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Corticosteroids in Advanced CancerPublished on Diagnostic Imaging (http://www.diagnosticimaging.com)

Corticosteroids in Advanced CancerReview Article [1] | February 01, 2001By James E. Wooldridge, MD [2], Clay M. Anderson, MD [3], and Michael C. Perry, MD, FACP [4]

Despite the fact that there are only a few controlled trials demonstrating the benefits associatedwith the use of corticosteroids in specific situations, these agents are administered frequently topatients with advanced cancer. Corticosteroids may be used alone or as adjuvants in combinationwith other palliative or antineoplastic treatments. For example, corticosteroids may help preventnausea, vomiting, and hypersensitivity reactions to treatment with chemotherapy or radiation. Theyare also commonly used as appetite stimulants in patients with advanced cancer. In the adjuvantsetting, corticosteroids help to alleviate pain in advanced cancer patients, including specificsituations such as back pain related to epidural compression. This article reviews the evidencesupporting the use of corticosteroids in a broad range of situations seen in patients with advancedcancer. [ONCOLOGY 15(2):225-236, 2001]

Introduction

Corticosteroids are commonly used in the treatment of patients with advanced cancer. However,much of this use stems from the experience of practitioners rather than from data collected incontrolled clinical trials.[1] Although little is known about the actual mechanisms by whichcorticosteroids exert their effects in patients, a substantial amount of evidence supports theirmonitored use in specific situations. This article will review the available evidence on the use ofcorticosteroids in advanced cancer, including treatment of refractory malignancies, use aspremedication with chemotherapy, and symptom palliation.

Background Information

The most commonly used corticosteroids in the United States include prednisone, prednisolone,methlyprednisolone, dexamethasone, and hydrocortisone, all of which were approved by the Foodand Drug Administration in the 1950s. There does not appear to be evidence to support the use ofone corticosteroid over another in any given situation, although physicians have their preferences.

Corticosteroids exhibit varying glucocorticoid and mineralocorticoid effects (Table 1).[2,3] Morepotent glucocorticoid effects are desirable in inflammatory states, whereas mineralocorticoid effectsare needed to treat adrenal insufficiency. Corticosteroids inhibit inflammatory and immuneresponses, most likely through alteration of cellular transcription and protein synthesis as well asthrough effects on lipocortins, which inhibit the release of arachidonic acid. The use ofcorticosteroids in advanced cancer revolves around their glucocorticoid effects, combined with anavoidance of the salt-retaining properties that characterize mineralocorticoids.

That said, it is important to remember that patients previously treated with corticosteroids may havesome degree of adrenal suppression and, therefore, may require supplemental corticosteroidtherapy during stressful situations. In this setting, mineralocorticoid properties are desired.

Effects of Long-Term Use

Chronic use of corticosteroids causes adrenal suppression and may blunt or prevent normal adrenalresponse to physiologic stress. To avoid this effect, many cancer patients may receive intermittentdoses of steroids as antiemetics to prevent hypersensitivity reactions, or as adjuvants for paincontrol. Spiegel and colleagues performed adrenocorticotropic hormone (ACTH)-stimulation tests in14 patients receiving high-dose prednisone for emesis prophylaxis prior to chemotherapy.[4] Adrenalfunction was suppressed in 13 patients at 24 hours and remained suppressed in 5 patients for morethan 1 week.

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Investigators at the University of Rochester performed ACTH-stimulation tests in nine women withovarian cancer before and during chemotherapy in which dexamethasone premedication wasused.[5] They noted effects on the hypothalamic-pituitary axis for up to 8 days, but reported nolong-term suppression. It is probably not necessary to taper steroids when they are administered inbrief, intermittent doses, but adrenal suppression should be considered when patients who havereceived such treatment present with hypotension and severe illness. The use of replacement-dosesteroids in patients with cancer who are undergoing surgery was recently reviewed by Lefor.[6]

The risks associated with corticosteroid use in patients with advanced cancer have been reviewedextensively.[2] Acute side effects include dyspepsia, peptic ulcer disease, insomnia, oral and vaginalcandidiasis, anxiety, and glucose intolerance. Side effects from chronic use include development of acushingoid appearance, weight gain, edema, cataracts, osteoporosis, proximal myopathy, thinning ofthe skin, infection, and impaired wound healing. Corticosteroids can also lead to neuropsychiatricchanges including depression, agitation, and delirium.[6]

It is important, therefore, to carefully weigh the potential benefits of corticosteroid therapy againstpotential side effects, and to closely monitor the efficacy of therapy. If no improvement is noted,treatment should be adjusted or discontinued.

