Novel therapeutic approaches to cancer patients with bone metastasis

Critical Reviews in Oncology/Hematology 40 (2001) 239– 250 www.elsevier.com/locate/critrevonc

Novel therapeutic approaches to cancer patients with bone metastasis R. Maisano a*, S. Pergolizzi b, S. Cascinu c a

IST (Istituto Nazionale per la Ricerca sul Cancro) Geno6a, Sez. Dec. Messina, Italy Istituto di Scienze Radiologiche, Di6isione di Radioterapia, Uni6ersita` degli Studi di Messina, Italy c Dipartimento di Patologia Umana, Di6isione di Oncologia Medica-Uni6ersita` degli Studi di Messina, Italy b

Accepted 21 December 2000

Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1. Skeletal complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

240 240

2. Bisphosphonates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Bisphosphonates as single agent for tumor-induced hypercalcaemia and metastases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Bisphosphonates in combination with systemic therapy . . . . . . . . . . 2.3. Bisphosphonates for maintenance of skeletal health in breast cancer . . 2.4. Pharmaco-economic considerations. . . . . . . . . . . . . . . . . . . . . .

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241 242 244 244

3. New bisphosphonates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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4. Radiation therapy . . . . . . . . . 4.1. Local-field radiation therapy 4.2. Wide field radiation therapy 4.3. Radionuclide therapy. . . . .

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5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Biographies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Abstract Bone metastases are a common event in advanced cancer. Breast, lung, prostate and thyroid neoplasms have striking osteotropism. Bone metastatic cancer may be associated with catastrophic consequences for the patients. Therefore, new strategies * Corresponding author. Present address: Divisione di Oncologia Medica, Pad. H, 5° piano, Azienda Policlinico Universitario, Via Consolare Valeria, Gazzi, 98147 Messina, Italy. Tel.: + 39-090-391604; fax: +39-090-2213231. E-mail address: [email protected] (R. Maisano). 1040-8428/01/$ - see front matter © 2001 Elsevier Science Ireland Ltd. All rights reserved. PII: S 1 0 4 0 - 8 4 2 8 ( 0 1 ) 0 0 0 9 2 - 0

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are warranted in order to reduce the incidence of bone metastases and to palliative established skeletal disease. External beam radiation therapy, endocrine treatments, chemotherapy, bisphosphonates and radioisotopes are all important. Bisphosphonates have become the treatment of choice for tumor-induced hypercalcaemia and more recently they have been used alone or in combination with cytotoxic agents in the palliative treatment of patients with bone metastases. The results are encouraging. Currently, new bisphosphonates that are a hundred times more powerful with respect to clodronate and pamidronate are under investigation. The treatment of metastases to bone and mechanisms of pain relief after radiation therapy are poorly understood. Up to date, there are not standard criteria for the irradiation of bone metastases and bone pain relief may be reached using a variety of fractionation schemes. Radionuclide therapy is the systemic use of radioisotopes for bone pain. It is currently regarded as suitable for comparison with wide-field irradiation, but appears to have major disadvantages in terms of pain relief and toxicity. © 2001 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Bone metastases; Bisphosphonates; Radiation therapy

1. Introduction Bone metastases are a common event in advanced cancer. Certain neoplasms such as breast, lung, prostate, kidney and thyroid have striking osteotropism. These cancers probably account for more than 80% of cases of metastatic bone disease [1]. Since they have an important impact on patients’ quality of life, new strategies are warranted both in order to reduce the incidence of bone metastases and to palliate established skeletal disease. According to radiographic appearance bone metastases are lytic, sclerotic or mixed. For example, lytic lesions are common in multiple myeloma, breast, lung, thyroid, renal, melanoma and gastrointestinal cancers. The sclerotic aspect is typically seen in prostate, but also in breast, lung, carcinoid and medulloblastoma neoplasms. Usually both processes are present in the bone lesion. Osteolysis is due to the activation of osteoclasts in the tumour cell microenvironment [2– 4], mediated by the parathyroid hormone-related peptide (PTH-rP) and other mediators produced by activated host immune cells by the presence of the tumor in this microenvironment. Conversely, sclerotic lesions refer to new bone around the tumour-cell deposits in the marrow cavity. There is less information on the mechanism responsible for osteoblastic metastases. Many mediators have been implicated in bone formation. These include the bone-derived growth factors, such as the bone morphogenetic proteins, the fibroblast growth factors and some members of the TGFb family [5,6]. Recently, endothelin-1 which is a powerful mitogen for osteoblasts and is produced by normal prostate cells has been recognised as a new mediator implicated in osteoblastic metastasis [7].

