- Email: [email protected]
30. A randomized phase 11 evaluation of oral pamidronate for advanced bone metastases from breast cancer
Abstracts of the 4th Nottingham International Breast Cancer Conference defined as metastases causing fracture (63%), impending fracture (1 l%), spinal cord compression (14%), and nerve root irritation (12%). Clinical review by an orthopaedic surgeon would have been appropriate in 89% of this group, but was sought in only 46% of cases. Orthopaedic referral was via the oncologist (54%), casualty (23%), general practice (18%), and others (5%). Surgery would have been appropriate for 65% of the episodes of SSBD, but was only performed in 31% of cases; intramedullary nail (32%), internal fixation (24%), spinal procedures (20%), arthroplasty (16%), and biopsy (8%). Bracing would have been appropriate in 40% of cases, but was provided in only 18%. Median survival from presentation with SSBD was 8.5 months (range O-63 months). Women treated with combination radiotherapy/surgery had a speedier and more prolonged resolution of symptoms, and a lower incidence of symptom recurrence. From these data, we would recommend earlier and more frequent orthopaedic review of women with symptomatic BM, possibly in combined orthopaedie/oncology clinics.
28. Long-term metastases J. Walls,
review of breast cancer bone
D. S. O’Donoghue,
N. J. Bundred,
A. Howell
Departments of Breast and Orthopaedic Surgery, University Hospital of South Manchester and CRC Department of Medical Oncology, Christie Hospital, Manchester, UK Bone metastases (BM) in women with breast cancer cause considerable morbidity; the natural history and complications of BM are not well documented. Two hundred and sixty-nine women with BM were studied, from a consecutive group presenting with primary breast cancer over a 25-year period. To date, 94% have died; median disease-free interval from initial diagnosis to first relapse was 15 months (range O-228 months). At first relapse 81% of women developed BM; 54% of women developed BM as their sole site of first relapse, and 22% did not develop metastases at any other site. Twenty-six per cent of women had a solitary BM, and of these 20% remained solitary until death; median survival was 28 months (range l-186+ months). For those women with > 1 BM, median survival was only 19 months (range O-124 months). At least one pathological fracture developed in 27% of women (19 long bone; 54 non-long bone). Median time from BM diagnosis to fracture was 2.5 months, and time from fracture to death was 12 months (range O-61 months) seventy-five out of 269 (28%) of women became hypercalcaemic, 5% at primary presentation, (when 1 l/13 had BM). Median time to hypercalaemia from diagnosis of BM was 3 months, with a median 7-month survival time (range O-59 months). There were 197 treatment changes to tamoxifen in the presence of BM, and only 6 (3%) patients developed true ‘flare’ hypercalcaemia. A ‘flare’ response to other treatment changes developed in lo/269 (4%). These data demonstrate the natural history of bone metastases in a large consecutive series.
29. Evaluation of new bone resorption markers in a comparison of pamidronate or clodronate for hypercalcaemia of malignancy J. Vinholes, C. Y. Guo, 0. P. Purohit, A. P. B. Vinholes, R. Coleman
R. Eastell,
YCRC Department of Clinical Oncology, Weston Park Hospital, Department of Human Metabolism and
235
Clinical Biochemistry, Northern General Hospital, Shefleld, UK The bisphosphonates are an important new class of compounds in the treatment of advanced breast cancer. however, objective assessment of their effects on bone is difficult. Urinary excretion of calcium (uCa) and hydroxyproline (hyp) are the traditional markers of bone resorption but recently assays for more specific markers of collagen breakdown have been developed. These include the collagen cross-links deoxypyridinoline (Dpd) and pyridinoline (Pyd) measured by HPLC, and the Ctelopeptide of the crosslinking molecule (Crosslaps) measured by an ELISA assay. We have assessed these new assays in 32 patients receiving