Bisphosphonates in the prevention and treatment of metastatic bone disease

The Brmrr (1999) 8, 5742 0 1999 Harcoufl Brace & Co Ltd

REVIEW

Bisphosphonates in the prevention and treatment of metastatic bone disease R. E. Coleman Department of Clinical Oncology, Weston Park Hospital, Shefield, UK S CJA4 M A R Y. Metastatic bone disease results from the many interactions between tumour cells and bone cells and causes disruption of normal bone metabolism. In addition to the known benefits of both external beam radiotherapy and systemic endocrine and cytotoxic treatments, it is now clear that the bisphosphonates provide an additional treatment strategy which reduces both the symptoms and complications of bone involvement. Ongoing research is aimed at trying to define the optimum route, dose, schedule and type of bisphosphonate, and their value in the adjuvant setting to inhibit the development of bone metastases and treatment-induced osteoporosis.

INTRODUCTION

STRUCTURE AND ACTIONS BISPHOSPHONATES

There is now a much greater understanding of the mechanisms underlying the development of bone metastases and the interdependence between cancer cells and bone.’ In addition to the well recognized release of bone cell activating factors from the tumour, it is now appreciated that release of bone derived growth factors and cytokines from resorbing bone can both attract cancer cells to the bone surface and facilitate their growth and proliferation. Inhibition of bone resorption could, therefore, have an effect on the development and progression of metastatic bone disease. Bone metastases are typically referred to as ‘lytic’, ‘sclerotic’ or ‘mixed’, according to the radiographic appearances of the lesions. Where bone resorption predominates, with little new bone formation, focal bone destruction occurs and the metastases have a lytic appearance. Conversely, in bone metastases characterized by increased osteoblastic activity, the lesions appear sclerotic. However, this classification is simplistic and typically both processes are accelerated in the affected bone. This may be evident on the radiograph as illustrated by the appropriately termed mixed lesion, which histologically shows evidence of increased osteoclast activity and resorption cavities even within sclerotic lesions2 and more recently on biochemical evaluation of bone resorption rates in patients with bone metastases?

OF

The bisphosphonates are an important new class of agents for the treatment of metastatic bone disease. They are characterized by a P-C-P containing central structure, which promotes their binding to the mineralized bone matrix, and a variable R’ chain which determines the relative potency, side-effects and probably also the precise mechanism of action. Following administration, bisphosphonates bind avidly to exposed bone mineral around resorbing osteoclasts leading to very high local concentrations of bisphosphonate in the resorption lacunae. On release from the bone surface, bisphosphonates are internalized by the osteoclast, where they cause disruption of the biochemical processes involved in bone resorption including destruction of the osteoclast cytoskeleton, preventing formation of the sealing zone at the bone surface, and loss of the ruffled border across which the hydrolytic enzymes and protons necessary for bone dissolution are normally secreted.” Other actions of the bisphosphonates include osteoclast apoptosis, with the appearance of distinctive changes in cell and nuclear morphology following exposure to bisphosphonates5 effects on the generation of new osteoclasts by inhibition of the fusion of precursor cells and their subsequent maturation, and inhibition of bone-resorbing cytokine release from macrophages adjacent to the bone surface.6 Recent studies have also indicated that bisphosphonates can induce apoptosis in human myeloma cell lines,’ and promote apoptosis in bone metastases derived from an intraventricular inoculation of nude mice with the MDA-231 human breast cancer cell line.x

correspondence to: R. E. Coleman MD, FRCP, Reader & Consultant Medical Oncologist, YCR Department of Clinical Oncology, Weston Park Hospital, Sheffield, UK. Tel.: +44 (0) 114 226 5213; Fax: +44 (0) 1 14 226 55 11; E-mail: [email protected]

