000 IU, subcutaneously, once weekly), initiated within 7d of the start of the first on-study chemotherapy cycle (defined as early intervention) versus epoetin alfa when Hb

A phase II study of raltitrexed and gemcitabine in patients with advanced pancreatic carcinoma.

Advanced adenocarcinoma of the pancreas has a very poor prognosis. The aim of this study was to assess the efficacy and tolerability of a combination of the chemotherapeutic agents gemcitabine and raltitrexed. Chemonaive patients with advanced adenocarcinoma of the pancreas were treated with a combination of raltitrexed (3.5 mg m(-2) on day 1 of a 21-day treatment cycle) and gemcitabine (800 mg m(-2) intravenously (i.v.) on days 1 and 8 of a 21-day cycle). Between April 2000 and February 2003, 27 patients were enrolled onto the study. The mean duration of treatment was 11 weeks. Four of 27 patients experienced at least one episode of grade 3 or 4 neutropenia. One patient with grade 4 neutropenia died due to sepsis. Four of 27 patients experienced grade 4 diarrhoea. There was one partial remission (4%) and 12 patients experienced disease stabilisation (44%). The 6-month and 1-year survival rates were 37 and 11%, respectively. Symptomatic benefit occurred in seven (26%) patients. We conclude that a combination of raltitrexed and gemcitabine, using the schedule and doses in this study, cannot be recommended for patients with advanced pancreatic cancer.

Superior efficacy of letrozole versus tamoxifen as first-line therapy for postmenopausal women with advanced breast cancer: results of a phase III study of the International Letrozole Breast Cancer Group.

PURPOSE: To compare the efficacy and tolerability of tamoxifen with that of letrozole, an oral aromatase inhibitor, with tamoxifen as first-line therapy in postmenopausal women with advanced breast cancer. PATIENTS AND METHODS: Nine hundred seven patients were randomly assigned letrozole 2.5 mg once daily (453 patients) or tamoxifen 20 mg once daily (454 patients). Patients had estrogen receptor- and/or progesterone receptor-positive tumors, or both receptors were unknown. Recurrence during adjuvant antiestrogen therapy or within the following 12 months or prior endocrine therapy for advanced disease precluded enrollment. One prior chemotherapy regimen for metastatic disease was allowed. The primary end point was time to progression (TTP). Secondary end points included overall objective response rate (ORR), its duration, rate and duration of clinical benefit, time to treatment failure (TTF), overall survival, and tolerability. RESULTS: TTP was significantly longer for letrozole than for tamoxifen (median, 41 v 26 weeks). Treatment with letrozole reduced the risk of progression by 30% (hazards ratio, 0.70; 95% confidence interval, 0.60 to 0.82, P =.0001). TTP was significantly longer for letrozole irrespective of dominant site of disease, receptor status, or prior adjuvant antiestrogen therapy. Similarly, TTF was significantly longer for letrozole (median, 40 v 25 weeks). ORR was higher for letrozole (30% v 20%; P =.0006), as was the rate of clinical benefit (49% v 38%; P =.001). Survival data are currently immature and not reported here. Both treatments were well tolerated. CONCLUSION: Letrozole was significantly superior to tamoxifen in TTP, TTF, ORR, and clinical benefit rate. Our results support its use as first-line endocrine therapy in postmenopausal women with advanced breast cancer.

Does supportive pamidronate treatment prevent or delay the first manifestation of bone metastases in breast cancer patients?

