Prevention of anastrozole induced bone loss with monthly oral ibandronate: Final 5 year results from the ARIBON trial.

PURPOSE: The ARIBON trial is a double blind, randomised, placebo controlled study designed to evaluate the impact of ibandronate on bone mineral density (BMD) in women taking anastrozole for adjuvant treatment of breast cancer. METHODS: 131 postmenopausal women with early breast cancer were recruited to the study. Of these, 13 had osteoporosis, 50 osteopenia and 68 normal BMD. Patients with osteoporosis at baseline were treated with monthly oral ibandronate 150 mg for 5 years; osteopenic patients were randomised to receive either ibandronate or placebo for two years and offered open label ibandronate depending upon the results of their 2-year BMD result. RESULTS: Of the 20 patients with osteopenia who were randomised to ibandronate and evaluable at the 2 year visit, 17/20 were not offered a bisphosphonate and the improvements in BMD accrued during the first 2 years were lost both at the LS (-3.21%) and TH (-5.0%). Of the 16 patients randomised to placebo 8/16 with high rates of bone loss during years 0-2 received ibandronate over the next 3 years with improvements in BMD of +5.01 and +1.19 at the LS and TH respectively. The 8 patients who were not offered a bisphosphonate experienced relatively little change in BMD throughout the 5 years of the study (LS +0.15%, TH -2.72%). BMD increased steadily in the 9/13 patients initially identified as having osteoporosis (LS +9.65%, TH +2.72%). CONCLUSIONS: Monthly oral ibandronate provides an option to clinicians considering use of a bisphosphonate to prevent bone loss during aromatase inhibitor therapy.

Review of testing and use of adjuvant trastuzumab across a cancer network--are we treating the right patients?

This review of practice assessed all early breast cancer patients diagnosed over 12 months to determine the frequency of human epidermal growth factor receptor 2 (HER2) positivity and trastuzumab use. The frequency of HER2 positivity in routine practice (185/1319; 14%) was less than expected. A significant proportion of patients (56/185; 30%) did not receive trastuzumab, largely due to concerns about chemotherapy tolerability.

Adjuvant trastuzumab in routine clinical practice and the impact of cardiac monitoring guidelines on treatment delivery.

Trastuzumab delivery and changes in left ventricular ejection fraction (LVEF) in 110 patients receiving adjuvant trastuzumab in routine practice are investigated. The potential impact of new, less stringent UK cardiac monitoring guidelines is examined. 86 patients (78%) completed trastuzumab on schedule. 11 (10%) completed treatment despite delay(s) to allow LVEF recovery, 7 (6%) discontinued trastuzumab because of insufficient LVEF recovery, 2 (2%) of whom developed symptomatic cardiotoxicity. 6 (5%) discontinued trastuzumab for non-cardiac reasons. With the newer guidelines, the value of LVEF lower limit of normal is important in determining the proportion of patients who require angiotensin-converting enzyme inhibitors (ACEIs) and cardiology referral: up to 100% could potentially complete trastuzumab on schedule with up to 60% receiving ACEIs and 25% requiring cardiology referral. Adjuvant trastuzumab was well tolerated overall. The new guidelines potentially allow more patients to complete trastuzumab on schedule but require higher levels of cardiological intervention.

Epirubicin/vinorelbine adjuvant chemotherapy in young women with breast cancer is associated with preservation of menstrual function.

AIMS: To determine whether the epirubicin and vinorelbine regimen in the adjuvant (neoadjuvant) treatment of breast cancer has minimum adverse effects on menstrual function. PATIENTS AND METHODS: Thirty-six premenopausal women with a median age of 32 (25-47) years received epirubicin and vinorelbine. Twenty-eight received only epirubicin and vinorelbine without any other neo/adjuvant chemotherapy agents. Amenorrhoea was defined as absence of periods 6 months after the completion of chemotherapy. The medical records of all patients were reviewed retrospectively. RESULTS: Twenty-six patients were assessable for effects of epirubicin and vinorelbine on menstruation. All the 26 patients resumed menstruation within 6 months of completing epirubicin and vinorelbine treatment. Epirubicin and vinorelbine was well tolerated. After a median follow-up of 38.5 (11-78) months, six (21%) patients had developed disease relapse and three (11%) had died. The 6.5-year disease-free survival and overall survival probabilities were 77 and 86%, respectively. CONCLUSION: Adjuvant (neoadjuvant) epirubicin and vinorelbine is an effective and well-tolerated regimen that is associated with the retention of menstrual function.

