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Keywords:

  • bisphosphonate;
  • bone metastasis;
  • lung metastasis;
  • renal cell carcinoma

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case report
  5. Discussion
  6. References

Abstract:  Bisphosphonates (BP) are inhibitors of bone-resorption and have become the current standard of care for preventing skeletal complications associated with bone metastases. Although previous reports have also suggested potent antitumor, antiangiogenic and immunomodulatory properties of BP, there is debate about the clinical relevance of experimental in vitro and in vivo findings. We report a renal cell carcinoma case in which multiple lung and bone metastases displayed remarkable remission to BP therapy using 30 mg pamidronate once, 4 mg zoledronate once, and weekly 10 mg incadronate 10 times for 3 months. This is the first case report to demonstrate that BP therapy is effective to non-osseous visceral metastasis as well as bone metastases in the clinical setting.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case report
  5. Discussion
  6. References

Patients with metastatic bone disease often have severe bone pain and debilitating skeletal complications. Bisphosphonates (BP) are inhibitors of bone-resorption and have become the current standard of care for preventing skeletal complications associated with bone metastases. Among BP, zoledronic acid is shown to be effective in reducing skeletal-related events, including pathological fractures, spinal cord compression, and radiation or surgery to bone in patients with bone metastases from advanced renal cell carcinoma or prostate cancers.1 BP inhibit the resorptive activity of osteoclasts, promote the induction of apoptosis in these cells and make a less favorable site for tumor cell growth. Recently, accumulated data have demonstrated that BP may also affect cancer cells as well as osteoclasts. BP are cytostatic to tumor cells in vitro,2 induce apoptosis, inhibit cell adhesion and interfere with the metastatic process.3 Moreover, BP is shown to be a potent inhibitor of angiogenesis,4 and to stimulate γδ T-cells5 which play important roles in innate immunity against cancer. There is, however, debate about the clinical relevance of some experimental findings in vitro and in vivo. We report a renal cell carcinoma case in which multiple lung and bone metastases displayed remarkable remission to the BP therapy using 30 mg pamidronate once, 4 mg zoledronate once, and weekly 10 mg incadronate 10 times for 3 months.

Case report

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case report
  5. Discussion
  6. References

A 50-year-old man underwent radical nephrectomy for incidentally discovered renal cell carcinoma (pT2N0M0, clear cell type) in April 1992. The patient developed multiple pulmonary metastases 6 months after surgery, and was treated with subcutaneous injection of interferon-α (IFN-α). Pulmonary metastases remained unchanged and no other metastatic lesions emerged during 6 years of IFN-α therapy (6 million units twice a week for 3 years and thereafter once a week for 3 years) and then for the next 4 years without INF-α treatment. Ten years after the surgery, he developed brain and thoracic vertebral metastases, and underwent gamma-knife therapy twice for the former, and radiation therapy for the latter over the next 3 years. He refused to recommence IFN-α therapy because of pyrexia and general malaise induced by the drug. At 13 years after the nephrectomy, he developed osteolytic metastases of the bilateral pelvic bone with invasion into the iliopsoas muscle (Fig. 1a). He had rapid growth of pulmonary metastases (Fig. 1b) and consciousness disorder due to malignancy associated hypercalcemia. He received palliative radiation therapy to the right ileum (20Gy/5f) and narcotic analgesics. Concurrently, BP therapy was initiated with intravenous pamidronate 30 mg for bone pain and hypercalcemia. The serum calcium level was normalized immediately, but the duration of normalization was only about 1 week. Therefore, pamidronate was changed to incadronate whose inhibitory activity of bone-resorption was shown to be 10 times as high as pamidronate.6 He had weekly 10 mg incadronate 10 times for 3 months. Zoledronic acid, which has 10 times as high inhibitory activity as incadronate,6 was also tried once during the incadronate course, but he refused to continue because of pyrexia. A few months later, there was dramatic improvement in his subjective symptoms, including his consciousness disorder, along with continuous normalization of serum calcium, and BP and analgesics were stopped. Eight months after starting BP treatment computed tomography revealed partial remission of multiple lung metastases (Fig. 1d) as well as calcification of osteolytic lesion of the right ileum with the complete disappearance of the soft tissue mass (Fig. 1c). After 19 months of BP therapy, lung metastases progressed again, and 7 months later he died of the disease despite the use of zoledronic acid. There was no progression of bone lesions or hypercalcemia until death.

image

Figure 1. Computed tomography shows bilateral pelvic bone metastases with invasion into the iliopsoas muscle (A), and multiple lung metastases (B). After 8 months of bisphosphonate therapy, calcification of osteolytic lesion of the right ileum with complete disappearance of soft tissue mass (C) and reduction of the size and the number of multiple lung metastases (D) were demonstrated.