The effect of pamidronate treatment on the first development of bone metastases was investigated in 124 patients with breast cancer, with either locally advanced disease (n = 33) or extraskeletal metastases (n = 91), but no bone metastases in a randomised, multicentre, open controlled study. Patients were assigned to treatment with oral pamidronate, 300 mg/day, (n = 65) or to a control group (n = 59). Tumour therapy was freely allowed. A first clinical event of skeletal morbidity occurred in 22% pamidronate and 20% control patients; unequivocal first radiological manifestation of bone metastases was found in 36% pamidronate and 27% control patients (n.s.). The actuarial risk of a first skeletal event was similar in both groups. Quality-of-life measurements of bone metastases-related aspects showed no differences between the two groups. 19 patients withdrew from the study because of gastrointestinal complaints attributed to pamidronate. We conclude that supportive oral pamidronate treatment (300 mg/day) does not prevent nor delay the development of bone metastases in breast cancer patients at risk.

Palliative pamidronate treatment in patients with bone metastases from breast cancer.

PURPOSE: An open, randomized study was performed to assess the effects of supportive pamidronate treatment on morbidity from bone metastases in breast cancer patients. PATIENTS AND METHODS: Eighty-one pamidronate patients and 80 control patients were monitored for a median of 18 and 21 months, respectively, for events of skeletal morbidity and the radiologic course of metastatic bone disease. The oral pamidronate dose was 600 mg/d (high dose [HD]) during the earliest study years, then changed to 300 mg/d (low dose [LD]) because of gastrointestinal toxicity. Twenty-nine of 81 pamidronate (HD/LD) patients first received 600 mg/d and were then changed to 300 mg/d; 52 of 81 pamidronate LD patients received 300 mg/d throughout the study. Tumor treatment was unrestricted. RESULTS: An overall intent-to-treat analysis was performed. In the pamidronate group, the occurrence of hypercalcemia, severe bone pain, and symptomatic impending fractures decreased by 65%, 30%, and 50%, respectively; event-rates of systemic treatment and radiotherapy decreased by 35% (P < or = .02). The event-free period (EFP), radiologic course of disease, and survival did not improve. Subgroup analyses suggested a dose-dependent treatment effect. Compared with their controls, in pamidronate HD/LD patients, events occurred 60% to 90% less frequently (P < or = .03) and the EFP was prolonged (P = .002). In pamidronate LD patients, event-rates decreased by 15% to 45% (P < or = .04). Gastrointestinal toxicity of pamidronate caused a 23% drop-out rate, but other cancer-associated factors seemed to contribute to this toxicity. CONCLUSION: Pamidronate treatment of breast cancer patients efficaciously reduced skeletal morbidity. The effect appeared to be dose-dependent. Further research on dose and mode of treatment is mandatory.

Pharmacodynamics and pharmacokinetics of intravesical mitomycin C upon different dwelling times.

The schedule in dosing of intravesical chemotherapy has thus far received little attention. Correlation of optimal contact time with bladder toxicity, as well as maximal chemotherapeutic effect for one of the drugs of first choice for intravesical instillation, i.e. mitomycin C (MMC), is a particularly important question. In a randomized study, we treated bladder cancer patients with intravesical MMC using 30-min and 60-min dwelling times. There were 28 evaluable patients in each of the 2 groups. The groups were comparable with respect to mean age, sex ratio and distribution of primary or recurrent and single or multiple tumors. Stages and grades of tumors were also comparable over both treatment groups. Pharmacokinetics of MMC and degradation/metabolism were monitored during the first 4 cycles and the last (8th) cycle using HPLC and mass spectrometry. Recurrence was significantly lower in the 60-min treatment group (35.7% vs. 14.3%, chi 2 test; 0.01 less than p less than 0.05). No recurrences were found in patients with Ta and T1 tumors when the 60-min dwelling time was used. Toxicity was mild and transient; the incidence was, surprisingly, lower in the 60-min group but the difference failed to reach the level of significance. Pharmacokinetics of systemic MMC and recovery in the urine was comparable over both groups and systemic absorption was calculated to be in the range of 1-5%.

[Coma due to an overdose of valnoctamide]. / Coma door overdosering van valnoctamide.