The use of bone markers in a 6-week study to assess the efficacy of oral clodronate in patients with metastatic bone disease.

Biochemical markers of bone metabolism are strongly associated with skeletal complications in metastatic bone disease. The bisphosphonate clodronate reduces skeletal morbidity by inhibiting bone resorption. This study investigated the use of bone markers to assess the efficacy of oral clodronate across a range of clinically relevant doses. There were 125 patients with metastatic bone disease randomized to daily oral clodronate (800, 1,600, 2,400 and 3,200 mg) or placebo in a double-blind, multicenter study. Urinary N-terminal telopeptide of type I collagen (U-NTX), serum C-terminal telopeptide of type I collagen (S-CTX), urinary calcium (U-Ca), and bone alkaline phosphatase were measured weekly for a 6-week treatment period. Doses of >or=1,600 mg clodronate produced mean reductions of >40% in U-NTX, S-CTX and U-Ca, all significantly different from placebo (P=0.0015, 0.001, 0.0036, respectively), after 6 weeks. Evaluation of least significant changes in markers suggested that the commonly used 1,600 mg dose was most appropriate for breast cancer patients. However, this dose was suboptimal for other (mainly prostate cancer) patients, who showed better response to 2,400 mg. The number of adverse events in the treatment arms was not significantly different from that in placebo, but a higher number of patients had diarrhea in the 3,200 mg arm and withdrew from the study. This trial is the first to explore the dose-response relationship of clodronate in oncology using specific markers of bone turnover. It has confirmed that the 1,600 mg dose is safe and effective for breast cancer patients but may be suboptimal for the other tumors studied.

Bone resorption predicts for skeletal complications in metastatic bone disease.

Relationships between the rate of bone resorption (measured by urinary N-telopeptide (Ntx) excretion) and a range of skeletal complications have been evaluated in patients with metastatic bone disease. A total of 121 patients had monthly measurements of Ntx during treatment with bisphosphonates. All skeletal-related events, plus hospital admissions for bone pain and death during the period of observation, were recorded. Data were available for 121 patients over the first 3-month period of monitoring (0-3 months) and 95 patients over the second 3-month period (4-6 months). N-telopeptide levels were correlated with the number of skeletal-related events and/or death (r=0.62, P<0.001 for 0-3 months and r=0.46, P<0.001 for 4-6 months, respectively). Patients with baseline Ntx values > or =100 nmol mmol(-1) creatinine (representing clearly accelerated bone resorption) were 19.48 times (95% CI 7.55, 50.22) more likely to experience a skeletal-related event/death during the first 3 months than those with Ntx <100 (P<0.001). In a multivariate logistic regression model, Ntx was highly predictive for events/death. This study is the first to indicate a strong correlation between the rate of bone resorption and the frequency of skeletal complications in metastatic bone disease. N-telopeptide appears useful in the prediction of patients most likely to experience skeletal complications and thus benefit from bisphosphonate treatment.

Double-blind, randomised, placebo-controlled, dose-finding study of oral ibandronate in patients with metastatic bone disease.

BACKGROUND: Bisphosphonates are an important component of the treatment of metastatic bone disease but more potent, oral formulations are required to improve the effectiveness and convenience of treatment. An oral formulation of the new bisphosphonate, ibandronate (BM 21.0955) has recently been developed. PATIENTS AND METHODS: One hundred ten patients with bone metastases (77 breast, 16, prostate, 3 myeloma, 14 others) were recruited from a single institution to this double blind placebo-controlled evaluation of four oral dose levels (5, 10, 20 and 50 mg) of ibandronate. No changes in systemic anti-cancer treatment were allowed in the month before commencing treatment or during the study period. After an initial four-week tolerability phase, patients could continue on treatment for a further three months without unblinding; patients initially allocated to placebo received ibandronate 50 mg. The primary endpoint was urinary calcium excretion (UCCR). Bone resorption was also assessed by measurement of pyridinoline (Pyr), deoxypyridinoline (Dpd), and the N-terminal (NTX) and C-terminal (Crosslaps) portions of the collagen crosslinking molecules. RESULTS: Two patients did not receive any trial medication thus, 108 patients were evaluable for safety. Ninety-two patients were evaluable for efficacy. A dose dependent reduction was observed in both UCCR and collagen crosslink excretion. At the 50 mg dose level, the percentage reductions from baseline in UCCR, Pyr, Dpd, Crosslaps and NTX were 71%, 28%, 39%, 80% and 74% respectively. One or more gastrointestinal (GI) adverse events occurring in the first month of treatment were reported by six (30%), seven (33%), nine (39%), nine (41%) and eleven (50%) patients at the placebo, 5, 10, 20 and 50 mg dose levels respectively. One patient (20 mg dose) developed radiographically confirmed oesophageal ulceration. GI tolerability may have been adversely affected by concomitant administration of non-steroidal anti-inflammatory agents. Nine (8%) patients stopped treatment within the first month due to GI intolerability but these patients were evenly distributed across the five treatment groups. There was no difference in non-GI adverse events between groups. CONCLUSIONS: Oral ibandronate has potent effects on the rate of bone resorption at doses which are generally well tolerated. Further development is appropriate to evaluate the effects of long-term administration in the prevention of metastatic bone disease and the management of established skeletal metastases.