Hypercalcemia is the most common metabolic complication of malignant disease. It is frequent in squamous cell carcinomas of the lung, adenocarcinomas of the breast and kidney as well as in multiple myeloma and lymphoma. In cancer patients hypercalcemia is related to increased bone resorption in multifocal metastases or as metabolic stimulus by PTH-rP or other mediators of osteolysis. Other mechanisms of hypercalcemia include impaired renal perfusion, as in multiple myeloma, in which case renal impairment may result from deposition of Bence–Jones proteins. Some lymphomas produce active metabolites of vitamin D, which increase both bone resorption and intestinal absorption of calcium. Metastatic disease of the bone reduces its loadbearing resistance and can lead to serious disability. The rates of pathologic fracture are uncertain ranging from 8 to 53% [8,9]. On the whole, the longer the duration of metastatic involvement, the greater the probability of developing pathologic fracture. The appearance of back pain in the cancer patient with radiographic spinal abnormality should alert the clinicians to the possibility of the presence of spinal cord compression. In this situation the devastating consequences require urgent diagnosis and treatment. Bone pain is the most frequent type of pain from cancer and causes considerable discomfort for patients. In the presence of bone metastases the aim of treatment is the palliation of symptoms. External beam radiation therapy, endocrine treatments, chemotherapy, bisphosphonates and radioisotopes are all important. Treatment decisions depend on several parameters, for example, if bone disease is localised or widespread, if there is evidence of extraskeletal metastases, the type of neoplasm and prior treatment history as well as disease response.

1.1. Skeletal complications 2. Bisphosphonates Bone metastatic cancer may be associated with catastrophic consequences for the patients. These include bone pain, impaired mobility, hypercalcemia, pathologic bone fracture, spinal cord or nerve root compression and bone marrow infiltration.

The principle role of osteoclast activation in the osteolysis of bone provides the rationale for the use of an osteoclast inhibitor drug such as bisphosphonates for treatment of bone metastases. Bisphosphonates are

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analogues of pyrophosphate, a natural inhibitor of bone demineralisation. They bind to hydroxyapatite crystals of the bone by adsorption, resulting in stabilisation of bone mineral and inhibition of its dissolution; moreover, it inhibits osteoclast function by various not fully understood mechanisms [10–14]. Recently, Yoneda et al. [15], in an experimental study employing animal models of bone metastasis have shown that bisphosphonates impaired the progression of bone metastases primarily through enhancing apoptosis in osteoclasts and breast cancer cells colonised in bone. Moreover, the combination of bisphosphonates with cytotoxic drugs enhanced the suppression of tumour in both bone and visceral organs, leading to prolonged survival of tumourbearing animals. In recent years, bisphosphonates have become the treatment of choice in tumourinduced hypercalcemia and more recently they have been used alone or in combination with cytotoxic agents in the palliative treatment of patients with bone metastases.

2.1. Bisphosphonates as single agent for tumor-induced hypercalcaemia and painful bone metastases Bisphosphonates are now standard therapy for tumour-induced hypercalcemia (TIH). In fact the introduction of these drugs has dramatically changed the treatment of TIH [16]. At the moment (Table 1) both clodronate at a single dose of 1500 mg [17] and pamidronate at 90 mg [18] have good activity and tolerability. Recently, a randomized study has shown the superiority of pamidronate compared with clodronate in reducing the level of calcium in the blood [19]. Forty-one patients were randomized to receive 90 mg intravenous infusion of pamidronate or 1500 mg of clodronate. Nineteen out of 19 patients in pamidronate group achieved normocalcemia and 16 out of 20 patients in clodronate group. The median duration of normocalcemia was 28 days after pamidronate and 14 days after clodronate. Radiotherapy is the treatment of choice for localised bone pain, but in the presence of poorly localised bone pain or recurrence of pain in previously irradiated skeletal sites the bisphosphonates are an alternative treatment approach. Several studies have examined the

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effects of bisphosphonates on metastatic bone pain (Table 2) above all in breast cancer patients. To date, the intravenous route has been necessary to obtain analgesic effects. This will be standard until new and well-tolerated oral bisphosphonates become available. Both clodronate and pamidronate have been employed. There are randomized placebo-controlled studies indicating symptomatic relief after clodronate therapy [20– 23]; for pamidronate several phase II studies showed symptomatic responses in about 50% of the patients. These data have been confirmed by Vinholes et al. [24] in a double blind, placebo-controlled, randomized trial of high-dose pamidronate for metastatic bone disease. The authors reported pain relief in 48% of patients and in the responders concomitant improvement in quality of life. Moreover, this study identified an important correlation between metastatic bone pain and rate of bone resorption. Patients with high-grade bone resorption will probably respond poorly to bisphosphonates. In this study, more specific bone resorption markers, such as deoxypyridinoline and pyridinoline were measured. These are the collagen breakdown products and N-terminal and C-terminal portions of the collagen crosslinking molecules. When bone resorption occurs, these markers are released into circulation and excreted in the urine where they can be measured by a variety of high performance liquid chromatography and immunoassay techniques. Therefore, if these data are confirmed, in patients with aggressive neoplasm or high tumour burden, intravenous high doses of pamidronate or more active bisphosphonate or concomitant anticancer therapy and bisphosphonates treatment may be required to relieve pain. The dose–effect relationship was investigated by several authors. Radziwill et al. [25] carried out an intra-patient dose escalation study with pamidronate. They conclude that a dose intensity with at least 10 mg of pamidronate per week is necessary for relevant improvement of the palliative effect in patients pre-treated with pamidronate and unsatisfactory pain control. Subsequently, Glover et al. [26] reported the data of our study. Sixty-one patients with breast cancer metastatic to bone were randomized to receive one of four intravenous pamidronate regimens for 12 weeks: 30 mg every 2 weeks, 60 mg every 4 weeks, 60 mg every 2 weeks or 90 mg every 4 weeks. At 3 months the significant relief of bone pain, in the majority of the

Table 1 Bisphosphonates in the treatment of tumour-induced hypercalcemia Authors

Drug

Patients

Dose

Results

Ref.