Corticosteroids as Anticancer Agents

Corticosteroids have been used as anticancer agents since the 1940s,[8] with activity reported in awide variety of solid tumors, including breast and prostate cancer, and the lymphoid hematologicmalignancies. They are commonly found in regimens for acute lymphocytic leukemia, Hodgkin’s andnon-Hodgkin’s lymphoma, myeloma, and chronic lymphocytic leukemia. This section will focus on theuse of corticosteroids as palliative anticancer treatment once chemotherapeutic options have beenexhausted or abandoned.

Multiple Myeloma

Several studies have been reported suggesting a benefit with the use of corticosteroids in refractorymultiple myeloma. Alexanian et al reported the use of pulse prednisone therapy in patients withmyeloma refractory to melphalan (Alkeran).[9] Prednisone was administered at 60 mg/m2/d for 5 of8 days, for three pulses followed by a 3-week rest, with the cycle repeated. The investigators noted agreater than 50% reduction in tumor mass in 5 of 16 patients, and found that responding patientsbenefited clinically with less pain, improved performance status, and increased hemoglobin.

Norfolk and Child performed a similar study in 17 patients with relapsed or refractory disease.Patients in this study received prednisolone, 60 mg/m2/d for 5 days, followed by a 9-day rest.[10]Fourteen patients completed six cycles of treatment, and 10 had more than a 25% reduction inserum paraprotein or a 50% reduction in urinary light-chain excretion. An overall improvement inquality of life was also noted. Notably, two of the nonresponders demonstrated an improvement inperformance status. Median survival for the group was more than 19 months.

In 1991, the Eastern Cooperative Oncology Group reported a pilot study of high-dose, pulseddexamethasone in patients with relapsed or refractory disease.[11] Patients receiveddexamethasone, 40 mg/d, 4 days a week for 8 weeks. Of 32 patients enrolled, 13 (40%) achievedobjective responses and 28.5% showed improvement in pain or performance status. The study alsoreported significant toxicity, with 19 patients experiencing side effects assessed as at least grade 2.Median survival was 19 weeks, and the authors suggested that less frequent administration at longerintervals should be considered.

Alexanian also reported on the use of intermittent, high-dose dexamethasone, noting a 27%response rate in patients who did not respond to their prior treatment.[12] The Southwest OncologyGroup reported a trial of alternate-day administration of corticosteroids (oral prednisone, 100 mgevery other day for 2 weeks, then 50 mg every other day for 10 weeks) in 121 patients with relapsedor refractory myeloma. They measured glucocorticoid receptors from patient samples and found animproved response, but no change in overall survival among patients with a moderate number of

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receptors, compared with patients with a low number of receptors. They reported a 10% partialresponse rate (defined as a 50% to 75% decrease in M-protein), although 81 patients maintainedstable disease while enrolled in the study.

Prednisone, as used in this study, was well tolerated and appeared to be associated with responseand median survival rates (12 months) similar to those reported with other drug schedules used inmyeloma.

Non-Hodgkin’s Lymphoma

In 1996, Newcom reported on the outcome of two patients with refractory, poorly differentiatedlymphocytic lymphoma who had been treated with continuous corticosteroids (prednisone, 60 to 100mg/d).[13] Both patients improved within 3 weeks of the initiation of single-agent prednisone, andboth reportedly experienced regression of nodes and organomegaly as well as an improvement infunction. However, the patients died 14 and 15 months after initiation of therapy with prednisone.

Breast Cancer

have been used in the primary treatment of breast cancer in elderly women after failure of front-linehormonal therapy.[8] Minton et al followed 91 women aged 65 years and older in whom diseaseprogressed following initial hormonal therapy with estrogens, tamoxifen (Nolvadex), orandrogens.[14] A treatment-free period of 1 month was recommended to control for a withdrawalresponse. The majority of patients received prednisolone, 15 mg daily, and 10 patients receivedhydrocortisone acetate, 75 mg daily. Objective responses were noted in 13 patients (14%). Another19 (21%) achieved stable disease for at least 6 months. There was no correlation with any priorresponse to endocrine therapy, and toxicity was felt to be acceptable. Unfortunately, the authors didnot report a clinical benefit as subjectively reported by the patients.

