Corticosteroids in Advanced Cancer

Corticosteroids play a vitally important role in the treatment ofpatients with advanced cancer. While the scientific data, as reviewed byWooldridge et al, are often slim, most physicians who treat patients with cancerquickly become comfortable with prescribing synthetic glucocorticoids for avariety of indications. Wooldridge et al have provided a much needed synthesisof the medical literature on the use of steroids, both as part ofchemotherapeutic treatment for a variety of malignancies and in symptom control.

Steroids and Neuro-Oncology

In his classic textbook, Neurological Complications of Cancer,Jerome Posner notes that steroids are "the most widely used drugs inneuro-oncology."[1] However, despite their frequent use, the precisemechanism of action of these agents remains unclear. In the setting ofmetastatic disease, steroids are thought to exert their action as anti-edemaagents by repairing the disruption seen in the blood-brain barrier. Indeed, Dr.Posner suggests that, "many scans [magnetic resonance imaging and computedtomography] do show decreased contrast enhancement with the tumor, suggestingpartial restoration of the blood-brain barrier."[1] Steroids may alsocontrol brain edema by inhibiting the effect of arachadonic acid on vascularpermeability.

In the setting of spinal cord compression, steroids decrease theassociated vasogenic edema and thereby substantially improve neurologic functionand decrease pain. Although the one available study of high-dose vs low-dosedexamethasone cited in the review by Wooldridge et al did not demonstrate abenefit with the use of a higher dose, compelling animal data and decades ofclinical experience at Memorial Sloan-Kettering Cancer Center suggest thatpatients with acute spinal cord compression should be treated with a 100-mgbolus of dexamethasone followed by a steroid taper while more definitivetreatment—usually radiation or chemotherapy—gets underway.[2]

Although tapering the steroid to the lowest effective dose iscritical, there are no reports in the medical literature of any deleteriousoutcomes associated with the administration of a single bolus of 100 mg. Amongthe available corticosteroids, dexamethasone is used most commonly because ofits lack of mineralocorticoid activity and a half-life of greater than 30 hours,which allows for more convenient daily dosing.

The best time to begin other forms of therapy after steroidshave been administered is unclear. Given the tissue swelling that may occur withthe onset of radiation therapy to the brain, some clinicians recommend treatmentwith steroids, usually dexamethasone, for a short time (1 to 2 days) prior tobeginning a course of radiotherapy. In the treatment of epidural spinal cordcompression, there is no evidence that immediate radiotherapy worsens neurologicfunction.

A rapid taper or abrupt cessation may result in "steroidpseudorheumatism," which is characterized by the onset of acute arthralgiasand/or myalgias.[3] Clinicians may avoid this undesirable effect by implementinggradual dose reduction schedules, although side effects due to steroidwithdrawal can occur even when steroids are tapered slowly.

Malignant Bone Pain

Bone metastases are the most common cause of cancer-relatedpain, occurring in 60% to 84% of patients with metastatic cancer.[4] Autopsystudies demonstrate that 85% of patients who die with stage IV breast, prostate,or lung cancer have bone metastases. In an excellent review of thepathophysiology and treatment of malignant bone pain, Mercadante notes,"The presence of pain is not correlated with the type of tumor, location,number and size of metastases, gender, or age of patient." He explains thata metastasis may develop near the primary site (eg, prostate cancer via thevalveless paravertebral plexus) or at a more distal location secondary tochemotactic factors responsible for the "osteotropism" of certainmalignancies—namely breast, lung, thyroid, kidney, and prostate cancers.[5]

A variety of mechanisms for the bone pain caused by metastaticdisease have been suggested, including invasion of the richly innervatedperiosteum, microfractures of the trabeculae causing bone distortion, mechanicalstress, nerve entrapment, and bone destruction/collapse.[6] Recently, a murinemodel of bone cancer pain has been proposed that demonstrates massive astrocytehypertrophy without neuronal loss, an increase in the neuronal expression ofc-Fos, and an increase in the number of dynorphin-immunoreactive neurons indorsal horn deep laminae neurons ipsilateral to a limb with cancer.[7] Becausethese changes have not been found in other murine models of inflammatory orneuropathic pain, Schwei et al suggested that bone cancer pain may have a unique"neurochemical signature."