O’Rourke Body Purohit

Clodronate Pamidronate Clodronate vs. Pamidronate

30 160 20 19

1.5 g iv single dose 90 mg iv single dose 1.5 g iv vs. 90 mg iv

20/30 reached normocalcemia 147/160 reached normocalcemia 16/20 reached normocalcemia 19/19 reached normocalcemia

[17] [18] [19]

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Table 2 Bisphosphonates in the treatment of bone pain due to breast cancer Authors

Drug

Patients

Dose

Results

References

Martoni

Clodronate

38

300 mg iv for 7 days followed 100 mg im day for 3 weeks and finally 100 mg im on alternate days for 2 months

[20]

O’Rourke

Clodronate

84

Robertson

Clodronate

55

400 mg 1600 mg 3200 mg of oral clodronate daily for 4 weeks 1600 mg oral/day

Ernst

Clodronate

60

600 mg iv single dose

Vinholes

Pamidronate

52

120 mg iv/every 4 weeks

Cascinu

Pamidronate

64

Koeberle

Pamidronate

70

45 mg iv 60 mg iv 90 mg iv every 3 weeks 60 mg iv 90 mg iv every 3 weeks

Reduction in the intensity of pain, a more frequent reduction in the daily consumption of analgesics in clodronate group No discernible change in pain scores or analgesic requirements Significant decrease in pain scores in clodronate group Significant decrease in pain scores in clodronate group Pain relief and improvement in quality of life Pain relief in all three different doses. At 90mg faster symptom relief Pain relief in both different doses. At 90mg more pronounced remineralization

patients, was reached at the three highest doses. Thurlimann et al. [27] published the results of a prospective dose–effect study with pamidronate for pain control in patients with malignant osteolytic bone disease. Eighty patients were randomized to receive pamidronate at the doses of 30, 45, 60 and 90 mg every 4, 3 or 2 weeks. The end points were pain score, analgesic score and improvement of performance status. Regression analysis showed a close correlation between dose intensity and effect. They conclude that the best results are obtained with high dose of 60 or 90 mg of pamidronate. Recently, Cascinu et al. [28] carried out a randomized study in order to evaluate three different doses of pamidronate, 45, 60 and 90 mg intravenous every 3 weeks in 70 patients with painful osteolytic bone metastases which had failed to respond to initial treatment with hormones and/or chemotherapy. A reduction in bone pain was observed in all three dose groups, but the patients receiving 90 mg of pamidronate achieved statistically significant improvement of bone pain at the 6th week, compared with the patients receiving the 45 or 60 mg doses who achieved improvement of bone pain at 12th and 9th week, respectively. Another randomized study performed by Koeberle et al. [29] shows the efficacy of high dose of intravenous pamidronate 60 or 90 mg every 3 weeks. Both the doses were active in terms of pain relief but the patients in the 90 mg group had more pronounced bone remineralization. These results confirm the utility of the higher dose of pamidronate in patients with painful bone metastases. Since 1983, clodronate and, later, pamidronate have been employed in order to reduce skeletal complications (Table 3). Elomaa et al. [30] reported that oral clodronate inhibits osteoclastic activity and improves

[21] [22] [23] [24] [28] [29]

symptoms in metastatic breast cancer. Subsequently, several authors have evaluated regular intravenous infusions of pamidronate, oral pamidronate and oral or intravenous infusions of clodronate. The results have been previously analysed and reported in a review article [31]. Two trials in patients with bone metastases from breast cancer, one with clodronate [32] and one with pamidronate [33] showed that the prolonged administration of these oral bisphosphonates can reduce the frequency of skeletal complications, but the authors did not report a survival benefit. In a later study, a dose response was suggested, but the high-dose group that received pamidronate 600 mg/day recorded severe gastrointestinal intolerance, leading to therapy interruption.

