Targeted etanercept for treatment-refractory pain due to bone metastasis: Two case reports

Case Report Targeted Etanercept for Treatment-Refractory Pain Due to Bone Metastasis: Two Case Reports Edward Lewis Tobinick, MD Institutefor Neurological Research, Los Angeles, Cal$ornia

ABSTRACT

Background: Parallel bodies of research suggest both a central role for osteoclasts in tumor-induced destruction of bone and the ability of biologic tumor necrosis factor-alpha (TNF-alpha) antagonists to attenuate the osteoclastmediated bone destruction that accompanies a variety of nonmalignant disorders. Additional studies have implicated TNF-alpha in the promotion of osteoclastmediated malignant osteolysis and the pathogenesis of neuropathic pain. TNFalpha antagonists have the potential to interfere in both processes. Objective: This article reviews the cases of 2 patients with treatment-refractory pain due to cancer metastases to bone who were given targeted injections of the biologic anti-TNF agent etanercept based on its potential to interfere directly with both malignant activation of osteoclasts and neuropathic pain. Methods: One patient had a diagnosis of non-small cell lung cancer and the other had a diagnosis of breast cancer. Both presented with treatment-refractory pain due to bone metastases. The 2 patients received etanercept 25 mg by targeted SC injection in anatomic proximity to the site of spinal metastasis for relief of their treatment-refractory pain. Results: Both patients experienced rapid, substantial, and sustained relief of chronic refractory pain at the treatment site after targeted administration of etanercept. Symptomatic improvement was correlated with objective measures of improvement, including weight gain in 1 patient and decreased uptake of radioactive tracer at the targeted site on positron emission tomography in the other. Accepted Joorpublication June 20, 2003. Printed in the USA. Reproduction in whole or part is not permitted.

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Conclusions: Etanercept delivered by targeted SC injection may be of clinical benefit in selected patients with treatment-refractory pain caused by bone metastases. Clinical trials are needed to define the potential benefit of biologic TNFalpha antagonists in the treatment and prevention of malignant osteolysis. (Clin Ther: 2003;25:2279-2288) Copyright 0 2003 Excerpta Medica, Inc. Key words: TNF, osteoclastogenesis, breast cancer, lung cancer, etanercept, bone metastases.

INTRODUCTION

Tumor metastasis to bone is a common clinical event, often leading to intractable pain and bone destructi0n.r Certain cancers, most commonly those of the breast, lung, and prostate, have a proclivity to metastasize to bone and induce bone destruction in up to 80% of patients.2 A substantial body of research has established the central role of osteoclasts in the malignant destruction of bone.3-12 Recognition of the important role of osteoclasts in tumor-induced osteolysis has resulted in the introduction of osteoclast antagonists.r3J4 The results of a number of studies from researchers in different fields suggest that the inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) can stimulate osteoclast formation, activity, and survival. 15-21Biologic TNF-alpha antagonists, including etanercept,* an anti-TNF fusion protein, have been shown to be capable of preventing and reducing osteoclast-mediated osteolysis in a variety of disorders, including immune-mediated arthritis and wear-debris osteolysis.22-26 There is also in vitro evidence that TNF-alpha produced by cancer cells may be responsible for stimulation of osteoclast activity and the resulting bone resorption.5a27 Taken together, the data support TNF-alpha antagonism as a potential method for the attenuation of tumor-induced bone destruction. TNF-alpha antagonists may also have the potential to rapidly reduce neuropathic pain.28-31 This article reviews the cases of 2 patients who presented to a private medical clinic with treatment-refractory pain due to cancer metastases to bone and, as part of routine clinical practice, were given the biologic anti-TNF agent etanercept based on its potential to interfere directly with both malignant activation of osteoclasts and neuropathic pain. The patients were informed that etanercept had not been shown to be safe or effective for the treatment of pain due to cancer metastasis to bone and that this use represented an off-label indication (etanercept is approved by the US Food and Drug Administration only for the treatment of rheumatoid arthritis and related diseases). The package insert, which details the possible risks of etanercept use, was given to the patients to read before treatTrademark:

2280

Enbrel@ (Immunex

Corporation,

Seattle, Washington).