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Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case report
  5. Discussion
  6. References

The present renal cell carcinoma case showed remarkable remission of multiple bone and lung metastases to the administration of BP. Although antitumor effects of BP to several cancer cells including renal cell carcinoma cell lines have been demonstrated in in vitro and in vivo animal studies, there have been few cases reported in which actual antitumorigenic effects were shown in the clinical setting.7 To our knowledge, this is the first case to demonstrate that BP is effective for the treatment of non-osseous visceral metastatic diseases as well as bone lesions.

The precise mechanism why the metastatic lesions in our case responded well to BP is unclear. BP have a high affinity for mineralized bone and rapidly localize to bone, which may result in the therapeutically effective local concentrations for the cancer cells in bone. Therefore, the bone metastases in our case might react to BP through the inhibition of bone resorption or some direct effects on cancer cells. Palliative radiation therapy might also contribute to remission. On the other hand, the rapid accumulation of BP in bone results in a very short plasma half-life and low exposure of visceral tissues. Therefore the anticancer effects against visceral metastatic cancer cells have remained controversial to date. It is not likely that the response of the lung metastases to BP was attributed to the direct antitumor effects or inhibition of angiogenesis. It may be possible that the regression of the lung metastases was through the immunomodulatory effects of BP. For example, some BP can stimulate a specific γδ T-cell subset, which demonstrates major histocompatibility complex (MHC)-unrestricted cytotoxicity against various types of malignant cells including renal cancer cells.8

Previously, the only effective agents for metastatic renal cell carcinoma were interferon-α and interleukin-2. However, combined data for these agents resulted in an overall chance of partial or complete remission of only 10–20%.9 Recently, novel molecularly targeted agents including sorafenib, sunitinib, and temsirolimus have been shown as promising agents. Although sorafenib and sunitinib can produce tumor shrinkage in more patients and prolong progression-free survival than cytokines, they have been rarely associated with complete remission and now lack evidence for long-term clinical benefit. Therefore, there has remained a clear need for novel, more effective therapies for advanced renal cell carcinoma. The present case suggests that BP could be used not only to reduce the skeletal complications associated with bone metastases or improve hypercalcemia, but also as therapeutic agents for metastatic renal cell carcinoma. BP was effective as monotherapy in our case. BP might be combined with the current standard treatment because recent studies have shown that BP augment the interferon-α/β-mediated inhibition of renal cancer cell growth both in vitro and in vivo.10 The efficacy of BP for metastatic renal cell carcinoma and other cancers should be verified by future trials.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case report
  5. Discussion
  6. References
  • 1
    Saad F, Lipton A. Zoledronic acid is effective in preventing and delaying skeletal events in patients with bone metastases secondary to genitourinary cancers. BJU Int. 2005; 96: 9649.
  • 2
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  • 3
    Clezardin P, Fournier P, Boissier S, Peyruchaud O. In vitro and in vivo antitumor effects of bisphosphonates. Curr. Med. Chem. 2003; 10: 17380.
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    Santini D, Vincenzi B, Dicuonzo G et al. Zoledronic acid induces significant and long-lasting modifications of circulating angiogenic factors in cancer patients. Clin. Cancer Res. 2003; 9: 28937.
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    Schilbach K, Geiselhart A, Handgretinger R. Induction of proliferation and augmented cytotoxicity of γδ T lymphocytes by bisphosphonate clodronate. Blood 2001; 97: 291718.
  • 6
    Dunford JE, Thompson K, Coxon FP et al. Structure-activity relationships for inhibition of farnesyl diphosphate synthase in vitro and inhibition of bone resorption in vivo by nitrogen-containing bisphosphonates. J. Pharmacol. Exp. Ther. 2001; 296: 23542.
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    Kikuno N, Urakami S, Nakamura S, Shiina H, Igawa M. Effect of zoledronic acid on metastatic hormone-refractory prostate cancer resistant to taxane, estramustine, carboplatin, and dexamethasone. Int. J. Urol. 2007; 14: 824.
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    Kato Y, Tanaka Y, Miyagawa F, Yamashita S, Minato N. Targeting of tumor cells for human γδ T cells by nonpeptide antigens. J. Immnol. 2001; 167: 50928.
  • 9
    Campbell SC, Novick AC, Bukowski RM. Renal tumors. In: KavoussiLR, NovickAC, PartinAW, PetersCA, WeinAJ (eds). Campbell-Walsh Urology. Saunders, New York, 2007; 1567637.
  • 10
    Yuasa T, Nogawa M, Kimura S et al. A third-generation bisphosphonate, minodronic acid (YM529), augments the interferon-α/β-mediated inhibition of renal cell cancer cell growth both in vitro and in vivo. Clin. Cancer Res. 2005; 11: 8539.