Mercer and colleagues reported a prospective randomized trial of aminoglutethimide (Cytadren, 125mg twice daily) vs hydrocortisone (20 mg twice daily) in advanced breast cancer.[15] All patientswere postmenopausal and had experienced disease progression on tamoxifen. Of 61 patientsentered into the trial, 56 were included in the analysis. Three patients who receivedaminoglutethimide achieved a partial response (11%), while one partial and five complete responses(21%) were reported in the hydrocortisone group. Although this difference was not statisticallysignificant, it does serve as evidence that corticosteroids have activity in breast cancer. The authorsdid not report on clinical benefit.

Prostate Cancer

Hormone therapy is well established in the treatment of prostate cancer. However, progressivedisease after failure of hormone therapy is a difficult problem for patients in this setting. Tannockand colleagues from the Princess Margaret Hospital in Toronto have reported their experience withprednisone in the treatment of hormone-refractory disease.[16] In an informative study, theseinvestigators prospectively treated 37 men with symptomatic bone metastases with 7.5 to 10 mg ofprednisone daily. Pain scores were assessed by three different measures at monthly intervals.

An improvement in all three pain scales without an increase in opiate dosages was reported for aminimum of 1 month in 14 (38%) patients. Responses did not correlate with alkaline or acidphosphatase measures, but did appear to correlate with suppression of adrenal androgens. Althoughthe median duration of response was only slightly more than 4 months, the investigators concludedthat there was improvement in quality of life with little toxicity or expense. These investigators havenow reported on the superiority of the combination of mitoxantrone (Novantrone) and prednisone aspalliation for a similar group of patients; however, this therapy was not associated with a survivaladvantage.[17] Some patients will opt not to receive chemotherapy, although corticosteroids alonemay be beneficial.

Sartor and colleagues assessed the effects of prednisone, 10 mg twice daily, on prostate-specificantigen (PSA) in 29 men with progressive, hormone-refractory prostate cancer.[18] Twenty-six of thepatients were symptomatic. PSA levels declined by at least 25% in 14 (48%) of the patients, and 23

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of 26 reported an improvement in appetite, weight gain, or pain control. The medianprogression-free survival was 2 months; however, median overall survival was 12.8 months afterinitiation of therapy with prednisone. The duration of symptom control and any correlation with PSAmeasurements were not reported, but would be of interest as patients lived an average of 10 monthsbeyond the development of progressive disease.

Corticosteroids for Symptom Prevention

Nausea and Vomiting

Many patients with advanced cancer receive treatment with chemotherapy or radiation therapy forpalliation of symptoms. Corticosteroids can be used to prevent nausea related to chemotherapy andradiation therapy, and these preventive effects may be enhanced with concurrent use of otherantiemetics.

In 1980, Rich et al reported the initial use of methylprednisolone as an antiemetic.[19] This wasfollowed by reports of individual use based on "casual observations."[20] Aapro and Alberts showedpositive results with the use of dexamethasone beginning the night before and continuing 48 hoursafter completion of chemotherapy with cisplatin (Platinol).[21] Cassileth et al performed arandomized, double-blind, crossover trial of premedication with oral dexamethasone as outpatientchemotherapy in patients with breast cancer.[22] They found that nausea and vomiting improved inpatients who received chemotherapy cycles containing dexamethasone.

In a double-blind, placebo-controlled trial, Metz et al treated 27 women for prophylaxis of nausea andvomiting with 1 to 2 g of methylprednisolone in divided doses vs placebo.[23] These women receivedmoderate- to high-dose therapy with cisplatin (50 to 118 mg/m2) for ovarian or cervical cancers. Theyreported total or major protection in 38.5% of cycles using methylprednisolone, compared with 25%in the placebo group (not a significant difference). Notably, half of the placebo patients (7 of 14),compared with only 1 of 13 methylprednisolone-treated patients, dropped out of the study (P = .02).This ultimately lowered the power of the study. Investigators were forced to conclude thatmethylprednisolone alone was not sufficient for prophylaxis against nausea associated withhigh-dose cisplatin.

Parry and Martin reported a randomized, single-blind study of intravenous (IV) dexamethasone (20mg) vs placebo (0.9% saline) in patients receiving moderately emetogenic chemotherapy.[24]Significantly less nausea was seen in the treated group at 24 and 48 hours, with 63% of the treatedgroup reporting no nausea, compared with 37% of the placebo group.