Address

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58

The Breast

Bisphosphonates hone disease

as adjunctive

therapy in metastatic

In addition to their confirmed status as the treatment of choice for hypercalcaemia of maligancy,’ the bisphosphonates are now being used as an adjunct to standard therapies. In 1983, a small study from Elomaa and colleagues in Finland reported that oral clodronate could inhibit osteoelastic activity and result in symptomatic improvement in patients with metastatic breast cancer.” Subsequently, other investigators reported beneficial effects on bone pain,” sclerosis of lytic lesions” and a reduction in skeletal morbidity.“-** It is now clear that long-term bisphosphonate treatment reduces skeletal morbidity rates in multiple myeloma and breast cancer (Table 1). Paterson and colleagues randomized 173 patients with bone metastases from breast cancer to receive either clodronate capsules 1600 mg daily or placebo capsules in addition to appropriate anticancer treatment(s).13 In the patients who received clodronate, there was a significant reduction in skeletal morbidity. Overall the combined rate of all skeletal events was 219 per 100 patient years with clodronate compared to 305 on placebo. Most of the benefit was accounted for by a reduction in hypercalcaemic episodes (28 vs 52, P = < 0.01) and the incidence of vertebral fractures (84 vs 124 per 100 patient years, P = < 0.025). There was no significant effect on non-vertebral fractures, radiotherapy requirements, changes in antitumour therapy or survival. Oral clodronate was well tolerated but difficulty swallowing the large capsules was encountered such that 26% of patients receiving treatment for more than 6 months were non-compliant. There are now no plans for oral pamidronate to be

Table 1 metastatic

Summary of phase II/III breast cancer

Phase II i.v. pamidronate (9 studies, n=323) Oral pamidronate (I study, n=47)

Phase III Oral clodronate (2 studies, n=207) Oral pamidronate (1 study, n=161) iv. pamidronate (4 studies, n=1452)

= quality

of bisphosphonates

Improvements in pain and analgesic Sclerosis of lytic lesions in 25% Modest improvement Occasional sclerosis

i.v./im codronate (5 studies, n=I 10) Oral clodronate (2 studies, n=124)

QOL

studies

in

use in 50%

in pain of lytic lesions

Improvements

in pain and analgesic

No significant

clinical

use

improvement

Reduced

vertebral

fractures

Reduced

skeletal

complications

Significant Improved Prolonged

reduction in all skeletal complications pain, analgesic use and QOL time to progression in bone

of life, i.v. = intravenous.

and hypercalcaemia

marketed due to the poor gastro-intestinal tolerability of oral amino-bisphosphonates. However, van Holten and colleagues reported an influential study of enteric-coated oral pamidronate which was produced within their hospital pharmacy.14 One hundred and sixty-one women with bone metastases from breast cancer were randomized to standard anticancer treatment with or without oral pamidronate, initially at a dose of 600 mg/day but subsequently reduced to 300 mg/day because of poor gastro-intestinal tolerability. A significant reduction in skeletal morbidity with a reduction in pathological fractures, episodes of severe bone pain and hypercalcaemia leading to a reduction in radiotherapy requirements and the need to change the underlying systemic treatment was reported. In the first randomized study of intravenous pamidronate, Conte et al. randomized 295 patients with breast cancer and bone metastases in a multicentre open trial, to standard chemotherapy alone or chemotherapy plus intravenous pamidronate 45 mg every 3 weeks - a dose-intensity of pamidronate which is now considered suboptimaLi5 A blinded, extramural review of the serial radiographs revealed a 48% increase in the median time to progression in bone in favour of the patient group who received pamidronate (249 vs 168 days - P = 0.02). Additionally, a marked improvement in pain was seen more often in the pamidronate group (44% vs 30%, P = 0.025) indicating that intravenous pamidronate adds to the symptom relief achieved by chemotherapy alone. Similar results to these were seen also in a randomized trial from Scandinavia of 401 patients receiving chemotherapy with either pamidronate 60 mg every 4 weeks or a placebo infusion.16 The time to first skeletal complication and number of events were significantly less with pamidronate. The median times to symptoms of skeletal progression were 9 and 14 months for the pamidronate and placebo groups respectively. The results of two double-blind, placebo-controlled trials of 90 mg pamidronate infusions every 3 to 4 weeks in addition to cytotoxic or endocrine treatments for breast cancer patients with lytic bone metastases have also been published.“,” These two studies were of similar design, with the exception of the systemic anticancer treatment at study entry, with patients receiving 90 mg pamidronate (or placebo) infusions every 3 to 4 weeks in addition to cytotoxic or endocrine treatments. Three hundred and eighty-two patients were randomized in the chemotherapy study. The time to first skeletal related episode (excluding hypercalcaemia of malignancy (HCM)) was 7 months in the placebo group (i.e. with chemotherapy alone) and 14 months in the pamidronate group (P = < 0.01). The difference in the two groups was apparent within 4-5 months of treatment and was maintained for at least 2 years. The proportion of pamidronate patients having any skeletal complications at 24 months was 50% compared with 70% for the placebo

