Introduction

For women with breast cancer, bone metastases are the most common site of metastatic spread [7, 23]. Over 70% of women with metastatic breast cancer will develop bone metastases at some time during the course of their disease, causing significant morbidity due to pain, pathological fractures, hypercalcemia, and spinal cord compression [26, 27]. Clinical studies have shown that bisphosphonates in advanced breast cancer can decrease skeletal morbidity, including pain, and improve quality of life [9, 11, 17, 18, 21, 28, 29, 30]. There may be a trend towards a reduced use of radiotherapy for bone pain with the increased use of bisphosphonates. However, results from clinical studies [3, 4, 1] and a recent meta-analysis [31] indicate that the pain relief obtained with bisphosphonate treatment alone may not be optimal. We therefore undertook a retrospective review of the utilization rate of palliative radiotherapy for breast cancer patients with bone metastases treated with bisphosphonates before and after 1998 when the first guideline on bisphosphonates use was published by Cancer Care Ontario [6]. These guidelines allowed the use of bisphosphonates at the time of diagnosis of bone metastases in women with breast cancer. The funding formula associated with the guideline allowed for oral clodronate (800 mg twice a day) to be prescribed first, and pamidronate could be subsequently used only if the patient developed intolerable side effects with oral clodronate.

Methods

All breast cancer patients at our cancer center receiving pamidronate or clodronate at any time from January 2000 to December 2001 were identified. Patient medical records, diagnostic imaging, and laboratory reports were examined. The dates of diagnosis of bone metastases, the start dates of bisphosphonates, whether palliative radiotherapy was employed, and the dates of radiation therapy were extracted and grouped yearly by the reference year of 1998. Data was then analyzed for the following:

  1. 1.

    The percentage of patients on bisphosphonates who also received palliative radiotherapy for bone metastases

  2. 2.

    Whether bisphosphonates or palliative radiotherapy was the first-line therapy, and

  3. 3.

    The time to initiation to each therapy.

Other data collected, using a standardized data collection form, included patient demographics, systemic therapies and clinical outcomes, skeletal-related events (defined as pathological bone fracture, spinal-cord compression, bone metastases progression, tumor-induced hypercalcemia, surgery to bone, and radiation to bone) occurring between the time the bisphosphonate was initiated and the end of the study period.

Pharmacy records were evaluated, and it was assumed that oral clodronate treatment was initiated on the same date as the first outpatient prescription. It was also assumed that administration of oral clodronate was continued if a subsequent copy of an outpatient prescription was filed in the chart or if a clinician’s report in progress notes confirmed that the agent had been continued. To identify the doses and dates of intravenous administrations of a bisphosphonate, the chemotherapy order section of the patient’s chart was consulted. To confirm that administration of the intravenous drug had actually occurred, the presence of the administering nurse’s signature on the prescription was verified during data abstraction. Radiation records were checked for the delivery of palliative radiotherapy for bone metastases.

Patients were excluded from this analysis if they were documented as receiving bisphosphonates for the management of osteoporosis. Patients with concomitant malignancies, those transferred from other institutions, and those who received intermittent doses of bisphosphonates for the treatment of tumor-induced hypercalcemia were also excluded.

Results

One hundred and twenty-eight patients were eligible for the retrospective review. The mean age of the patients at the time of breast cancer diagnosis was 51 (range 26–86) years. Of those patients, 52%, 42%, and 6% were pre-, post-, or perimenopausal at that time (Table 1). Details about clinical treatments and complications are listed in Table 2. At the time of this analysis, 60 (46.5%), 60 (46.5%), and 8 (7.0%) of patients were alive, dead, or lost to follow-up, respectively.

Table 1 Patient demographics and clinical characteristics. ER estrogen receptor, HER-2 human EGF receptor-2
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Table 2 Patient clinical characteristics following the diagnosis of bone disease. BP bisphosphonates, SRE skeletal-related events
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Of the 128 patients, 35 (27%) had the bone metastases diagnosed before January 1, 1998 (the effective date of the provincial bisphosphonate guidelines). Twenty-seven (77%) received palliative radiotherapy for their bone metastases also. Ninety-three of 128 patients had the bone metastases diagnosed after January 1, 1998. Sixty-seven of 93 patients (72%) received palliative radiotherapy (Table 3). The percentage of patients receiving bisphosphonates for treatment of bone metastases who also received palliative radiotherapy to bone remained relatively constant over our study period—in the range of 70%. The sites of radiotherapy included trunk (37%) and extremities (63%). The radiation fractionations employed were a single 8 Gy (24%), 20 Gy in 5 daily fractions (58%), and others (18%).