E.L. Tobinick

ment was provided. After the patients were informed of the possible risks and benefits of etanercept therapy and the treatment alternatives, their written informed consent was obtained. CASE I

A 77-year-old woman began having severe, unrelenting mid-back pain in January 2001. In May, she developed a dry, unproductive cough. In July a rapidly growing nodule appeared on her right forehead. Biopsy revealed thyroid transcription factor-l immunoperoxidase stain-positive adenocarcinoma with papillary features. Chest radiography and computed tomographic imaging of the lung in August showed a 5-cm mass in the right lower lobe of the lung. Bone scan showed intense focal areas of increased uptake of radioactive tracer involving the right frontal skull and the spine at Tl 1. Plain radiographs of the back showed a metastatic lesion of the Tll vertebra, with compression fracture and destruction of 1 pedicle (Figure 1). The patient underwent 2 courses of radiation for the right forehead lesion and a single course of radiation to Tll in September, but her severe, unremitting back pain continued. The patient was prescribed fentanyl transdermal patches and morphine, which were required daily throughout August and September, but pain control continued to be poor. She had difficulty walking due to pain and could not enter or exit an automobile without assistance. In October 2001, the patient presented to the author’s clinic for treatment of localized mid-back pain that was constantly present despite the use of oral morphine 120 mg/d and fentanyl patches (50 pg/h). Physical examination revealed a large, fixed cutaneous metastasis on the forehead, tenderness over the lower thoracic spine on palpation, and difficulty rising from a chair. The neurologic examination was unremarkable. After the patient gave informed consent, etanercept 25 mg was delivered by targeted SC injection immediately over the area of spinal tenderness using a 23-gauge, 16-mm needle. The patient reported substantial pain relief within 10 minutes of etanercept administration. Within 24 hours, she reported complete pain relief. Morphine and fentanyl were completely discontinued, the patient reported improved appetite, and she was able to get in and out of a car without assistance. At 1 month, the patient reported continued complete relief from back pain. At 5 weeks, moderately severe mid-back pain returned, accompanied by difficulty in rising from a chair without assistance. The patient gave her informed consent, and a second targeted SC injection of etanercept 25 mg was administered. Onset of pain relief was reported 1 day after the second injection. After 2 days, relief of back pain was complete, and the patient no longer had difficulty standing or walking. Her appetite remained improved, and she gained 10 kg over 2 months. Although she experienced no further back pain, the patient died from brain metastasis 5 months later. 2281

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Figut-e I.

Plain radiograph of patient

I, showing pedicle destruction

fracture of TI I secondary to adenocarcinoma of the lung.

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and compressiion

E.L. Tobinick

CASE 2

A 50-year-old woman had been healthy until 7 years before presentation to the authors clinic, when infiltrating ductal carcinoma of the right breast (estrogenreceptor [ER] negative and node negative) was diagnosed. She underwent lumpectomy and radiation therapy Bilateral hip pain developed 4 years later, and low back pain began several months after that. Bone scan showed increased uptake of radioactive tracer in the ischium, ribs, and lumbar spine at L4. The patient underwent left hip reconstruction and replacement due to metastatic disease. Biopsy specimens from the hip surgery yielded tissue characterized as ER and 3+ Her-2 positive. Treatment was begun with trastuzumab, bisphosphonates, and strontium 89. Despite use of daily narcotics, pain control was inadequate. One month before her visit to the author’s clinic, positron emission tomography (PET) revealed increased metabolic activity in the lower lumbar spine at L4 and a lower right rib that was consistent with bone metastases (Figure 2A). The patient presented to the author’s office for treatment of intractable, constant low back pain at the site of spinal metastasis at L4 that had been present for >2 years. She was able to walk only with the use of crutches due to pathologic fractures of both hips. Informed consent was obtained, and etanercept 25 mg was administered to the lumbar region by SC injection directly over the area of spinal tenderness. The patient experienced rapid relief of spinal pain, reported as 90% improvement within 5 minutes. Five weeks later, she continued to report 90% relief of lower back pain. At 7 weeks, the patient continued to experience significant relief of back pain but had become more aware of right rib pain at the site of a single metastasis and requested a second dose of etanercept. After the patient gave informed consent, she received SC injections of etanercept 12.5 mg over L4 and directly over the site of right rib tenderness. She reported complete relief of rib pain and lumbar pain within minutes. Pain at these sites has been absent for 11 months at the time of this writing. Pain due to hip metastases continued, but the patient was able to reduce her daily use of opioids by 50% (before receiving etanercept, she had required oxycodone 180 mg/d). Repeat PET scan at 11 months showed continued marked diminution of cancer activity in the lumbar spine, which was clinically correlated to the absence of pain at this site (Figure 2B). DISCUSSION