Markman et al conducted a randomized double-blind crossover trial that compared dexamethasone(20 mg IV, then 10 mg orally every 6 hours for 24 hours) with prochlorperazine (10 mg IV, then 10mg orally every 6 hours for 24 hours) in patients being treated with non-cisplatin-containingchemotherapy.[25] They reported significantly less nausea and vomiting with less appetitesuppression in patients receiving dexamethasone. Of 42 patients in the study, 29 achieved totalantiemetic protection with dexamethasone, compared to 18 with prochlorperazine (P < .001).

In a similar study, 25 women with stage II breast cancer treated with intravenous CMF(cyclophosphamide [Cytoxan, Neosar]/methotrexate/ fluorouracil) received nausea prophylaxis withdexamethasone (24 mg in 5 divided doses), metoclopramide (1 mg/kg IV in a single dose), or acombination of the two drugs vs placebo. Dexamethasone, with or without metoclopramide, provided45.7% to 50% complete protection from emesis (respectively), and was more effective than placebo(12.5%) or metoclopramide (20.8%) alone. Metoclopramide was not significantly better than placebo,and did not improve the efficacy of dexamethasone.

Dexamethasone has also been used in the prevention of radiation-induced emesis. In aplacebo-controlled trial, the National Cancer Institute of Canada studied 154 patients who receivedfractionated radiotherapy to fields that included the upper abdomen for at least five fractions andtreated them with 2 mg of oral dexamethasone three times daily.[26] Patients were followed forcontrol of emesis as well as quality of life. Total prevention of emesis was reported in 54 (72%) of 75

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patients receiving dexamethasone vs 37 (49%) of 75 patients receiving placebo (P = .025). Using theEuropean Organization for Research and Treatment of Cancer (EORTC) quality-of-life instrument(QLQ-C30+1), patients receiving dexamethasone reported significantly less nausea, vomiting, andloss of appetite, but more insomnia. Global quality-of-life scores were not significantly different.

The authors concluded that dexamethasone at this dosage and with the schedule described above iseffective as emesis prophylaxis for patients receiving radiation therapy who are at moderate to highrisk of developing emesis. They cautioned against prolonged use of dexamethasone and suggestedthat future studies should also incorporate 5-HT3-receptor antagonists.

Most clinicians now use 5-HT3-receptor antagonists for nausea and emesis prophylaxis with highlyemetogenic chemotherapy. Several studies have suggested the superiority of ondansetron (Zofran)in combination with dexamethasone over ondansetron alone.[27-30] It is interesting to note thatondansetron and dexamethasone appear to be superior to metoclopramide, dexamethasone, anddiphenhydramine when used with cisplatin chemotherapy regimens,[31] yet ondansetron alone maybe less effective than dexamethsone and metoclopramide in women treated with CMF.[32]Ondansetron and dexamethasone have been reported to display similar efficacy in controllingemesis, although dexamethasone may have proven superior for preventing delayed symptoms.[33]

Similarly, granisetron (Kytril) was as effective as dexamethasone in one study, although thecombination was significantly superior to either drug alone.[34] Again, dexamethasone appeared tooffer some protection against delayed symptoms. In a subsequent randomized, double-blind placebocontrolled study in patients receiving cisplatin chemotherapy, dexamethasone appeared to be aseffective as dexamethasone plus granisetron in preventing delayed nausea and vomiting.[35]

Thus, there is sufficient evidence to suggest that dexamethasone as a single agent is as effective as5-HT3-receptor antagonists and is probably superior for delayed nausea and vomiting. Thecombination likely represents our most efficacious treatment for the prevention of nausea andvomiting in patients receiving chemotherapy.

Hypersensitivity

Corticosteroids have become standard premedications for regimens containing the taxanes.Hypersensitivity reactions from paclitaxel (Taxol) and docetaxel (Taxotere) can be preventedeffectively with corticosteroids administered prior to initiating chemotherapy. Initial regimens withpaclitaxel incorporated oral dexamethasone the night before and the day of chemotherapy.Paclitaxel can be delivered safely with 10 mg of intravenous dexamethasone 30 to 45 minutes priorto treatment.