A randomised phase II study of oral pamidronate for the treatment of bone metastases from breast cancer.

47 patients with progressive, painful, predominantly lytic bone metastases from breast cancer were included in a randomised double-blind phase II trial comparing the effects of pamidronate 150 and 300 mg daily. Oral pamidronate produced either sclerosis or stabilisation of lytic metastases for at least 24 weeks in 5 of 24 and 3 of 23 patients at the 300 and 150 mg dose levels, respectively. Evidence of symptomatic improvement was observed in 5 of 22 (23%) and 7 of 22 (32%) patients for symptomatic disease at the respective doses. These improvements were accompanied by a reduction in the rate of bone resorption as shown by suppression (P = < 0.01) of urinary calcium and a non-significant fall in deoxypyridinoline. No obvious differences in efficacy were observed between the two dose levels. Gastrointestinal adverse events, principally comprising nausea and vomiting, were the most commonly reported side-effects leading to discontinuation of trial treatment in 4 of 24 and 2 of 23 patients at 300 and 150 mg dose levels, respectively. The poor tolerability of oral pamidronate coupled with the modest clinical effects reported here suggest that oral pamidronate will not replace the current strategy of regular intravenous infusions of pamidronate for the treatment of osteolytic bone disease.

High dose pamidronate: clinical and biochemical effects in metastatic bone disease.

Eighty-six patients with heavily pretreated progressive bone metastases (52 with breast carcinoma, 17 with prostate carcinoma, and 17 others) were included in 2 studies designed to assess the clinical and biochemical effects of a single 120 mg, 2-hour infusion of pamidronate. No other systemic anticancer treatment or radiotherapy were administered. Pamidronate had a significant beneficial effect, with a reduction in a symptom score measuring pain, World Health Organization performance status, and analgesic consumption and improvement in quality of life when compared with a placebo infusion. Symptomatic improvement corresponded with changes in the rate of bone resorption as indicated by the concentrations of pyridinoline crosslinks in the urine. In patients with the highest rates of bone resorption (N-terminal peptide-bound portion of the collagen crosslink or crosslaps excretion > or = twice that of normal) clinical response or normalization of the rate of bone resorption were rarely observed, with all clinical responses occuring in those patients with bone resorption rates of < twice that of normal. Intriguingly, symptomatic response also correlated with a modest (> 10%) fall in tumor marker levels, suggesting a possible effect of bisphosphonates on tumor activity.

Evaluation of new bone resorption markers in a randomized comparison of pamidronate or clodronate for hypercalcemia of malignancy.

PURPOSE: To compare the effects of two bisphosphonates on markers of bone resorption in a randomized double-blind trial for the treatment of hypercalcemia of malignancy. PATIENTS AND METHODS: Thirty-two patients with a serum calcium (sCa) level > or = 2.7 mmol/L that persisted after 48 hours of saline rehydration were randomized to receive pamidronate 90 mg or clodronate 1,500 mg. Bone resorption markers measured included urinary calcium (uCa), hydroxyproline (Hyp), deoxypyridinoline (Dpd), pyridinoline (Pyd), the cross-linking molecule at either the N-telopeptide (NTx) or the C-telopeptide (Crosslaps) regions of type I collagen, and free Dpd. RESULTS: Both bisphosphonates restored normocalcemia, but the duration of action was longer after pamidronate (P < .01). There was a mean pretreatment sevenfold increase in NTx, fivefold increase in Dpd and Crosslaps, and 2.5-fold increase in free Dpd. The changes in uCa were confounded by an increase in parathyroid hormone (PTH) (P < .05), which, through effects on the kidney, inhibits calcium excretion. Most resorption markers showed a larger decrease after pamidronate than clodronate (P < .01). NTx and Crosslaps showed the greatest decrease, being significantly different from any other marker in both arms (P < .01). There was a significant correlation between Dpd, NTx, and Crosslaps (P < .002), but not with uCa. CONCLUSION: The superiority of pamidronate in controlling hypercalcemia is mirrored by the changes observed in these markers. uCa is not an accurate bone resorption marker, which reflects the renal handling of calcium by PTH. NTx and Crosslaps showed the largest increase at baseline and the greatest change after treatment, which suggests these new markers may be more sensitive indicators of bone resorption.