bisphosphonates for hypercalcaemia of malignancy as a model for possible wider application. After rehydration patients were randomized (double-blind) to receive an intravenous infusion of either 90 mg pamidronate or 1500 mg clodronate. Serum and urine samples were collected at baseline, 2, 4, 7, 14, 21 and 28 days. Both bisphosphonates were effective in restoring normocalcaemia but clinically important and statistically significant differences were seen in the duration of normocalcaemia (pamidronate 28 vs clodronate 14 days, P = 0.01). After pamidronate and clodronate respectively, the maximum % decrease from baseline for uCa was 90% vs 77% (P < O.Ol), for hyp 42% vs 35% (NS), for Pyd was 38% vs 20% (P <0.05), for Dpd 68% vs 38% (P < 0.01) and for Ctelopeptide 96% vs 78% (P < 0.01). For both bisphosphonates C-telopeptide showed the largest fall (P < O.OOl- multifactor anova). The duration of reduction in Dpd, Pyd and Ctelopeptide excretion was longer with pamidronate than clodronate (P < O.Ol-multifactor anova). The changes in uCa were confounded by a rise in the parathyroid-hormone (median increase 180% after clodronate and > 500% after pamidronate), which through effects on the kidney, inhibit calcium excretion. In conclusion, the superiority of pamidronate in controlling hypercalcaemia is mirrored by the changes observed in the collagen breakdown products. C-telepeptide is the most sensitive marker and because it is much easier to measure than Dpd and Pyd could be used in the monitoring of normocalcaemic patients with bone metastases.
30. A randomized phase II evaluation of oral pamidronate for advanced bone metastases from breast cancer R. E. Coleman, R. D. Rubens, S. Houston, J. Ford
C. Rose, 0. P. Purohit,
YCRC Department of Clinical Oncology, Weston Park Hospital, Sheffield, ICRF Department of Clinical Oncology, Guy’s Hospital, London UK, Department of Oncology, Odense University Hospital, Odense, Department, Ciba-Geigy Ltd, Basel, Switzerland Forty-seven women with heavily pretreated progressive bone metastases from breast cancer were recruited to this doubleblind study of an enteric coated micropellet formulation of pamidronate (Ciba-Geigy, Basel). Patients received either 75 mg bd or 150 mg bd. No other systemic treatment or drugs known to affect bone metabolism were administered during the course of the study. Radiological response was assessed by extramural review, and symptomatic response based on a combination of pain intensity, analgesic intake and mobility. Blood and urine were collected for safety monitoring and assessment of bone metabolism. No difference in objective or symptomatic response was seen between the two dose levels. Six out of 47 (13%) patients showed sclerosis of lytic disease consistent with a UICC partial
236 The Breast response, 19/47 (40%) of patients showed a symptomatic response (12 major and 7 minor). Six patients showed an improvement in performance status. The median times to progressive disease in bone were 121 days for the 300 mg dose and 91 days for the 150 mg dose (P = NS). The median duration of treatment was 84 days in both groups with 12 patients at 300 mg requiring dose reductions versus 6 patients at 150 mg. Gastrointestinal adverse experiences considered causally related to the trial treatment were more frequent at the 300 mg dose (13 vs 6). One patient developed asymptomatic hypocalcaemia. There was a marked reduction in urinary calcium at both dose levels. This was in part mediated by the increase in parathyroid hormone induced by the fall in serum calcium. No significant fall in the more specific bone resorption markers pyridinoline or deoxypyridinoline was observed. Oral pamidronate is a reasonably well tolerated treatment capable of providing pain relief and occasional healing of lytic disease. However, the clinical and biochemical effects are small and parenteral treatment remains preferable for rapid palliation of advanced painful bone metastases. The value of long-term oral pamidronate therapy as an adjunct to systemic treatment is currently being evaluated.