Preliminary reports of treatment with weekly paclitaxel suggest that premedication withcorticosteroids may be gradually tapered and possibly eliminated.[36] Docetaxel is associated withthe development of pleural effusions that can be effectively prevented with oral dexamethasoneadministered 1 day before and 4 days after treatment.[37] Weekly docetaxel regimens have utilizedthree doses of dexamethasone.[38]

Corticosteroids in Supportive Oncology

Brain Metastasis

It is widely accepted standard practice to administer corticosteroids to patients with primary ormetastatic brain tumors. It is interesting to note that in spite of this acceptance, there is littleevidence establishing the optimal drug, dose, schedule, or duration of treatment. Corticosteroids aretypically used as an adjunct to radiation or surgery, and there is evidence that patients withoutneurologic symptoms can be treated definitively without steroids.[39] An early report suggestedimprovement in neurologic function with prednisolone,[40] and another report suggested that 16 mgof dexamethasone daily was an acceptable schedule.[41]

In two double-blind, randomized trials of different doses of dexamethasone, 4 mg was found to be as

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effective as 16 mg with significantly fewer side effects.[42] There is evidence supporting the use ofthe corticosteroids in the initial treatment of brain metastases; however, patients without symptomswho receive timely definitive therapy may not require corticosteroids. The optimal dose has not beenestablished, but there appear to be no data on dexamethasone dosages above 16 mg daily.

Epidural Metastasis

Corticosteroids are commonly used for the initial treatment of epidural metastasis causingcompression of the spinal cord, and guidelines for treatment have been published.[43] Theusefulness of corticosteroids in the treatment of epidural metastasis is strongly suggested from workdone in animal models. Ushio et al performed elegant studies in a rat model demonstrating thathigh-dose dexamethasone results in transient improvement of weakness in animals that have beeninjected with tumor cells near the spine.[44,45] These effects were lost by the fourth day oftreatment.

These findings were translated into the clinic using a protocol of high-dose dexamethasone (100 mgIV bolus, followed by 96 mg/d orally in divided doses) with immediate initiation of external-beamradiation therapy.[46] After the first day, 39 of 61 evaluable patients (64%) reported a reduction inpain. Although the contribution of dexamethasone to this response is clouded by the immediate useof radiation, the authors felt that this degree of immediate improvement was higher than in theirprevious experience. In addition, six patients had complete pain relief after use of dexamethasonealone. The same group later reported experiments suggesting a dose-response relationship in favorof high-dose dexamethasone in the treatment of epidural compression.[47]

The value of corticosteroid treatment of epidural metastatic spinal cord compression was furthersupported by a report from Sorensen and colleagues.[48] They performed a randomized, single-blindstudy of high-dose dexamethasone (96 mg IV, followed by 96 mg/d orally for 3 days, then taperedover 10 days) vs no corticosteroids in patients with confirmed cord compression who had beentreated with radiation.

Of 57 eligible patients, 27 were treated with dexamethasone and 30 received no corticosteroids.Patients were stratified by primary tumor and ambulatory status. A significantly greater number ofpatients were ambulatory at 6 months in the dexamethasone group (59% vs 33%, P = .05),although not at 1 year (30% vs 20%, P = .40). Patients with breast cancer treated withdexamethasone appeared to derive the greatest benefit. Median survival was identical in bothgroups at 6 months.

The optimal initial dose of corticosteroids in metastatic spinal cord compression remains to bedetermined. Vecht et al reported a randomized, double-blind trial of intravenous dexamethasonewith an initial high-dose (100 mg) vs low-dose (10 mg) bolus followed by 16 mg/d orally.[49] Eligiblepatients had to have an abnormal myelogram and were stratified according to histology (lymphomaor carcinoma). Of the 37 patients enrolled, 22 were treated with high-dose dexamethasone and 15were treated in the low-dose arm. All patients received external-beam radiation therapy within 12hours of therapy; however, pain scores for the group were significantly decreased at 3 hours.

There was no difference detected with respect to reduction in pain or neurologic function. Theauthors recommended 10 mg of intravenous dexamethasone as initial therapy in the treatment ofpatients with epidural compression caused by metastatic disease. Other authors continue torecommend high-dose corticosteroids, particularly in patients with profound neurologicdysfunction.[50,51] There is also evidence that patients without neurologic dysfunction can proceedto radiation without receiving corticosteroids.[52]

Corticosteroids for Palliative Care

Physicians often use corticosteroids for the treatment of cancer patients facing the end of life.Moertel and colleagues from the Mayo Clinic reported the first controlled study of corticosteroids interminally ill patients with cancer.[53] They randomized patients with advanced gastrointestinalcancers to dexamethasone or placebo, and noted significant improvement in both strength and

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appetite among patients receiving dexamethasone.