2.2. Bisphosphonates in combination with systemic therapy In agreement with experimental data [15,47], the use of bisphosphonates with cytotoxic agents could possibly yield better results than systemic cytostatic therapy alone. In order to evaluate this hypothesis, three randomized trials with regular intravenous infusions of pamidronate in combination with systemic therapy have been published. In the first, Conte et al. [34] enrolled 295 patients with lytic bone metastases and no previous chemotherapy to receive first line chemotherapy with or without 45 mg of pamidronate every 3 or 4 weeks until progression disease. Radiologic response was assessed in 224 patients and bone pain score was self-evaluated by the patients through a six point scale. The median time to radiologic progression was 249 days with pamidronate and 168 for the control group (P=0.02). Improvement of pain

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was also recorded in the pamidronate arm, 44 versus 30% (P =0.025), while median survival was not significantly different (592 versus 642 days). Hortobagyi and coworkers [35] randomized 382 patients to receive chemotherapy plus pamidronate 90 mg every 4 weeks for 12 cycles or chemotherapy alone. After 1 year of treatment, 43% of women in the pamidronate group compared with 56% of women in the placebo group had experienced a skeletal event (P = 0.008), and the median time to first progression was 13.1 versus 7 months (P =0.005); there was no survival advantage. The same group [36] carried out a randomized, placebo-controlled trial enrolling 372 women with lytic bone lesions from breast cancer receiving hormonaltherapy plus pamidronate 90 mg every 4 weeks for 24 cycles or hormonal therapy alone. After 24 cycles, the proportion of patients having had any skeletal complications was 56% in the pamidronate group and 67% in the control group (P = 0.027). The median time to the first skeletal complications was 10.4 months for patients receiving pamidronate versus 6.9 months for those receiving placebo (P =0.049); no survival advantage was noted. On the whole, no major toxicity was reported, whereas a rare ocular toxicity was recorded. From these data, the intravenous infusion of bisphosphonates appears to be better than the oral administration, but several questions remain unresolved. The choice between intravenous or oral administration depends on particular circumstances. Patients who receive chemotherapy are suitable for the intravenous route while the oral route would be preferred for patients who receive hormonal therapy. Moreover, the criteria about the selection of patients is still controversial; even if it is likely that patients with multiple bone lesions will benefit more than those with a solitary lesion. Finally, the optimal duration and dosage of treatment is unknown. It is likely that prolonged administration may be useful and that the higher dose of pamidronate may be more effective in patients with

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painful bone metastases, because of the faster symptom relief which is achieved. The majority of the patients with advanced prostate cancer have skeletal metastases. Most of these metastases are osteosclerotic, but this abnormal bone formation is preceded by osteoclastic activation [37]. This observation has served as the basis for the use of bisphosphonates (Table 4), even if there has been no evidence of real activity of bisphosphonates in this condition. Its efficacy in relieving pain in patients with skeletal metastases due to prostate cancer has been confirmed in a few studies. Elomaa et al. [38] randomized 99 patients with bone metastases which had failed to respond to at least one hormonal therapy, to receive oral clodronate 3.2 g/day for 1 month then 1.6 g/day for 5 months or placebo. All patients were treated with estramustine. On the experimental arm more patients were free of pain without analgesic use in the first 3 months of the trial, but this was not statistically different. Clarke et al. [39] treated 25 patients with metastatic bone disease from prostate cancer with pamidronate 30 mg weekly for 4 weeks, then 30 mg twice per month for 5 months. No other treatment was administered during the study. Eleven of 17 patients with pain at the beginning of the study were free of pain at the end. However, the absence of large, randomized, double blind trials does not permit an adequate evaluation of bisphosphonate therapy in prostate cancer [40]. In multiple myeloma, the activity and proliferation of the osteoclasts is very marked. The increase of osteoclast activity is mediated by the release of various stimulating factors [41,42]. Bisphosphonates may be of great clinical benefit in multiple myeloma. The data from completed trials support this hypothesis (Table 5). Clodronate and pamidronate have been shown to play an active role in management of multiple myeloma. Two large randomized trials of oral clodronate in multiple myeloma have been published. In the Finnish

Table 3 Bisphosphonates for the prevention of skeletal events in breast cancer patients with bone metastases Authors

Drug

Patients

Dose

Results

Ref.

Paterson

Clodronate

173

1600 mg oral/day with chemotherapy vs. placebo

[32]

Conte

Pamidronate

295

45 mg iv/3 weekly with chemotherapy vs. placebo

Hortobagyi

Pamidronate

382

90 mg iv/3-4 weekly with chemotherapy vs. placebo

Theriault

Pamidronate

372

90 mg iv/4 weekly with hormonotherapy vs. placebo

Statistically significant reduction of any skeletal complications (PB0.001); no survival advantage Statistically significant reduction of median time to disease progression in bone (PB0.02); no survival advantage Statistically significant reduction of any skeletal complications (PB0.008); no survival advantage Statistically significant reduction of any skeletal complications (PB0.027); no survival advantage

[34]

[35]

[36]

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244

Table 4 Bisphosphonates in prostate cancer Authors

Drug

Patients

Dose

Results

Ref.