Bisphosphonates in prevention and treatment patients (P = < O.OOl).” A significant reduction in all skeletal complications was seen with the percentage of patients experiencing a pathological fracture (36% vs 49%, P = 0.014), requiring radiation therapy to bone (28% vs 45%, P = < O.OOl)), requiring surgery to bone (5% vs 12%, P = < 0.01) and developing HCM (7% vs 15%, P = 0.01) all favourably influenced. There was no effect on survival. Three hundred and seventy-four patients took part in the endocrine study. The time to first SRE (excluding HCM) was 6 months in the placebo group (i.e. with endocrine therapy alone) and 10 months in the pamidronate group (P = < 0.049). Again the effect was maintained for at least 2 years. The proportion of pamidronate patients having any skeletal complications at 24 months was 56% compared with 67% for the placebo patients (P = 0.027). Survival was not influenced.

TREATMENT

OF METASTATIC

BONE PAIN

Radiotherapy remains the treatment of choice for localized bone pain but many patients have widespread poorly localized bone pain while others will experience recurrence of pain in previously irradiated skeletal sites. The bisphosphonates provide an alternative treatment approach to the management of these patients. Most experience with bisphosphonates for bone pain is from their use for skeletal metastases from advanced breast cancer. The majority of studies have been with pamidronate, but clodronate will also relieve pain.20 Clodronate has a relatively short duration of action in comparison to pamidronate.” As a result, infusions of clodronate every lo-14 days would probably be necessary to provide durable symptom control whereas pamidronate is given every 4-8 weeks.“,” To obtain optimal effects, the intravenous route is necessary, at least until more potent and well tolerated oral bisphosphonates have been developed, as it has not been demonstrated that any of the currently available oral bisphosphonates, in the absence of systemic anticancer treatment, can reduce metastatic bone pain to any clinically significant degree.” Our own studies of single infusions of high dose pamidronate (in the absence of specific anticancer treatments) have demonstrated that subjective benefit is seen in about one-half of patients2” and that the effect of bisphosphonates on pain seems to be independent of the radiographic appearance of the metastases, with sclerotic lesions responding similarly to lytic metastases. Additionally, these studies identified an important link between metastatic bone pain and the rate of bone resorption. Patients achieving a ~50% reduction in deoxypyridinoline (Dpd) were more likely to respond than those with a < 50% fall in this specific marker of bone resorption