Bruera and colleagues performed a randomized, double-blind crossover trial of methylprednisolonein terminally ill patients with cancer to determine the effects on pain, depression, appetite, andactivity.[54] Included in the study were 40 patients with a variety of primary tumor sites who had"failed" multiple anticancer treatments. They received only opiate analgesics and had nocontraindications to treatment with steroids.

These patients were randomized to methylprednisolone (16 mg orally twice daily) or placebo on days1 to 5 followed by a 2-day rest, then crossed over on days 8 to 12, followed by another 2-day rest.After the 14-day double-blind phase was completed, all patients received 32 mg ofmethylprednisolone for 20 days. Notably, pain scores improved, appetite and activity increased,depression and analgesic use decreased, and patients requested methylprednisolone over placebo.No significant toxicity was noted, and the authors concluded that methylprednisolone improved thecomfort level of patients with cancer.

Hanks et al looked at corticosteroid use in terminal cancer patients by performing a prospectivestudy in patients admitted to an inpatient hospice unit.[55] Physicians prescribing steroids forpatients in the unit noted the reason, and assessed them for response. Patients receivedprednisolone, 10 to 30 mg followed by 5 to 20 mg/d, or dexamethasone, 4 to 16 mg followed by0.5 mg to 4 mg/d every other day. The most common uses included nerve compression, raisedintracranial pressure, chemotherapy, airway obstruction, and nerve compression.

Of the 373 patients studied, 75 received corticosteroids for "nonspecific" uses. The most commonside effects with either agent were thrush, fluid retention, and moon facies. The median duration oftreatment was 4 to 8 weeks. Response rates greater than 30% were achieved when corticosteroidswere used for nerve compression, chemotherapy, raised intracranial pressure, airway obstruction,metastatic arthralgias, and nonspecific reasons. The authors concluded that corticosteroids werevaluable for symptom management, and overall, 40% of patients appeared to respond.

A retrospective review of the use of corticosteroids in terminally ill patients was reported byNeedham et al.[56] Records of 100 consecutive patients admitted to hospice were reviewed for useof steroids, indications, and response, and 33 patients were found to have prior or presentprescriptions for corticosteroids. Of those 33 patients, 20 had been taking corticosteroids for morethan 1 month, and only 8 out of 28 (who were able to answer questions) reported benefits from thecorticosteroids. Approximately, 15 patients did not know why they were taking corticosteroids, and 4had severe side effects. Only 8 patients knew not to stop using steroids abruptly.

The authors suggest that the use of steroids should be accompanied by a clear goal and bemonitored for response, and that the dose should be adjusted accordingly. They suggested that thedrug should be stopped after 1 week if no response is noted, and if the patient improves, thecorticosteroids should be adjusted to the lowest beneficial dose. In an accompanying editorial,Twycross suggests starting corticosteroids at a higher dose to prevent missing a beneficial effect,and then adjusting the dose as necessary.[57] He incisively notes, "If they are not working, stopthem."

Pain

As previously discussed, pain relief is often achieved when corticosteroids are used for otherindications. Corticosteroids are also used as adjuvants to opiate pain medications in many situations,mostly in the terminal phases of cancer. Their use for this indication is well documented in themedical literature, as reviewed by Watanabe and Bruera.[58] Again, drug, dose, route, and scheduleare not standardized. Dexamethasone, prednisone, and prednisolone are commonly used for thisindication.

Cancer Cachexia

Weight loss and anorexia are common problems in patients with advanced cancer. This topic wasreviewed by Bruera in this journal in 1992.[59] In Moertel’s study of dexamethasone vs placebo in

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advanced gastrointestinal cancer, an improvement in appetite was noted in the dexamethasonearm; however, treatment did not result in weight gain. Bruera reported improved appetite withmethylprednisolone.[54] Willcox et al reported improvement in appetite without weight gain incancer patients using prednisolone.[60] Unfortunately, these effects are short-lived, and otheragents may be more efficacious.[61,62]

Two studies have investigated weight loss and anorexia by comparing corticosteroids to megesterolacetate, a commonly used appetite stimulant in patients with cancer cachexia. Lai et al comparedoral administration of megesterol (40 mg four times daily), prednisolone (10 mg three times daily),and placebo (1 tablet three times daily) in 52 patients experiencing anorexia during external-beamradiation to the pelvis.[63] During the 21-day trial, megesterol proved significantly better thanplacebo, but not superior to prednisolone. Prednisolone did not significantly improve appetite overplacebo, but was significantly better in preventing further loss of appetite. Performance status andwell-being were said to have improved; however, this study could have benefited from blinding andaltered dosing schedules.