We report a 27-year-old man, who became comatose after autopoisoning with a high dose of valnoctamide. He was mechanically ventilated for 12 hours and survived without serious side effects. Valnoctamide blood levels were monitored in order to study the pharmacokinetics of oral overdosing of this drug. Serum half-time levels appeared to be approximately 15 hours.

Behavior and resorption of mitomycin C following multiple intravesical administrations.

Although several pharmacological data of intravesical mitomycin C (MMC) are available now, data about resorption following subsequent intravesical instillations with different instillation times are lacking. We have analyzed MMC concentrations in blood plasma and urine following eight subsequent instillations, with 0.5- and 1.0-h instillation times. The relationships between urinary pH, urinary MMC concentrations, and MMC blood plasma concentrations were determined, as well as the stability of MMC in urine at pH 5-8 at 37 degrees C. An average of 40.3 and 46.4% of the total parent drug was recovered for the 0.5- and 1.0-h instillations, respectively. Blood plasma concentrations of MMC could be measured in nearly all patients and were independent of instillation times, urine concentration, or urinary pH. Resorption of MMC and recovery was stable during eight subsequent instillations. It was demonstrated that MMC can be degradated in urine at physiological conditions (pH less than 6; 37 degrees C). However, neither an influence of prolongation of the instillation time on MMC recovery from urine, nor a significant correlation between urinary pH and urinary MMC concentrations could be demonstrated. Since MMC can be degradated at pH less than 6 within 0.5 h, buffering of instillation fluids containing MMC is recommended. Reuse of instilled MMC, therefore, cannot be advised.

Mitomycin C resorption following repeated intravesical instillations using different instillation times.

In a prospective and randomized trial, 31 patients with superficial and/or CIS transitional cell carcinoma were treated by complete transurethral resection of all visible tumours, followed by instillation of 40 mg mitomycin C (MMC). The instillation time was 0.5 and 1.0 h. The resorption of MMC by the bladder wall was not influenced by the instillation time. There was no cumulative effect on MMC resorption observed in consecutive instillations. Less than 1% of the instilled dose of MMC was resorbed. The maximum plasma concentration of MMC never exceeded 31 ng/ml. After instillation, mean percentages of MMC found in urine were 40.3 (0.5 h group) and 46.4 (1.0 h group), respectively. The only side-effects observed were chemical cystitis, contact and general exanthema. The instillation time had no influence on these side-effects. Bone marrow toxicity has not been observed.

Role of bone and kidney in tumor-induced hypercalcemia and its treatment with bisphosphonate and sodium chloride.

The efficacy of intravenous aminohydroxypropylidene bisphosphonate as treatment for the hypercalcemia of malignancy was examined in a phase II multicenter study in 132 patients with a large variety of primary tumors. This provided an opportunity for an analysis of the separate influences of bone resorption and renal calcium handling on the genesis and maintenance of hypercalcemia. The results demonstrated that increased bone resorption is the major contributory factor and that inhibition with bisphosphonate normalizes the serum calcium concentration within five days in more than 90 percent of patients. Hypercalcemia is sustained by an inability of the kidney to deal efficiently with a chronically increased calcium load. This is influenced by the requirements of volume regulation in the presence of a sodium diuretic effect of hypercalcemia and is very sensitive to induced variations of sodium load. In addition, in a minority of patients, direct renal actions of tumor-derived humoral factors adversely reduce the ability to excrete calcium. For optimal treatment of tumor-induced hypercalcemia, bisphosphonate treatment should be combined with intravenous administration of saline solution.

Osteolytic bone metastases in breast carcinoma pathogenesis, morbidity and bisphosphonate treatment.