31. Efficacy of pamidronate on skeletal complications from breast cancer metastases. A prospective randomized double-blind placebocontrolled trial R. Hultbom, S. RydCn, S. Gundersen, U-B. Wallgren
E. Holmberg,
Department of Oncology, Sahlgrenska Hospital, GBteborg, Department of Surgery, University Hospital, Malmii, Sweden Radiumhospitalet, Oslo, Norway. Oncological Centre, Giiteborg, Sweden Women with skeletal metastases from breast cancer were treated by pamidronate 60 mg iv. q 4 w or saline at the same interval in a double-blind placebo-controlled randomized study. Patients were recruited at 27 institutions in Sweden and Norway from November 1990 to September 1993. Specific antitumor treatment, endocrine and/or cytotoxic, was individually chosen at the discretion of the physician. Endpoints of the study were the incidence of skeletal-related symptoms, i.e. increased pain, hypercalcaemia, fractures and paresis due to vertebral metastases, as well as the incidence of palliative measures indicated by the skeletal complications, i.e. osteosynthesis, radiotherapy and laminectomy. Changes in antitumour therapy were recorded as well as analgestic medication. Quality of life related to pain parameters as recorded by the patients were analysed. Recordings of these parameters were made every third month up to 24 months, when the patients left the study without uncoding the study medication. At present the code is not broken and treatment will be referred to as arm A and B. Four hundred and one patients were recruited with a mean age of 59 and 60 years in the A and B groups respectively. Other pretreatment parameters were well balanced. The number of patients in the study over time was not significantly different between the two arms. The cumulated incidence of symptoms of skeletal progression as well as survival without symptoms of skeletal progression was significantly different between the two treatment groups. The median time for symptoms of skeletal progression was 9 and 14 months respectively. No difference was found in the incidence of fractures nor need of palliative radiotherapy. The incidence of changed baseline antitumour therapy was not different. In a large randomized double-blind placebo-controlled trial of the efficacy of pamidronate 60 mg iv. q 4 weeks, differences were found in the progression of skeletal symptoms, though
not in the need for palliative radiotherapy base-line antitumour treatment.
nor for changes in
32. Ibandronate: a well-tolerated new oral bisphosphonate for the treatment of bone metastases. R. E. Coleman, 0. P. Purohit, C. Black, J. Vinholes, A. Kanis, K. Schlosser, H. Huss, K. .I. Quinn
J.
YCRC Department of Clinical Oncology, Weston Park Hospital, Shefield, Department of Human Metabolism and Clinical Biochemistry, Royal Hallamshire Hospital, Sheffield, Boehringer Mannheim Therapeutics, UK The value of currently available oral bisphosphonates is limited by their poor absorption and the gastrointestinal (GI) toxicity of high oral doses. More potent bisphosphonates may overcome these limitations. One hundred and ten patients with bone metastases (77 breast, 16, prostate, 3 myeloma, 14 others) were recruited from a single institution to this Phase II double-blind placebo-controlled evaluation of 4 oral dose levels (5, 10, 20 and 50 mg) of ibandronate (BM 21.0955). No changes in systemic anti-cancer treatment were allowed in the month before commencing treatment or during the study period. Other drugs known to affect bone metabolism were avoided. After an initial 4-week tolerability phase, patients on placebo received 50 mg Ibandronate for a futher 3 months without unblinding the study. The planned total duration of treatment was 4 months. Bone resorption was assessed by measurement of pyridinoline (Pyr) and deoxypyridinoline (Dpd) crosslinks, and the N-terminal (NTX) and C-terminal (Crosslaps) portions of the collagen crosslinking molecules. All patients are evaluable for toxicity and overall ibandronate was well tolerated. One or more GI adverse events occurring in the first month of treatment were reported by 9 (41%), 9 (39%), 9 (41%), 10 (45%) and 11 (52%) patients at the placebo, 5, 10, 20 and 50 mg doe levels respectively. Nine (8%) patients stopped treatment within the first month due to gastrointestinal toxicity but these patients were evenly distributed across the five treatment groups. There was no difference in non-G1 side effects between groups. One hundred and one patients are evaluable for efficacy although the dose of ibandronate remains blinded until analysis is complete. However, a significant fall in the biochemical markers of bone resorption was seen and for all patients, after 4 weeks treatment, the percentage reduction-from baseline was 10% for Pyr, 21% for Dpd, 37% for NTX and 42% for Crosslaps. Subjective benefit was reported by many patients and 20 patients requested follow-on supplies because of symptomatic improvement on completion of the four month trial period.