Loprinzi and colleagues at the Mayo Clinic also tested this hypothesis by comparing dexamethasone(0.75 mg four times daily) with megestrol (800 mg daily) and fluoxymesterone (10 mg twice daily).Responses with dexamethasone were equivalent to those reported with megestrol, with the majordifferences occurring in side-effect profiles and cost. Trends were noted, however, suggesting thesuperiority of megestrol. Even though dexamethasone did not produce significantly greater sideeffects than megestrol, a higher rate of treatment discontinuation was seen with dexamethasone.Treatment with megestrol, however, resulted in a slightly higher rate of venous thrombosis.

The authors provided a stimulating discussion about whether or not cancer cachexia should betreated at all, and if so, at what cost. They point out that dexamethasone costs far less than a dollara day, or up to 60-fold less than megestrol. Even if improved dosing were to have reduced costs, thecost analysis by Loprinzi et al did not include the excess cost of treating venous thrombosis. It is,therefore, important to assess the particular clinical situation before choosing one agent over theother. Dexamethasone may be the preferred agent for short-term use in terminally ill patients, forwhom corticosteroids may provide other palliative benefits.

Hypercalcemia

corticosteroids have historically been used for the treatment of hypercalcemia, although their use inmalignant hypercalcemia appears most beneficial in cancers responsive to corticosteroids, such asmyeloma. With the development of bisphosphonates, corticosteroid use has become less importantfor the treatment of this complication. Initial symptomatic treatment, particularly in volume-depletedpatients, includes the administration of normal saline.

Percival and colleagues conducted a comparative trial of saline and furosemide, with and withoutprednisolone (20 to 60 mg/d).[64] There was no difference in outcome between the groups, and theinvestigators concluded that corticosteroids were ineffective in the treatment of hypercalcemiarelated to solid tumors. This trial was limited in that it was apparently not a randomized trial, calciumlevels were adjusted for albumin (rather than using a more precise measure), tumor types andcorticosteroid dosages varied, and statistical methods were not detailed.

Another randomized trial of normal saline and furosemide, with and without methylprednisolone (25mg po tid), was reported by Kristensen et al in 1992.[65] Thirty women with metastatic breastcancer were evenly divided between treatments, and significant decreases in ionized calcium werenoted in each group, with the greatest differences seen in those receiving methylprednisolone.Furthermore, seven patients (47%) treated with methylprednisolone achieved normal ionizedcalcium levels, while none of the control group normalized.

Although there was no survival advantage for either arm, the data indicate that corticosteroids areeffective in the treatment of hypercalcemia—at least in women with breast cancer—and may beuseful adjuncts to bisphosphonates, which require several days of treatment to lower calcium levels.This trial was not weakened by design problems similar to those in the prior report, in that thepatient population and treatment doses were similar, precise measures were utilized, and statistical

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methods were provided.

Chemotherapy-Induced Lung Toxicity

Several chemotherapeutic agents are known to predispose patients to pulmonary toxicity,particularly bleomycin (Blenoxane). This may occur long after the chemotherapy was received, andin the case of bleomycin, can be activated by the administration of supplemental oxygen. Severalreports suggest that symptoms of pulmonary toxicity as a result of treatment with bleomycin,[66-68]mitomycin (Mutamycin),[69] or gemcitabine (Gemzar)[70] can be improved with the use ofcorticosteroids.

Obstructive Renal Failure

Abdominal and pelvic cancers frequently cause ureteral obstruction. Flombaum et al reported twocases in which this complication was relieved with high-dose methylprednisolone (500 to 1,000 mgIV).[71] In each case, corticosteroid treatment resulted in improved in the output of urine.

Ascites

A provocative trial of triamcinolone for the treatment of malignant ascites was recently reported.[72]In this investigation, 15 prospectively enrolled patients were treated with large-volume paracentesisfollowed by the intraperitoneal instillation of triamcinolone hexacetonide (Aristospan), 10 mg/kg, andthen by 10 mL of sterile normal saline flush.