59

(P=~0.05).~~ In addition, as patients returned requesting further treatment because of an increase in bone pain, the levels of Dpd were noted also to be rising at this time. In a more recent study from our institution, the relationships between bone pain and bone resorption rates have been evaluated more thoroughly.” Firstly, the pretreatment values of Ntx (N-terminal protein-bound crosslinking fragment of type 1 collagen) predicted for clinical response to treatment. Patients with an initial NTx value more than twice the upper limit of normal (13%) rarely showed a response to therapy, while clinical response was frequent (63%) in those patients with pretreatment levels of NTx below this cut-off level. Secondly, all patients in whom the rate of bone resorption, as measured by NTx, did not return into the normal range after treatment failed to achieve a clinical response, while if suppression of bone resorption was achieved or marker levels were always within the normal range, the frequency of reponse was much higher (59% - P < 0.01). These results suggest that patients with bone metastases and a very high rate of bone resorption will probably respond poorly to bisphosphonates, and that the aim of bisphosphonate treatment should be to restore the rate of bone resorption to normal. This is similar to the aims of bisphosphonate treatments for osteoporosis and Paget’s disease of bone. If these results continue to be confirmed by others, patients most likely to benefit from bisphosphonate treatment could in the future be selected on the basis of biochemical measures of bone resorption, and treatment only continued in those patients where the rate of bone resorption can be successfully controlled. For patients with more aggressive disease, more potent bisphosphonates, a higher dose or dose-intensity, may be required.

PREVENTION

OF BONE METASTASES

There are numerous animal studies indicating that bisphosphonates can prevent the development of metastastic bone disease,‘6 and attention is now being concentrated onto whether prophylactic bisphosphonates will be useful in the human situation. In the clinical situation, three studies with oral clodronate give cause for optimism.‘7-‘y The first small study, conducted with 133 women with recurrent extraskeletal breast cancer, reported a reduction in the number of bone metastases, although no effect on the actual number of patients with skeletal involvement or the time to first bone recurrence.” More recently, Powles and colleagues have reported a reduction in the development of bone metastases in a study of 1079 women with primary operable breast cancer. After a median follow-up of around 4 years, only 28 (5.2%) patients on clodronate had developed definite bone meta-

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The Breast

stases compared with 44 (8.1%) on placebo (P = 0.054). A larger effect was seen in post-menopausal women, perhaps due to their naturally higher bone turnover following ovarian failure.28 The third, and most interesting study is from Germany. Two hundred and eighty-four patients without overt evidence of metastatic disease, but selected on the basis of breast cancer cells in the bone marrow identified by immunocytochemistry, were randomized to receive oral clodronate or allocated to a control group. The two groups were well balanced for prognostic factors and use of standard adjuvant treatments, and followed an identical follow-up protocol. After a median follow-up of 36 months, those randomized to clodronate had a reduced incidence of bone metastases (11 vs 25, P = < 0.002) and, most suprisingly, a reduction in extra-skeletal metastases as we11.29Overall 19 patients (13%) treated with clodronate developed visceral metastases compared with 42 (29%) without bisphosphonate treatment (P < 0.001). The effects on extraskeletal metastases are difficult to explain but suggest that, in these patients with ‘in transit’ micrometastases, the growth factors and cytokines normally released from bone are necessary for tumour cell survival. To confirm the potential use of bisphosphonates for prevention of bone metastases adequately will require very large randomized trials. However, confirmation, coupled with the known positive effects of bisphosphonates on bone mass30 would make routine prescription of adjuvant bisphosphonate treatment a very high priority.

SELECTION OF PATIENTS FOR BISPHOSPHONATE TREATMENT At present, other than for the treatment of osteoporosis, bisphosphonates can only be recommended for use in patients with established metastatic disease. But should all women with bone metastases from breast cancer receive bisphosphonates?23 As indicated above, only around one-half of patients show symptomatic improvement from intravenous pamidronate and thus can be personally shown to benefit from treatment. In view of the drug costs and relative inconvenience of intravenous treatment it would clearly be advantageous to be able to identify patients for whom there is a high probability of bisphosphonate treatments either reducing skeletal morbidity or relieving metastatic bone pain. The median survival after first recurrence of breast cancer in bone is 24 months, in marked contrast to those with first recurrence of breast cancer in the liver (3 months).3’ The probability of survival with bone metastases in advanced breast cancer is influenced by the subsequent development of metastases at extra-osseus sites,32and there are a number