The clinical results in these 2 patients suggest that targeted administration of etanercept in anatomic proximity to a site of bone metastasis by certain solid tumors may lead to rapid, substantial, and prolonged pain relief. These results are in accordance with the findings of previous studies suggesting that biologic TNFalpha antagonists may inhibit osteoclast function, thereby reducing osteoclastmediated osteolysis, and that osteoclasts are responsible for the destruction of bone by solid tumors.7-12,23-25 2283

to the lower lumbar spine, showing marked diminution of tumor activity at L4.

tivity at L4, right rib, and other breast cancer metastases; and (B) I I months after a second dose of targeted etanercept

Figure 2. Positron emission tomography scans of patient 2 (A) before administration of targeted etanercept, showing increased ac-

E.L. Tobinick

It has been demonstrated that tumor invasion of bone releases growth factors as a result of bone resorption, and these growth factors provide further stimulation of the cycle of tumor invasion. 6,32-34It has been proposed previously that inhibition of osteoclast function, if profound, could lead to tumor being “trapped” by the surrounding bone, unable to effect bone destruction and therefore unable to gain access to the necessary tumor growth factorsi The author believes this is what has occurred in the present cases. It is hypothesized that by interfering with tumor-induced osteoclast function, etanercept may interrupt a self-amplifying osteoclast-mediated cycle of bone invasion + bone resorption + release of tumor growth factors -+ further bone invasion, and that this interference with tumor invasion of bone was responsible for the prolonged pain relief experienced by both patients after each etanercept dose. The PET scan results in patient 2 are therefore thought to reflect a real decrease in tumor activity at the site of targeted etanercept administration that lasted for an extended period, 11 months longer than etanercept’s known half-life of 102 hours. 35 The author believes that the prolonged and substantial pain relief reported by both patients reflects a decrease in tumor activity at the sites of targeted etanercept administration. Targeted delivery of etanercept may allow achievement of higher local concentrations of TNF-alpha antagonist at the pathologic site, which may produce a greater therapeutic effect.28*31 Targeted administration of other potent osteoclast antagonists, such as osteoprotegerin (OPG) and bisphosphonates, may also prove beneficial in inhibiting malignant osteolysis. 36 Properly designed, controlled, double-blind studies in larger numbers of patients will be necessary to confirm these hypotheses. Several limitations of the present reports must be taken into consideration. Treatment was open label, with no control group. Therefore, the contribution of a possible placebo response cannot be determined. In patient 2, the influence of previous medications is unknown. It is possible that use of a biologic TNF-alpha antagonist in combination with other osteoclast inhibitors, such as bisphosphonates, OPG, and OPG analogues, may be beneficial, but a search of MEDLINE revealed no published reports on the safety or efficacy of these combinations. Although etanercept seemed to be clinically beneficial in these patients with bone metastases from lung and breast cancer, similar results may not be observed in patients with different types of tumors or even with different histologic types of the same cancers. The effect of etanercept treatment on survival is unknown, and it must be considered that although TNF-alpha antagonism may be beneficial for skeletal metastases, it could theoretically accelerate extraskeletal tumor progression Finally, although generally well tolerated, the biologic TNF-alpha antagonists have known potential adverse effects. They should not be used in patients with active infection, lymphoma, history of lymphoma, or demyelinating disease and should be used with caution in patients with diabetes, congestive heart failure, or blood disorders.35 2285