33. Small breast cancer: an integrated index is still important C. A. Murphy, D. Morgan, C. W. Elston, J. F. R. Robertson, R. W. Blarney
J. 0. Ellis,
Nottingham City Hospital, Nottingham, UK It has been reported by Tabar et al that size is the most important factor in determining prognosis in small breast cancer. We routinely perform lymph node sampling in all patients with invasive breast cancer. The results are shown in Table 1. Table
1
Tumour size 15mm 6-10 mm The Nottingham
Lymph node +ve(%) 6149 571293
Prognostic
(12) (19)
Index (NPI) has then been calcu-
28. Long-term metastases J. Walls,
review of breast cancer bone
D. S. O’Donoghue,
N. J. Bundred,
A. Howell
Departments of Breast and Orthopaedic Surgery, University Hospital of South Manchester and CRC Department of Medical Oncology, Christie Hospital, Manchester, UK Bone metastases (BM) in women with breast cancer cause considerable morbidity; the natural history and complications of BM are not well documented. Two hundred and sixty-nine women with BM were studied, from a consecutive group presenting with primary breast cancer over a 25-year period. To date, 94% have died; median disease-free interval from initial diagnosis to first relapse was 15 months (range O-228 months). At first relapse 81% of women developed BM; 54% of women developed BM as their sole site of first relapse, and 22% did not develop metastases at any other site. Twenty-six per cent of women had a solitary BM, and of these 20% remained solitary until death; median survival was 28 months (range l-186+ months). For those women with > 1 BM, median survival was only 19 months (range O-124 months). At least one pathological fracture developed in 27% of women (19 long bone; 54 non-long bone). Median time from BM diagnosis to fracture was 2.5 months, and time from fracture to death was 12 months (range O-61 months) seventy-five out of 269 (28%) of women became hypercalcaemic, 5% at primary presentation, (when 1 l/13 had BM). Median time to hypercalaemia from diagnosis of BM was 3 months, with a median 7-month survival time (range O-59 months). There were 197 treatment changes to tamoxifen in the presence of BM, and only 6 (3%) patients developed true ‘flare’ hypercalcaemia. A ‘flare’ response to other treatment changes developed in lo/269 (4%). These data demonstrate the natural history of bone metastases in a large consecutive series.
29. Evaluation of new bone resorption markers in a comparison of pamidronate or clodronate for hypercalcaemia of malignancy J. Vinholes, C. Y. Guo, 0. P. Purohit, A. P. B. Vinholes, R. Coleman
R. Eastell,
YCRC Department of Clinical Oncology, Weston Park Hospital, Department of Human Metabolism and
235
Clinical Biochemistry, Northern General Hospital, Shefleld, UK The bisphosphonates are an important new class of compounds in the treatment of advanced breast cancer. however, objective assessment of their effects on bone is difficult. Urinary excretion of calcium (uCa) and hydroxyproline (hyp) are the traditional markers of bone resorption but recently assays for more specific markers of collagen breakdown have been developed. These include the collagen cross-links deoxypyridinoline (Dpd) and pyridinoline (Pyd) measured by HPLC, and the Ctelopeptide of the crosslinking molecule (Crosslaps) measured by an ELISA assay. We have assessed these new assays in 32 patients receiving bisphosphonates for hypercalcaemia of malignancy as a model for possible wider application. After rehydration patients were randomized (double-blind) to receive an intravenous infusion of either 90 mg pamidronate or 1500 mg clodronate. Serum and urine samples were collected at baseline, 2, 4, 7, 14, 21 and 28 days. Both bisphosphonates were effective in restoring normocalcaemia but clinically important and statistically significant differences were seen in the duration of normocalcaemia (pamidronate 28 vs clodronate 14 days, P = 0.01). After pamidronate and clodronate respectively, the maximum % decrease from baseline for uCa was 90% vs 77% (P < O.Ol), for hyp 42% vs 35% (NS), for Pyd was 38% vs 20% (P <0.05), for Dpd 68% vs 38% (P < 0.01) and for Ctelopeptide 96% vs 78% (P < 0.01). For both bisphosphonates C-telopeptide showed the largest fall (P < O.OOl- multifactor anova). The duration of reduction in Dpd, Pyd and Ctelopeptide excretion was longer with pamidronate than clodronate (P < O.Ol-multifactor anova). The changes in uCa were confounded by a rise in the parathyroid-hormone (median increase 180% after clodronate and > 500% after pamidronate), which through effects on the kidney, inhibit calcium excretion. In conclusion, the superiority of pamidronate in controlling hypercalcaemia is mirrored by the changes observed in the collagen breakdown products. C-telepeptide is the most sensitive marker and because it is much easier to measure than Dpd and Pyd could be used in the monitoring of normocalcaemic patients with bone metastases.