Elomaa

Clodronate

99

Pamidronate

25

More patients free of pain in clodronate group, without statistical differences 11/17 patients achieved pain free at the end of the study

[38]

Clarke

3.2 g oral per day for 1 month, 1.6 g oral per day for 5 months 30 mg iv weekly for 4 weeks 30 mg iv twice monthly

study [43], 336 patients with newly diagnosed, untreated and symptomatic multiple myeloma were randomized to receive oral clodronate 2.4 g/day for 24 months or placebo. All patients received alkeran and prednisone therapy. There were no differences in nausea, diarrhoea or abdominal pain. There was a significant decrease in bone pain and in the rate of progression of lytic bone lesions (24 vs. 12%, P =0.026) for the patients who received clodronate. McCloskey and colleagues [44] carried out a randomized trial, 536 patients with recently diagnoses multiple myeloma received either oral clodronate 1600 mg daily or placebo in addition to chemotherapy. Clodronate group patients reported a 50% decrease in the proportion of severe hypercalcaemia episodes (P = 0.06) and a similar reduction in reported non-vertebral fracture (P =0.04). There was no statistically significant difference in survival between the clodronate and placebo treated patients. Subsequently, in a German trial [45] the patients randomized to receive oral clodronate in addition to intravenous alkeran and prednisone showed a significant reduction of bone pain but there was no reported difference in skeletal events between the two patients groups. The efficacy of regular pamidronate infusions in multiple myeloma was evaluated in a double blind, placebo-controlled study [46]. Three hundred and ninety-two patients were randomized to receive either 90 mg of pamidronate or placebo infusions monthly for 21 months in addition to chemotherapy. Skeletal events, defined as pathologic fracture, irradiation of or surgery of bone and spinal cord compression, occurred in 41% of the patients in the placebo arm versus 24% in the experimental arm (P B0.02). The therapeutic benefit was independent of the line of chemotherapy. There was no significant overall survival difference between the two treatment groups. Finally, in multiple myeloma chemotherapy plus bisphosphonates have shown to be superior to chemotherapy alone in patients with stage III disease with respect to bone complications. Oral clodronate has not shown a reduction in skeletal complications. At present, intravenous pamidronate is the standard treatment and should be given to all patients with active multiple myeloma, even if the optimal duration and dose of pamidronate to be used are still unknown.

[39]

2.3. Bisphosphonates for maintenance of skeletal health in breast cancer To date, the results of clinical trials indicate that suppression of evident bone metastases does not improve the survival of patients. Further, bisphosphonates have little effect on visceral organ metastases. However, several animal studies indicate that bisphosphonates can prevent the development of metastases in bone and in visceral organs [15,47]. In clinical practice this remains controversial. Recently, Diel et al. [48] reported that the combination of oral clodronate of 1600 mg per day for 2 years plus conventional anti-cancer therapies reduces the incidence of bone and visceral metastases development in primary breast cancer. On the contrary, the similar study of Saarto et al. [49] did not find any benefit with adjuvant clodronate treatment. In order to evaluate the role of bisphosphonates for prevention of bone metastases, a large randomized trial will be required preferably with new and more powerful bisphosphonates.

2.4. Pharmaco-economic considerations The large use of bisphosphonates leads to major financial costs for health care systems; moreover, this drug does not increase survival and does not affect specifically the cancer. Bisphosphonates reduce an important disease-specific complications from bone metastases and to achieve this aim need to be given over a prolonged period. Therefore, the cost-effectiveness analysis is an important topic. Several studies have stressed this issue achieving different conclusions. Hillner et al. [50] affirm that the cost of pamidronate therapy exceeded the cost savings from prevented skeletal related events in breast cancer patients with osteolysis. Other authors came to different outcomes; Gessner et al. [51] conclude that the treatment with pamidronate reduced pain significantly but did not add noticeably to the cost. Dranitsaris and Hsu’s Canadian analysis [52] affirm that even though pamidronate has a high drug acquisition cost, the results of the cost–utility analysis suggest that this agent does provide in patients with advanced breast cancer a substantial quality-adjusted survival benefit at a reasonable cost to Canadian health care system. Another study published in abstract form

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confirm these data; the use of pamidronate does not increase the cost of management of breast cancer in a variety of common situations [53]. Finally, Laakso and coworkers [54] have published a cost-benefit analysis of the Finnish multicenter trial of clodronate in multiple myeloma. They conclude that the treatment with clodronate did not significantly increase the treatment cost while the clodronate therapy delayed the progression of osteolytic lesions. In conclusion, these data seem to confirm a positive cost –benefit ratio even though ideally future randomized trials will address these financial issues directly.

3. New bisphosphonates Currently, new bisphosphonates that are a hundred times more powerful with respect to clodronate and pamidronate are under investigation. The early results on alendronate [55], zoledronate [56] and ibandronate [57] have shown that at low doses and with brief intravenous infusions they are highly effective in the treatment of metabolic bone disorders and TIH [58]. In one randomized study, three doses of intravenous ibandronate were evaluated in 147 patients with severe cancer-associated hypercalcemia. The results showed that the 2 mg dose was significantly less effective than 4 or 6 mg doses in correcting hypercalcemia. No serious drug-related adverse events were observed. The authors concluded that ibandronate is a safe and effective treatment in TIH. It is still unclear if bisphosphonate potency coincides with efficacy. Diel et al. [59] reported in abstract form the results of a randomized, double blind, placebo-controlled trial in 462 patients with bone metastases from breast cancer. One hundred and fiftythree patients received 2 mg of intravenous ibandronate every 4 weeks for a maximum of 2 years; 152 patients received 6 mg of intravenous ibandronate monthly and 157 received a placebo. Significant improvements in