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Based on the results of the present study, it can be surmised that the other currently available biologic TNF-alpha antagonists (infliximab and adalimumab) or the biologic TNF-alpha antagonists currently in clinical development (onercept, CDP 571, CDP 870, and pegylated s-TNF receptor type I) also have the potential to interfere with malignant osteolysis. Controlled, double,blind studies will be necessary to investigate this hypothesis. CONCLUSIONS

Etanercept delivered by targeted SC injection may be of clinical benefit in selected patients with treatment-refractory pain caused by bone metastases. Clinical trials are needed to define the potential benefit of biologic TNF-alpha antagonists in the treatment and prevention of malignant osteolysis. REFERENCES 1. Coleman

RE. SkeletaI

complications

of malignancy.

Cancer

1997;8O(Suppl

8):

Semin Oncol. 2001;28(Suppl

11):

1588-1594. 2. Janjan N. Bone metastases: Approaches to management. 28-34. 3. Yoneda T, Sasaki A, Mundy

GR. Osteolytic

bone metastasis

in breast cancer. Breast

Cancer Res Treat. 1994;32:73-84. 4. Clohisy DR, Ogilvie CM, Carpenter RJ, Ramnaraine teolysis involves the recruitment

ML. Localized tumor-associated

5. Tumber A, Morgan HM, Meikle MC, Hill PA. Human breast-cancer fusion, migration

os-

and activation of osteoc1asts.J Orthop Res. 1996;14:2-6.

and resorptive

cells stimulate

activity of osteoclasts in bone explants.

the

Int J Cancel:

2001;91:665-672. 6. Kakonen

SM, Mundy GR. Mechanisms

noma. Cancer 2003;97(Suppl

of osteolytic bone metastases

in breast carci-

3):834-839.

E, Reid SA, et al. Scanning electron microscopy in bone 7. Boyde A, Maconnachie pathology: Review of methods, potential and applications. Scan Electron Microsc. 1986; Part 4:1537-1554. 8. Taube T, Elomaa I, Blomqvist mediated

bone resorption

C, et al. Histomorphometric

in metastatic

evidence

for osteoclast-

breast cancer. Bone. 1994;15:161-166.

9. Aoki J, Yamamoto I, Hino M, et al. Osteoclast-mediated osteolysis in bone metastasis from renal cell carcinoma. Cancer 1988;62:98-104. 10. Sasaki A, Boyce BF, Story B, et al. Bisphosphonate risedronate reduces metastatic human breast cancer burden in bone in nude mice. Cancer Res. 1995;55:3551-3557. 11. Clohisy DR, Palkert D, Ramnaraine ML, et al. Human breast cancer induces osteoclast activation and increases the number of osteoclasts at sites of tumor osteolysis. j Orthop Res. 1996;14:396-402. 12. Clohisy DR, Ramnaraine ML. Osteoclasts are required for bone tumors to grow and destroy bone. ] Orthop Res. 1998;16:660-666. 2286

E.L. Tobinick

13. Lipton A. Bisphosphonates

and metastatic

breast carcinoma.

Cancel: 2003;97(Suppl

3):848-853. 14. Hortobagyi

GN, Theriault

RL, Porter L, et al, for the Protocol 19 Aredia Breast Cancer

Study Group. Efficacy of pamidronate

in reducing

skeletal complications

in patients

with breast cancer and lytic bone metastases. N Engl J Med. 1996;335: 1785-l 79 1. 15 Thomson BM, Mundy GR, Chambers TJ. Tumor necrosis factors alpha and beta induce osteoblastic cells to stimulate osteoclastic bone resorption. J Irnmunol. 1987; 138: 775-779. 16 Lee SE, Chung WJ, Kwak HB, et al. Tumor necrosis factor-alpha supports the survival of osteoclasts through the activation of Akt and ERK. j Biol Chem. 2001;276: 49343-49349. 17 I I. McGowan NW, Walker EJ, Macpherson cruits osteoclast precursors. 18. Kobayashi

K, Takahashi

teoclast differentiation

H, et al. Cytokine-activated

endothelium

re-

factor alpha stimulates

os-

of the ODF/RANKI-RANK

in-

Endocrinology. 2001;142:1678-1681.