30. A randomized phase II evaluation of oral pamidronate for advanced bone metastases from breast cancer R. E. Coleman, R. D. Rubens, S. Houston, J. Ford
C. Rose, 0. P. Purohit,
YCRC Department of Clinical Oncology, Weston Park Hospital, Sheffield, ICRF Department of Clinical Oncology, Guy’s Hospital, London UK, Department of Oncology, Odense University Hospital, Odense, Department, Ciba-Geigy Ltd, Basel, Switzerland Forty-seven women with heavily pretreated progressive bone metastases from breast cancer were recruited to this doubleblind study of an enteric coated micropellet formulation of pamidronate (Ciba-Geigy, Basel). Patients received either 75 mg bd or 150 mg bd. No other systemic treatment or drugs known to affect bone metabolism were administered during the course of the study. Radiological response was assessed by extramural review, and symptomatic response based on a combination of pain intensity, analgesic intake and mobility. Blood and urine were collected for safety monitoring and assessment of bone metabolism. No difference in objective or symptomatic response was seen between the two dose levels. Six out of 47 (13%) patients showed sclerosis of lytic disease consistent with a UICC partial
236 The Breast response, 19/47 (40%) of patients showed a symptomatic response (12 major and 7 minor). Six patients showed an improvement in performance status. The median times to progressive disease in bone were 121 days for the 300 mg dose and 91 days for the 150 mg dose (P = NS). The median duration of treatment was 84 days in both groups with 12 patients at 300 mg requiring dose reductions versus 6 patients at 150 mg. Gastrointestinal adverse experiences considered causally related to the trial treatment were more frequent at the 300 mg dose (13 vs 6). One patient developed asymptomatic hypocalcaemia. There was a marked reduction in urinary calcium at both dose levels. This was in part mediated by the increase in parathyroid hormone induced by the fall in serum calcium. No significant fall in the more specific bone resorption markers pyridinoline or deoxypyridinoline was observed. Oral pamidronate is a reasonably well tolerated treatment capable of providing pain relief and occasional healing of lytic disease. However, the clinical and biochemical effects are small and parenteral treatment remains preferable for rapid palliation of advanced painful bone metastases. The value of long-term oral pamidronate therapy as an adjunct to systemic treatment is currently being evaluated.
31. Efficacy of pamidronate on skeletal complications from breast cancer metastases. A prospective randomized double-blind placebocontrolled trial R. Hultbom, S. RydCn, S. Gundersen, U-B. Wallgren
E. Holmberg,
Department of Oncology, Sahlgrenska Hospital, GBteborg, Department of Surgery, University Hospital, Malmii, Sweden Radiumhospitalet, Oslo, Norway. Oncological Centre, Giiteborg, Sweden Women with skeletal metastases from breast cancer were treated by pamidronate 60 mg iv. q 4 w or saline at the same interval in a double-blind placebo-controlled randomized study. Patients were recruited at 27 institutions in Sweden and Norway from November 1990 to September 1993. Specific antitumor treatment, endocrine and/or cytotoxic, was individually chosen at the discretion of the physician. Endpoints of the study were the incidence of skeletal-related symptoms, i.e. increased pain, hypercalcaemia, fractures and paresis due to vertebral metastases, as well as the incidence of palliative measures indicated by the skeletal complications, i.e. osteosynthesis, radiotherapy and laminectomy. Changes in antitumour therapy were recorded as well as analgestic medication. Quality of life related to pain parameters as recorded by the patients were analysed. Recordings of these parameters were made every third month up to 24 months, when the patients left the study without uncoding the study medication. At present the code is not broken and treatment will be referred to as arm A and B. Four hundred and one patients were recruited with a mean age of 59 and 60 years in the A and B groups respectively. Other pretreatment parameters were well balanced. The number of patients in the study over time was not significantly different between the two arms. The cumulated incidence of symptoms of skeletal progression as well as survival without symptoms of skeletal progression was significantly different between the two treatment groups. The median time for symptoms of skeletal progression was 9 and 14 months respectively. No difference was found in the incidence of fractures nor need of palliative radiotherapy. The incidence of changed baseline antitumour therapy was not different. In a large randomized double-blind placebo-controlled trial of the efficacy of pamidronate 60 mg iv. q 4 weeks, differences were found in the progression of skeletal symptoms, though
not in the need for palliative radiotherapy base-line antitumour treatment.