Relationships between biochemical and symptomatic response in a double-blind randomised trial of pamidronate for metastatic bone disease.

PURPOSE: The aim of this study was to evaluate pamidronate for bone pain in a randomised double-blind trial and to evaluate the contribution of new markers of bone resorption in patients with bone metastases. PATIENTS AND METHODS: Fifty-two patients with painful bone metastases were randomised to receive a two-hour infusion of pamidronate 120 mg or an identical infusion of saline. Four weeks later, all patients received pamidronate 120 mg. Bone resorption markers measured included urinary calcium (uCa), hydroxyproline (Hyp), and the collagen breakdown products: NTx, Crosslaps and Free Dpd. RESULTS: Symptomatic response during the first four weeks was seen after pamidronate, but not with placebo (P < 0.05). Quality of life was maintained with pamidronate and deteriorated after placebo (P < 0.05). Resorption markers did not decrease after placebo, but NTx and Crosslaps both decreased by 70% after pamidronate (P = 0.001). A second infusion of pamidronate did not decrease resorption further, but maintained the suppression of resorption at similar levels for a further four weeks. Symptomatic response to pamidronate correlated closely with the rate of bone resorption; it was more frequent in those patients with an initial NTx value of < 2 times the upper limit of normal (17 of 27, 62%) and in those where the level of Ntx returned to normal (19 of 32, 59%), than in the patients with either high baseline values of NTx (> 2 times the upper limit of normal) or Ntx levels which failed to normalise for whom the response frequencies were 2 of 16 (13%) and 0 of 11 (0%), respectively. CONCLUSIONS: Subjective benefit after intravenous pamidronate is confirmed in this placebo-controlled study. The new bone resorption markers of collagen breakdown were able to predict clinical response to pamidronate.

Metabolic effects of pamidronate in patients with metastatic bone disease.

We have evaluated the value of specific bone resorption markers in monitoring metastatic bone disease to define the duration of action of a single high-dose pamidronate infusion. Twenty patients received a single infusion of pamidronate 120 mg for painful bone metastases. Ten out of these 20 patients also received a second infusion. They were evaluated at baseline, 2, 4 and 8 weeks after each infusion. A composite pain questionnaire, serum and urine tests were carried out at these time points. Bone resorption markers measured included urinary calcium, hydroxyproline and two new markers: pyridinoline and deoxypyridinoline. Reference values were defined by 20 healthy controls matched by age and sex. Pamidronate induced a profound fall in bone resorption with a maximal effect within the first month after therapy. Changes in urinary calcium levels were confounded by a rise of 100% in the parathyroid hormone levels. Before treatment, pyridinoline and deoxypyridinoline were increased in 70% of patients, while urinary calcium was increased in only 40% of them. Thirteen patients had a > or = 50% fall in deoxypyridinoline levels and were considered as biochemical responders. These patients had a mean reduction in pain score of about 30% of baseline levels, which was significantly higher than the seven non-biochemical responders. In conclusion, urinary calcium is not a precise marker of bone resorption. Deoxypyridinoline seems to be the most specific bone resorption marker in cancer patients. Biochemical responders have the most benefit from pamidronate in terms of pain relief. This suggests that patients may benefit from more potent or repeated infusions of bisphosphonates.

The future of bisphosphonates in cancer.