In this review different aspects of osteolytic bone metastasis of breast carcinoma including morbidity, pathogenesis, accompanying hypercalcaemia and treatment, are discussed. Bone metastases occur in many patients with breast cancer (percentages of up to 85% have been reported); although patients seldom die of bone metastases morbidity is pronounced. Literature data point out that humoral factors, such as prostaglandins and the recently described growth factors are of importance beside cell interactions between monocytes, lymphocytes, osteoclasts and tumour cells. Nowadays, no significance is attributed to parathyroid hormone (PTH) overproduction in this respect. The differential diagnosis between primary hyperparathyroidism and tumour-induced hypercalcaemia is not always easy biochemically; combinations of both do occur less frequently than has been assumed in the past. A new and promising line of investigations involves the growth factors, which can increase osteolytic bone resorption and may bind to epidermal growth factor (EGF) or PTH receptors, thus inducing some of the biological effects of PTH (including hypercalcaemia). Until recently it was exceedingly difficult to treat tumour-induced hypercalcaemia (TIH) (the acute condition). Since the availability of the bisphosphonates dichloromethylidene bisphosphonate (Cl2MDP) and 3-amino-1-hydroxypropylidene-1, l-bisphosphonate (APD) this treatment has become very simple. Preliminary results, derived from the literature, point out that bisphosphonate treatment might also be effective in providing long-term control.

Comparison of intravenous (3-amino-1-hydroxypropylidene)-1, 1-bisphosphonate and volume repletion in tumour-induced hypercalcaemia.

In a group of thirty patients with tumour-induced hypercalcaemia the effects of volume repletion and intravenous (3-amino-1-hydroxypropylidene)-1, 1-bisphosphonate (APD) were examined. Volume repletion was only partially effective in lowering serum calcium and raising glomerular filtration rate and it increased the tendency towards hypomagnesaemia. In twenty-nine of the patients serum calcium, serum magnesium, and glomerular filtration rate were rapidly restored to normal by intravenous APD, in doses of 1.75-30 mg/day. Tubular reabsorption of phosphate was lower than normal in five of nine patients in whom it was studied and remained unchanged despite correction of hypovolaemia and serum and urine calcium levels or changes in parathyroid hormone. These findings suggested that tumours may produce a phosphate-lowering factor. The improvement in clinical condition with volume repletion depends on its ability to adjust calcium excretion to the abnormal production of calcium from bone. APD, in contrast, returns pathological bone destruction to normal without any undesirable side-effects.

In vitro effect of (3-amino-1-hydroxypropylidene)-1,1-bisphosphonic acid (APD) on the function of mononuclear phagocytes in lymphocyte proliferation.

The effect of (3-amino-1-hydroxypropylidene)-1,1-bisphosphonic acid (APD) on pokeweed mitogen-stimulated and non-stimulated cultures of peripheral blood mononuclear cells was studied in vitro. It is shown that APD can inhibit partially lymphocyte proliferation when added to a suspension of mononuclear cells before stimulation, but that lymphocyte proliferation can continue when the drug is withdrawn. In contrast; when APD is added to the cell suspension together with the mitogen, lymphocyte proliferation remains low even when the drug is withdrawn. Addition of different concentration of mononuclear phagocytes (MNP) to non-adherent cells, followed by stimulation in the presence of APD, indicates that APD acts on MNP function preferentially and does not affect lymphocyte proliferation.

Efficacy of amino-hydroxypropylidene bisphosphonate in hypercalcemia: observations on regulation of serum calcium.

For 2 weeks 27 patients with hypercalcemia received a standard oral treatment with (3-amino-1-hydroxypropylidene)-1,1-bisphosphonate (APD) as the sole agent. Results were grouped according to causes of hypercalcemia and compared with effects of APD in 13 normocalcemic patients with Paget's disease of bone and 7 with osteoporosis. In 12 hypercalcemic patients with osteolytic bone lesions and in the 20 normocalcemic patients, the mean serum calcium decreased to final levels that were subnormal and significantly lower than those obtained after treatment of 8 patients with primary hyperparathyroidism. In 3 patients with myeloma and in 4 tumor patients without bone lesions, serum calcium did not always decrease to the normal range. Implications of these observations for the mechanism of hypercalcemia are discussed.