Treatment of Bone Pain

Anti-inflammatory medications, including corticosteroids andnonsteroidal anti-inflammatory drugs (NSAIDs) are often successfully used forthe treatment of pain secondary to bone metastases.[8] Although there are fewrandomized double-blind clinical trials examining the role of NSAIDs in themanagement of metastatic bone pain, an understanding of the pathophysiology ofmalignant bone pain and the results of meta-analyses of the role of NSAIDs incancer pain compel many cancer pain specialists to add an anti-inflammatoryagent to the daily regimen of many of their patients with malignant bonepain.[9]

For patients with advanced disease whose cardiac,gastrointestinal, or renal comorbid illnesses may limit their ability to receivetraditional NSAIDs safely, the COX-2 inhibitors now represent a welcomealternative. There are no data from randomized controlled trials supporting theuse of COX-2 inhibitors in the setting of advanced cancer. However, theirdemonstrated safety and efficacy in other inflammatory pain settings make theseagents an important addition to the daily regimen of many patients withmalignant bone pain.

The risk of osteoporotic fracture and avascular necrosisassociated with long-term steroid use in patients whose bone is already weakenedfrom the spread of metastatic cancer limit their long-term use. However, in thesetting of acute, severe cancer pain, a large bolus followed by a taper to thelowest effective dosage can be enormously beneficial. In addition, in patientswho are unlikely to survive long enough to develop the well-known complicationsof systemic steroids, maintaining use of a daily corticosteroid can be helpfulnot only for analgesia but also for beneficial effects on respiration, appetite,nausea, and mood.

Conclusions

In conclusion, Wooldridge et al have offered a useful synthesisof the existing data on the use of corticosteroids in patients with advancedcancer. Competent clinical practice requires not only a thorough and criticalreview of the literature, but also an understanding of the relevant molecularmechanisms of action, which, taken together, may form the basis for a rationaltreatment strategy.

References:

1. Posner JB: Neurologic Complications of Cancer, pp 54, 56.Philadelphia, F.A. Davis Co, 1995.

2. Delattre J-Y, Arbit E, Thaler HT, et al: A dose-responsestudy of dexamethasone in a model of spinal cord compression caused by epiduraltumor. J Neurosurg 70:920-925, 1989.

3. Dixon RA, Christy NP: On the various forms of corticosteroidwithdrawal syndrome. Am J Med 68:224-230, 1980.

4. Lote K, Walloe A, Bjersand A: Bone metastases: Prognosis,diagnosis, and treatment. Acta Radiol Oncol 25:227-232, 1986.

5. Mercadante S: Malignant bone pain: Pathophysiology andtreatment. Pain 69:1-18, 1997.

6. Campa JA, Payne R: The management of intractable bone pain: Aclinician’s perspective. Semin Nucl Med 22:3-10, 1992.

7. Schwei MJ, Honore P, Rogers SD, et al: Neurochemical andcellular reorganization of the spinal cord in a murine model of bone cancerpain. J Neurosci 19:10886-10897, 1999.

8. Perreira J: Management of bone pain, in Portenoy RK, Bruera E(eds): Topics in Palliative Care, vol 3, pp 79-116. New York, Oxford UniversityPress, 1998.

9. Eisenberg E, Berkey C, Carr DB, et al: NSAIDS for cancerpain: Meta-analysis of efficacy, in Gebhart GF, Hammond DL, Jensen TS (eds):Proceedings of the 7th World Congress on Pain, Progress in Pain Research, andManagement, vol 2, pp 697-707. Seattle, IASP Press, 1994.