245

quality of life were demonstrated for ibandronate in all functions as well as for global health status. The improvements with 6 mg dose were more pronounced than with the 2 mg dose. It is noteworthy that in this study ibandronate-treated patients had a slightly better survival compared with the placebo group. Another phase II study reported by Lipton et al. [60] compared zoledronate with pamidronate in patients with osteolytic metastases from breast cancer and multiple myeloma. Two hundred and eight patients were randomized to receive 0.4, 2 or 4 mg of zoledronate as a 5-min intravenous infusion or 90 mg of pamidronate as a 2-h infusion. The results showed that a 5-min infusion of 4 mg of zoledronate was as effective as 90 mg of pamidronate in preventing the skeletal events of osteolytic disease. The optimal dose of zoledronate has not been determined, since phase I studies of bone markers suggest that higher doses of zoledronate may be more effective for inhibiting osteolysis. Moreover, these new bisphosphonates may be active in oral formulation, as demonstrated by Coleman et al. [61] in a double blind, randomized, placebo-controlled, dose-finding study of oral ibandronate. One hundred and ten patients with bone metastases were enrolled to receive one of four oral dose levels of ibandronate (5, 10, 20 and 50 mg). The conclusions were that oral ibandronate is well-tolerated, and has clear beneficial effects on surrogate markers of bone resorption. The 20 and 50 mg doses appear to be the most promising for further studies.

4. Radiation therapy The treatment of bone metastases and mechanisms of pain relief after radiation therapy are in general poorly defined, and the published guidelines for irradiation are especially confusing because of the great variation in beneficial results of reported clinical trials and because reports include a large variety of tumor types as well as

Table 5 Bisphosphonates for the prevention of skeletal events in multiple myeloma Authors

Drug

Patients

Dose

Lahtinen

Clodronate

336

2400 mg oral per day with chemotherapy vs. placebo

McCloskey

Clodronate

536

Heim

Clodronate

157

Berenson

Pamidronate

392

Results

Statistically significant reduction of median time to disease progression in bone (PB0.026); no survival advantage 1600 mg oral per day with chemotherapy 50% decrease in the proportion of severe vs. placebo hypercalcaemia episodes (P =0.06); reduction in reported non-vertebral fracture (P = 0.04); no survival advantage 1600 mg oral per day with chemotherapy Reduction of bone pain, no reduction of vs. placebo skeletal complications; no survival advantage 90 mg iv every 4 week with chemotherapy Statistically significant reduction of skeletal vs. placebo complications (PB0.02); no survival advantage

Ref. [43]

[44]

[45]

[46]

246

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different scoring methods and reporting techniques [62]. In 1998, a work group of experts of the American College of Radiology [63] was unable to formulate standard criteria for the irradiation of bone metastases. Many authors [64– 66] have reported relief of bone pain with radiotherapy using a variety of fractionating schedules. In the treatment of metastatic bone disease, the choice of radiation fractionation, total dose, delivery technique, indication, and timing of chemotherapy use, varies among virtually all radiation oncologists. These variations are expected because of the poor prognosis in this disease and the absence of universally accepted clinical standards. Radiation therapy can be delivered using three forms of treatment; local-field radiation therapy, wide-field radiation therapy, and radionuclide therapy.

4.1. Local-field radiation therapy Local-field radiation therapy is considered the conventional treatment of bone metastases. It treats the involved bone and yields a pain relief rate of 80– 90% [67]. Local-field irradiation is delivered using photon beam from megavoltage units (from Cobalt 60 to 6– 15 MeV linear accelerators). Tong et al. [68] reported the results of a Radiation Therapy Oncology Group (RTOG) randomized study of 756 patients with both solitary and multiple sites of bone metastases using different total radiation doses and fractionations (20 versus 40.5 Gy for solitary lesions; 15 versus 20 versus 25 versus 30 Gy for multiple sites). All the schedules were considered effective and a median duration of pain relief of 12 weeks was observed. Blitzer [69] reported a re-analysis of the study by Tong in which the author combined patients with solitary and multiple metastases, giving more power to the analysis, and included need for re-treatment. Blitzer observed that a more protracted course of irradiation (270 cGy× 15 fractions for solitary lesions and 300 cGy × 10 fractions for multiple lesions) was more effective in pain control. In a recent prospective study, Arcangeli et al. [70] reported the results using three radiation schedules. Conventional fractionation: 40– 46 Gy/20 –23 fractions in 5– 5.5 weeks; Short course: 30– 36 Gy/10 –12 fractions in 2– 2.3 weeks; Fast course: 8–28 Gy/1 –4 consecutive fractions. A statistically significant difference in pain relief was detected among the several ranges of total dose delivered with 81, 65, and 46% complete pain relief rates reported 22 in the 40–46, 30 – 36 (P =0.03), and 8–28 Gy (P = 0.0001) dose ranges, respectively. There has been considerable interest in the administration of large, single fractions for bone metastases. A Royal Marsden Hospital randomized study [71], compared a single fraction of 8 Gy versus 30 Gy/10 fractions. No difference was found, in terms of speed of