of factors which predict for whether the disease is likely to remain confined to the skeleton. Patients with bone only disease are more likely at diagnosis to be older, postmenopausal women with invasive lobular carcinoma with little or no involvement of axillary lymph nodes at the time of diagnosis, and less likely to have poorly differentiated ductal grade III tumours. The probability of survival after developing bone metastases from breast cancer is also dependent on a number of inherent clinical and biological characteristics.32 Patients whose initial presentation of breast cancer is complicated by metastatic bone disease appear to have the best survival. Low histological grade, oestrogen receptor positivity, a long disease-free interval (> 3 years vs < 3 years) and premenopausal status are other (relatively) good prognostic factors. In our centre, an order of priority for bisphosphonates for patients with solid tumours has been established which takes into account a number of these factors and has been incorporated into the recently published British Association of Surgical Oncology (BASO) Guidelines on the management of metastatic bone disease.33In the author’s opinion, all patients with multiple myeloma should receive bisphosphonates from the time of diagnosis, while for patients with breast cancer, highest priority is given to patients with symptomatic bone only disease of reasonable performance status (ECOG l-2) who have failed endocrine treatment and already experienced one skeletal event. In the context of life-threatening visceral disease, bisphosphonate treatment for bone metastases from breast cancer is probably unnecessary, particularly if the bone disease is asymptomatic (Table 2). It is hoped that the biochemical predictors of symptomatic response may also prove to be relevant in identifying patients most likely to experience a reduction in skeletal morbidity from bisphosphonate treatment and could be incorporated into a priority scoring system. Because bisphosphonates are providing supportive care, reducing the rate of skeletal morbidity but not necessarily abolishing it, the criteria for stopping their administration are different from those used for classical antineoplastic drugs and they should not necessarily be stopped when a skeletal event occurs or when there is progression in bone.

CONCLUSIONS

AND FUTURE DEVELOPMENTS

Over the next few years, we can expect the use of bisphosphonates in breast cancer to increase rapidly. Large randomized clinical trials will continue to be important but, in addition, comprehensive economic evaluation to assess the impact of this new treatment approach on the use of healthcare resources, and small detailed biochemical studies to determine the clinical relevance of potency, dose and schedule will be required.

Bisphosphonates in prevention and treatment Table 2 Suggested prioritization of bisphosphonate metastatic bone disease. The score for an individual from which the relative priority for recommending bisphosphonate treatment can be judged Tumour

treatment for patient is calculated repeated/long-term

type:

Disease

Myeloma Breast Other solid tumours

6 4 1

Bone (marrow) only Bone and soft tissue Bone and visceral disease

3 2 I

Previous skeletal Bone pain Asymptomatic

3 2 1

extent:

Bone morbidity:

ECOG

performance I,2 0.3 4

Underlying

Good

event +/- bone pain

status: 3 2 I

treatment: Chemotherapy or endocrine resisitant Potentially endocrine sensitive

prognostic

factors (breast cancer): Disease-free interval > 3 years Premenopausal Ductal grade 1 or 2 or lobular histology Bone metastastases at initial presentation Total

score

>15 11-15 6-10 <5

2 1 I I 1 1

Highest priority Moderate priority Low priority Not recommended

During the next few years bisphosphonates with up to a thousand times the relative potency of pamidronate will be evaluated in clinical trials. Will these new agents prove to be more effective than pamidronate? Our recent biochemical data suggest that 90-120 mg of pamidronate is already producing adequate inhibition of the rate of bone resorption in both normocalcaemic” and hypercalcaemic patients2* and that extra doses only maintain rather than increase the inhibitory effect. More potent bisphosphonates may not be clinically superior but simply enable more convenient intravenous bolus administration and the development of reliable oral or transdermal formulations. However, a reduction in the problems associated with bone metastases is a realistic prospect for the many women who develop breast cancer.

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3 1. 32.

33.

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