Bisphosphonates, in conjunction with rehydration, are now the treatment of choice for hypercalcaemia of malignancy. They can also relieve bone pain and improve quality of life as single agent therapy and, in conjunction with systemic anticancer treatments, can prevent skeletal complications and slow down the metastatic process. The clinical effects are greatest and most clearly defined in breast cancer and multiple myeloma, but, theoretically, clinical benefit should be achievable across the entire spectrum of metastatic bone disease. The new biochemical markers for measuring bone resorption are for the first time providing a direct assessment of the effects of treatment on bone. It is hoped that they will enable a more scientific selection of the type, dose and schedule of bisphosphonate required for the best compromise between efficacy, convenience and patient acceptability. We can expect to see a rapid increase in the use of bisphosphonates in malignancy (especially breast cancer and myeloma). Careful assessment of the health-care economics of this new treatment modality is urgently needed.

A randomised double-blind comparison of intravenous pamidronate and clodronate in the hypercalcaemia of malignancy.

In conjunction with rehydration, the bisphosphonates are the treatment of choice for hypercalcaemia of malignancy. Single infusions of either pamidronate or clodronate are usually effective, but a direct comparison of the two agents given at the highest doses commonly used has not been performed. Forty-one patients (15 breast, 12 squamous carcinomas, four lymphomas, four bladder, two prostate and four others) with hypercalcaemia of malignancy (corrected serum calcium > 2.7 mmol l-1) persisting after 48 h of saline rehydration were randomly allocated to receive a 4 h intravenous (i.v.) infusion of either pamidronate 90 mg or clodronate 1500 mg. No other systemic anti-cancer treatment was prescribed. There were no significant differences in the post-hydration serum calcium values (mean 3.17 mmol l-1 for pamidronate and 3.06 mmol l-1 for clodronate), tumour type or frequency of bone metastases between the two treatments. One patient on each treatment died within 2 days and was not assessable for response. A total of 19/19 (100%) patients achieved normocalcaemia following pamidronate and 16/20 (80%) with clodronate. The median time to achieve normocalcaemia was 4 days (range 2-14) for pamidronate and 3 days (range 2-6) with clodronate. The median duration of normocalcaemia was 28 days (range 10-28+ days) after pamidronate and 14 days after clodronate (range 7-21 days) (P < 0.01). Two patients who failed to respond to clodronate were successfully treated with pamidronate and achieved normocalcaemia for 14 and > 28 days respectively. Two patients experienced fever after pamidronate but no significant toxicity was observed with either treatment. We conclude that both agents are effective in the management of hypercalcaemia of malignancy. At the doses studied, the effects of pamidronate are more complete and longer lasting than those of clodronate.

High-dose intravenous pamidronate for metastatic bone pain.

The bisphosphonates are able to relieve pain from metastatic bone disease and, when given intravenously, may promote bone healing of lytic metastases. In this study, the aim was to assess the acute effects of a single 'high-dose' intravenous treatment with pamidronate on pain, mobility, analgesic consumption and quality of life (QOL). Thirty-four normocalcaemic patients with painful progressing bone metastases (22 from breast, five prostate and seven others) received a single intravenous infusion of 120 mg of pamidronate as palliative therapy. No other systemic therapy or drugs known to influence bone metabolism were administered during the study. Patients' subjective response to treatment was assessed weekly with a pain questionnaire recording a composite of pain intensity, mobility, performance status and analgesic consumption. In addition, patients completed the Rotterdam Symptom Check List (RSCL) for measurement of QOL and a mobility questionnaire. The mean reduction in the pain questionnaire score (recorded on at least two occasions) was 25% [standard error (s.e.) 3%, range 0-75%]. Twenty patients (59%) showed a > or = 20% improvement and were classified as responders. The median duration of symptomatic response was 12 (range 4-24 +) weeks. The responding patients showed a reduction in RSCL score (improvement in QOL) from 35% before treatment to 27% at 6 weeks, but no significant improvement was noted in non-responders. Twenty-one patients were retreated with pamidronate when their symptoms deteriorated again. Eight out of 15 responders showed a second reduction in pain score of > or = 20%, but this was not seen in any of the six non-responders. Five patients have remained well with no additional treatment for their disease other than repeat infusions of pamidronate every 3-6 months. Treatment was well tolerated. Eight (24%) experienced fever after the first treatment only, and four had asymptomatic, biochemical evidence of hypocalcaemia. The acute inhibition of osteoclastic bone resorption induced by a single high-dose treatment with pamidronate can provide useful palliation for patients with bone metastases. Responding patients may be retreated as symptoms dictate to good effect. We are currently running a phase III double-blind trial with high-dose pamidronate for progressive painful metastatic bone disease to exclude any placebo effect and observer bias.