N, Jimi E, et al. Tumor necrosis by a mechanism

independent

teraction. J Exp Med. 2000;191:275-285. 19. Azuma Y, Kaji K, Katogi R, et al. Tumor necrosis factor-alpha of and bone resorption

20. Kudo 0, Fujikawa Y, Itonaga I, et al. Proinflammatory induction

of human

osteoclast formation.

21. Udagawa N, Kotake S, Kamatani genesis in rheumatoid 22. Williams RO, Feldmann

induces

differentiation

by osteoclasts. J BinI Chem. 2000;275:4858-4864. cytokine (TNFalpha/IL-lalpha)

J Pathol. 2002;198:220-227.

N, et al. The molecular

mechanism

of osteoclasto-

arthritis. Arthritis Res. 2002;4:281-289. M, Maini RN. Cartilage destruction

and bone erosion in arthri-

tis: The role of tumour necrosis factor alpha. Ann Rheum Dis. 2000;59(Suppl 23. Redlich K, Hayer S, Maier A, et al. Tumor necrosis struction

is inhibited

by targeting

osteoclasts

factor alpha-mediated

with osteoprotegerin.

2002;46:785-792. 24. Childs LM, Goater JJ, O’Keefe RJ, Schwarz EM. Efficacy of etanercept induced 25. Ritchlin mediated

osteolysis. J Bone Miner Res. 2001;16:338-347. CT, Haas-Smith SA, Li P, et al. Mechanisms osteoclastogenesis

and bone resorption

l):i75-i80.

of TNF-alpha-

in psoriatic

joint de-

Arthritis Rheum. for wear debrisand RANKL-

arthritis. J Clin Invest.

2003;111:821-831. 26. Redlich K, Hayer S, Ricci R, et al. Osteoclasts

are essential for TNF-alpha-mediated

joint destruction. J Clin Invest. 2002; 110: 1419-1427. 27. Pederson L, Winding B, Foged NT, et al. Identification derived paracrine

factors that stimulate

of breast cancer cell line-

osteoclast activity Cancer Res. 1999;59:5849-

5855. 28. Tobinick E, Britschgi-Davoodifar S. Perispinal TNF-alpha inhibition for discogenic pain. Swiss Med Wkly. 2003;133:170-177. 29. Tobinick E. Targeted etanercept for discogenic neck pain: Uncontrolled, open-label results in two adults. Clin fier: 2003;25:1211-1218. 2287

CLINICALTHERAPEUTICS@

30. Karppinen

J, Korhonen

T, Malmivaara

A, et al. Tumor necrosis

factor-alpha

mono-

clonal antibody, infliximab, used to manage severe sciatica. Spine. 2003;28:750-753. 31. Sommer C, Schafers M, Marziniak M, Toyka KV Etanercept reduces hyperalgesia in experimental

painful neuropathy.

32. Guise TA. Parathyroid

J Peripher New Syst. 2001;6:67-72.

hormone-related

protein

and bone metastases.

Cancer: 1997;

8O(Supp1 8):1572-1580. 33. Roodman

GD. Role of stromal-derived

tasis. Cancer: 2003;97(Suppl 34. Green JR. Antitumor

cytokines

effects of bisphosphonates.

35. Enbrel [package insert]. Seattle, Wash: Immunex 36. Morony

S, Capparelli

Cancel: 2003;97(Suppl Corporation;

C, Sarosi I, et al. Osteoprotegerin

creases skeletal tumor burden bone metastasis.

and growth factors in bone metas-

3):733-738.

in syngeneic

3):840-847.

2002.

inhibits

osteolysis

and de-

and nude mouse models of experimental

Cancer Res. 2001;61:4432-4436.

Address correspondence to: Edward Lewis Tobinick, MD, Institute for Neurological Research, 100 UCLA Medical Plaza, Suites 205-210, Los Angeles, CA 90095. E-mail: [email protected] 2288