onset or duration of pain relief, between the two groups. In a review on local field RT for bone metastases, Ratanatharathorn et al. [72] affirmed that higher dose, fractionated treatments produced a greater frequency, magnitude, and duration of response with an improved ‘net pain relief’ with respect to lower dose single-fraction regimens. We think that it is important to stress that patients with predominantly bone metastases have longer durations of survival than patients with predominantly visceral metastases [73]. With long survival times, uncontrolled progression in the skeletal system may result in a lengthy period of severe and disabling symptoms. Generally, an ambulatory patient who has localised pain, fewer than four sites of metastases without visceral sites (lung, liver, central nervous system), and no hypercalcemia is an excellent candidate for successful long-term palliation and survival [74]. In this instance higher doses of RT may result in longer symptomatic control of bone pain and should be employed. A ‘short course’ palliative irradiation is delivered when there is no expectation of the patient surviving for a long period of time. Thus, the aim of this treatment is the patient’s comfort and improvement in quality of life.

4.2. Wide field radiation therapy Wide field (half-body, hemibody) radiation therapy is a form of ‘systemic’ radiation therapy and can be used as primary palliative therapy for widespread symptomatic bone metastases [75,76], or as an adjuvant to local-field irradiation to reduce the later expression of occult metastases and/or to reduce the frequency of re-treatment [77]. Wide field irradiation provides pain relief for 64– 100% of patients; and approximately 50–66% of patients maintain pain relief for the remainder of their lives [62]. The radiation fields must be shaped to reduce exposure of sensitive structures such as lung, gut, kidney, and liver; moreover, critical structures that have received previous irradiation up to tolerance must be blocked. Wide field irradiation is delivered using MeV units (from Co 60 to 15 MeV linear accelerators) given through antero-posterior and postero-anterior portals. It is possible to distinguish: “ Upper wide-field treatments (from skull or C1 to L2 –3). “ Lower wide-field treatments (from L3–4 to above the knees). “ Mid-body wide-field treatments (from L1 to upper third of the femurs). The optimal single-dose for upper wide field is 6 Gy, and for lower or mid-body wide field it is 8 Gy [75]. Zelefsky et al. [76] used wide-field irradiation in a fractionated schedule to a higher total dose (25–30 Gy in 8–10 fractions, three fraction per week).

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Table 6 Characteristics of radioisotopes used in the treatment of bone metastases Radioisotope

Emission

Energy

Half-life (days)

Side effects

Strontium 89

Beta

1.46 MeV

50.6

Rhenium 186

Beta (91%) Gamma (9%) Beta (87%) Gamma (13%)

1.07 MeV 137 KeV 0.81 MeV 130 KeV

3.8

Platelet and leucocyte depletion (nadir at 4 weeks); pain flare; flushing sensation Platelet and leukocyte depletion (nadir 4–6 weeks); pain flare

1.9

Reversible myelosuppression

Samarium 153

4.3. Radionuclide therapy Radionuclide therapy is the systemic use of radioisotopes (unsealed sources) for bone pain. It is currently regarded as suitable for comparison with wide-field irradiation, but appears to have major disadvantages in terms of pain relief and toxicity. Desirable characteristics of therapeutic unsealed radioisotopes include a high linear energy transfer (in order to destroy tumour tissue while sparing healthy structures); a half-life measured in h-days; a minimal exposure to medical staff. The unsealed radioisotopes used in the treatment of metastatic disease to bone are: Strontium 89 (89St); Rhenium 186 (186Re), and Samarium 153 (153Sm). New radiopharmaceutical agents, such as tin 117 m (4 + ) diethylene triaminepentacetic acid (DTPA) and Rhenium-188 (tin) hydroxyethylidine diphosphonate have been used up in phase I trials. Table 6 shows the main characteristics of 89St, 186Re, and 153Sm. Response rates for pain relief using Strontium 89 in the treatment of bone metastases range from 37 to 91%; onset of pain relief occurs at 10–20 days, maximum relief requires up to 6 weeks, and the median duration of pain relief is 12 weeks [62]. Han et al. [78], in a recent paper, using 186Reetidronate and strict pain assessment criteria, reported a response of 58% in the palliative treatment of metastatic bone pain originating from breast cancer. Lamb et al. [79] obtained some degree of pain relief in 72% of patients with bone metastases using Samarium 153 lexidronam. Radionuclide therapy should be not first employed when a ‘pending fracture’ is present, or in case of back pain with suspicion of medullary epidural compression. In these instances systemic treatment with radioisotopes may follow surgical therapy and/or external beam irradiation. Further research to better define the clinical indications of hemibody irradiation and Strontium 89 is needed [63].