Table 3 Utilization of radiation therapy
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In the pre-1998 era, of the 35 patients who received bisphosphonates, 15 (42.9%) had radiotherapy delivered prior to the initiation of bisphosphonates. In the post-1998 era, of the 67 patients who received bisphosphonates, 23 (34.3%) had radiotherapy as the initial therapy. There was a trend toward the use of bisphosphonates as the initial therapy after 1998 (Fig. 1). Fig. 2 shows there was a trend toward the rapid initiation of treatment of bone metastases in both bisphosphonates and palliative radiotherapy. There has been a marked improvement in the time between the diagnosis of bone metastases and the commencement of bisphosphonates—from a median of 446 days before 1998 to 21 days in 2001. At the same time, there was also an improvement in time between diagnosis of bone metastases and initiation of palliative radiotherapy—from a median of 265 days before 1998 to 49 days in 2001.

Fig. 1
figure 1

Radiation therapy versus bisphosphonates—first-line therapy

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Fig. 2
figure 2

Time to treatment—median time (in days) from diagnosis of bone metastases to initiation of therapy

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Discussion

The majority of women with metastatic breast cancer will either present with or subsequently develop bone metastases. Those with bone-only or dominant disease typically have a longer survival when compared with other primary cancers, with a median survival of 2–3 years. However, their survival will be significantly shortened if bone-related complications, such as pathological fractures, spinal-cord compression, or hypercalcemia of malignancy, develop [8, 15]. Aggressive treatments are therefore called for to improve the quality of life in this group of patients. Emerging information suggests that earlier intervention may result in the delay or even prevention of skeletal complications.

Palliative radiotherapy has been employed for decades in the treatment of bone metastases. In a recent meta-analysis of 3,260 trial patients, a complete response of pain was achieved in 30%, and the overall response rate was 60%. When the analysis was restricted to evaluated patients alone, the overall response rate to palliative radiotherapy was 73% [32]. There is also evidence that breast cancer patients with bone metastases respond better to palliative radiotherapy when compared with other histologies [25, 19, 5]. Morbidity associated with palliative radiotherapy for bone metastases is low [32].

Radiation therapy is also effective in prevention of impending fractures and promotion of healing in pathological fractures. Bessler and Weber reported 80% stabilization of bone destruction and 50% reossification after radiotherapy [2]. Garmatis and Chu found good recalcification in 80% of bony metastases in breast cancer patients treated with radiotherapy [14]. Koswig et al. employed CT density measurements to determine the remineralization of lytic bone lesions in breast cancer patients treated with palliative radiotherapy. At the 6-month follow-up, bone density was significantly increased to an average of 173% and 120% following 30 Gy/10 fractions and a single 8 Gy fraction respectively [20].

The bisphosphonates are potent inhibitors of bone resorption. The results of randomized controlled trials comparing a bisphosphonate with either placebo or no treatment in secondary prophylaxis (i.e., in patients with breast cancer and established bone metastases) have shown that once bone metastases are present, the use of bisphosphonates in addition to first-line chemotherapy or hormonal therapy can significantly reduce skeletal related events [27, 9, 11, 17, 18, 21, 28, 29, 30, 10, 13, 12, 22, 24]. These include bone pain and the need for radiation therapy. There is speculation that radiation therapy has not been as often utilized as before since the introduction of bisphosphonates.

However, bisphosphonates have been associated with modest improvement in pain control in several randomized trials of clodronate, pamidronate, ibandronate, and zoledronate in patients with breast cancer and bone metastases [3, 4, 1]. A recent meta-analysis in the Cochrane Library on bisphosphonates for the relief of pain secondary to bone metastases, 30 randomized controlled studies with a total of 3,682 subjects were examined. For the proportion of patients with pain relief (eight studies), pooled data showed benefits for the treatment group, with a number needed to treat (NNT) at 4 weeks of 11 (95% CI 6–36) and at 12 weeks of 7 (95% CI 5–12). One study showed a small improvement in quality of life for the treatment group at 4 weeks. The authors conclude there is evidence to support the effectiveness of bisphosphonates in providing some pain relief for bone metastases. There is insufficient evidence to recommend bisphosphonates for immediate effect and as first-line therapy for pain relief. Bisphosphonates should be considered where analgesics and radiotherapy are inadequate for the management of painful bone metastases [31]. Current guidelines recommend that when bisphosphonates are used for pain relief, they should be given in addition to, rather than instead of, other treatments for pain relief such as analgesics and radiotherapy [16]. The purpose of this study was to examine if patients with bone metastases were less readily referred for palliative radiotherapy.

The utilization rates of palliative radiotherapy have not decreased significantly with the use of bisphosphonates in our center. The use of hypofractionated radiotherapy (a single fraction or five treatments) may have facilitated the integration of radiotherapy with other systemic therapies by causing less interference to their scheduling. Moreover, there is a trend towards the rapid initiation of treatment of bone metastases. Bisphosphonate therapy is delivered earlier and also as the initial therapy for bone metastases in breast cancer. This is to be encouraged so as to improve the quality of life in our patients. However, our study has a small sample size. We only managed to study the longer-term survival of breast cancer patients for whom their bone metastases were diagnosed before 1998.

Nevertheless, our study illustrates that palliative radiation therapy should be recommended as complimentary to bisphosphonates to further improve patients’ pain and quality of life. It should be employed earlier in the course of metastatic disease for symptomatic bone disease rather than as salvage to failed bisphosphonates.