nor for changes in
32. Ibandronate: a well-tolerated new oral bisphosphonate for the treatment of bone metastases. R. E. Coleman, 0. P. Purohit, C. Black, J. Vinholes, A. Kanis, K. Schlosser, H. Huss, K. .I. Quinn
J.
YCRC Department of Clinical Oncology, Weston Park Hospital, Shefield, Department of Human Metabolism and Clinical Biochemistry, Royal Hallamshire Hospital, Sheffield, Boehringer Mannheim Therapeutics, UK The value of currently available oral bisphosphonates is limited by their poor absorption and the gastrointestinal (GI) toxicity of high oral doses. More potent bisphosphonates may overcome these limitations. One hundred and ten patients with bone metastases (77 breast, 16, prostate, 3 myeloma, 14 others) were recruited from a single institution to this Phase II double-blind placebo-controlled evaluation of 4 oral dose levels (5, 10, 20 and 50 mg) of ibandronate (BM 21.0955). No changes in systemic anti-cancer treatment were allowed in the month before commencing treatment or during the study period. Other drugs known to affect bone metabolism were avoided. After an initial 4-week tolerability phase, patients on placebo received 50 mg Ibandronate for a futher 3 months without unblinding the study. The planned total duration of treatment was 4 months. Bone resorption was assessed by measurement of pyridinoline (Pyr) and deoxypyridinoline (Dpd) crosslinks, and the N-terminal (NTX) and C-terminal (Crosslaps) portions of the collagen crosslinking molecules. All patients are evaluable for toxicity and overall ibandronate was well tolerated. One or more GI adverse events occurring in the first month of treatment were reported by 9 (41%), 9 (39%), 9 (41%), 10 (45%) and 11 (52%) patients at the placebo, 5, 10, 20 and 50 mg doe levels respectively. Nine (8%) patients stopped treatment within the first month due to gastrointestinal toxicity but these patients were evenly distributed across the five treatment groups. There was no difference in non-G1 side effects between groups. One hundred and one patients are evaluable for efficacy although the dose of ibandronate remains blinded until analysis is complete. However, a significant fall in the biochemical markers of bone resorption was seen and for all patients, after 4 weeks treatment, the percentage reduction-from baseline was 10% for Pyr, 21% for Dpd, 37% for NTX and 42% for Crosslaps. Subjective benefit was reported by many patients and 20 patients requested follow-on supplies because of symptomatic improvement on completion of the four month trial period.
33. Small breast cancer: an integrated index is still important C. A. Murphy, D. Morgan, C. W. Elston, J. F. R. Robertson, R. W. Blarney
J. 0. Ellis,
Nottingham City Hospital, Nottingham, UK It has been reported by Tabar et al that size is the most important factor in determining prognosis in small breast cancer. We routinely perform lymph node sampling in all patients with invasive breast cancer. The results are shown in Table 1. Table
1
Tumour size 15mm 6-10 mm The Nottingham
Lymph node +ve(%) 6149 571293
Prognostic
(12) (19)
Index (NPI) has then been calcu-