5. Conclusions In the natural history of cancers, the metastatization to bone is a common event. Certain neoplasms such as

breast, prostate, lung, kidney and thyroid have striking osteotropism. The bone metastases have an important impact on patient’s quality of life, therefore new strategies in order to reduce the incidence of bone metastases and to palliate established skeletal disease are warranted. Skeletal cancer is best managed with multimodality approach. Radiation therapy, endocrine treatments, chemotherapy, surgery, bisphosphonates and radioisotopes are all important. We have focused on the use of bisphosphonates, radiation therapy and radioisotopes in the treatment of bone metastatic disease. Bisphosphonates are the standard therapy for TIH. Moreover, pamidronate as single agent, delivered by intravenous route at the dose of 60 or 90 mg every 3 or 4 weeks has obtained analgesic effect in patients with painful bone metastases above all in breast cancer patients. The combination of bisphosphonates with systemic therapy has been used in breast and prostate cancer with bone metastases and in multiple myeloma with at least one osteolytic lesion. The concomitant therapy has reached a significant statistical reduction of skeletal related events in breast cancer and multiple myeloma without survival advantage. Intravenous pamidronate 90 mg delivered every 3 or 4 weeks given for 2 years or until patient refusal, unacceptable toxicity or death is recommended in these instances. Another field investigation regards the use of antiosteoclastic therapy in the primary prevention of bone metastases. Available clinical data are inconsistent and specific randomized studies are needed. Recently, new bisphosphonates that are a hundred times more powerful with respect to clodronate and pamidronate are under investigation. They may be delivered by intravenous and oral route; the early data of clinical studies show a good activity in TIH and in the control of bone pain. Further studies are recommended in order to provide information on relative clinical efficacy. The mechanisms of pain relief after radiation therapy are poorly understood. The published guidelines for bone irradiation are confusing because of the great variation in beneficial results of reported clinical trials and because reports include a large variety of tumor types as well as different scoring methods and reporting techniques. Radiation therapy can be delivered using three forms of treatment: local and wide-field radiotherapy and ra-

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dionuclide therapy. Relief of bone pain was reported by a variety of fractionation schemes. Radionuclide therapy is the systemic use of radioisotopes for bone pain, the comparison with wide-field irradiation appears to have major disadvantages in terms of pain relief and toxicity. The unsealed radioisotopes used in the treatment of metastatic disease to bone are: Strontium 89 (89St), rhenium 186 (186Rh) and Samarium 153 (153Sm). Radionuclide therapy should not be first employed when a ‘pending fracture’ is present or in case of back pain with suspicion of medullary epidural compression. In these instances surgical therapy and/or external beam irradiation are needed. Reviewers Dr Pierfranco Conte, Primario U.O. Oncologia Medica, Azienda Ospedaliera Pisana — Pisa, Via Roma 67, I-56126 Pisa, Italy. Dr Carla Ripamonti, Attending Physician, Department of Palliative Care, National Cancer Institute, Via Venezian 1, I-20133 Milan, Italy. Dr Beat Thu¨ rlimann, Kantonsspital, Division of Oncology/Hematology, Department of Internal Medicine C, CH-9007 St. Gallen, Switzerland. Dr Richard L. Theriault, The University of Texas MD Anderson Cancer Center, Departnent of Breast Medical Oncology, 1515 Holcombe Blvd, Box 56, Houston, TX 77001-0056, USA. Acknowledgements The authors would like to thank Emma Sardella for the editing of this paper. References [1] Rubens RD, Coleman RE. Bone metastases. In: Abeloff MD, Armitage JO, Lichter AS, editors. Clinical Oncology. New York: Churchill Linvingstone, 1995:643 – 65. [2] Mundy GR, Raisz LG, Cooper RA, et al. Evidence for the secretion of an osteoclast stimulating factor in myeloma. New Engl J Med 1974;291:1041 –6. [3] Boyde A, Maconnachie E, Reid SA, et al. Scanning electron microscopy in bone pathology: review of methods. Potential and applications. Scan Electr Microsc 1986;4:1537 –54. [4] Firkin F, Seymour JF, Watson AM, et al. Parathyroid hormonerelated protein in hypercalcemia associated with haematological malignancy. Br J Haematol 1996;94:486 –92. [5] Harris SE, Harris M, Mahy M, et al. Expression of bone morphogenetic proteins by normal rat and human prostate and prostate cancer cells. Prostate 1994;24:204 – 11. [6] Izbicka E, Dunstan C, Esparza J, et al. Human amniotic tumor which induces new bone formation in vivo produces a growth regulatory activity in vitro for osteoblasts identified as an extended form of basic fibroblast growth factor (bFGF). Cancer Res 1996;56:633 – 6.

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Biographies Roberto Maisano received a MD from Messina University in 1985 and fellowship in Oncology in 1988. He is currently Associate Attending of National Cancer Institute, Genova Satellite Unit of Messina. Stefano Pergolizzi received a MD from Messina University in 1986 and fellowship in Oncology in 1989 and in Radiotherapy in 1993. He is presently Assistant Professor in Radiation Oncology at the University of Messina. Stefano Cascinu received a MD from Ancona University in 1985 and fellowship in Oncology in 1988. He is currently Professor in Oncology at Messina University.