The interval between treatment and subsequent paracentesis was 17.5 days, compared withpretreatment intervals averaging 9.5 days. Individual measures of general well-being, appearance,and distention improved significantly, as did mean symptom scores. Pre- and posttreatmentparacentesis volumes were similar, and patients with low serum ascites-albumin gradients appearedto benefit most. This approach to palliation of this difficult problem deserves further study.

Superior Vena Cava Syndrome

Corticosteroids are occasionally used for initial symptomatic relief of superior vena cava obstructionrelated to malignancy, but few data exist regarding the efficacy of corticoteroids for thisindication.[73]

Mucositis

Corticosteroids are common components of institutional "special" or "magic" mouthwashes for thetreatment of oral mucositis. Rothwell and Spektor evaluated a cocktail of hydrocortisone,tetracycline, nystatin, and diphenhydramine, four times daily, in patients receiving radiation to thehead and neck.[74] Treatment was administered in a blinded fashion to 12 randomized patients. Thecontrol group comprised 7 patients, and 5 received treatment. Results of clinical dental exams andsymptom scores favored treatment with the cocktail. Although the trial was statisticallyunderpowered to determine a difference, the data appear to suggest a benefit, and furtherinvestigation is warranted.

Leborgne et al took a slightly different approach, and performed a randomized double-blind trial oforal prednisone (40 mg/d) vs placebo in patients receiving radiation for head and neckmalignancies.[75] No difference in the development of mucositis was detected, but a trend towardfewer treatment interruptions was noted. However, researchers did not specifically note whethertreatment delays were due to neutropenia, emesis, mucositis, or other factors.

Thus, it is unclear whether the reduction in treatment delays was the result of corticosteroid-inducedleukocytosis, improved nausea control, or effects on mucositis. The authors did not comment on theincidence of nausea in the study, but as previously discussed, corticosteroids may improveradiation-induced nausea. Thus, it would be helpful if future studies in this area also addressedpotentially confounding symptoms.

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Dyspnea/Lymphangitic Tumor Spread

Another oncologic scenario in which corticosteroids are occasionally used is the palliation ofaggressive "inflammatory" tumor progression such as lymphangitic spread of tumor in the lungs.[76]This problem is commonly seen in patients with breast cancer, lung cancer, or relapsed lymphoma.Our experience suggests that corticosteroids produce a clinical benefit in this setting, whether theare used alone for comfort or as part of aggressive anticancer therapy.

Summary

Corticosteroids are useful agents in the treatment of patients with advanced, refractory cancer.Although few well-designed trials exist to definitively outline indications for treatment and dosagesto be used, there is sufficient evidence to support their use in the palliation of symptoms related toadvanced cancer. That said, responses may be brief, and consideration should be given to taperingthem when efficacy is marginal or toxicity outweighs the benefit.

As with any cancer therapy, when the "art of medicine" leads us to a trial of corticosteroids, weshould remember to provide an appropriate explanation to the patient and family, including areasonable assessment of response and toxicity. References: 1. Ettinger AB, Portenoy RK: The use of corticosteroids in the treatment of symptoms associated withcancer. J Pain Symptom Manage 3(2):99-103, 1988.

2. Twycross R: The risks and benefits of corticosteroids in advanced cancer. Drug Saf 11(3):163-178,1994.

3. Haynes RC, Murad F: Adrenocorticotropic hormone; Adrenocortical steroids and their syntheticanalogs; Inhibitors of adrenal steroid biosynthesis, in Gilman AG, Goodman LS, Rall TW, et al (eds):The Pharmacologic Basis of Therapeutics, ed 7, pp 1466-1475. New York, MacMillan, 1985.

4. Spiegel RJ, Vigersky RA, Oliff AI, et al: Adrenal suppression after short-term corticosteroid therapy.Lancet 1(8117):630-633, 1979.

5. Del Priore G, Gurski KJ, Warshal DP, et al: Adrenal function following high-dose steroids in ovariancancer patients. Gynecol Oncol 59(1):102-104, 1995.

6. Lefor AT: Perioperative management of the patient with cancer. Chest 115(5 suppl):165S-171S,1999.

7. Jenkins CA, Bruera E: Difficulties in diagnosing neuropsychiatric complications of corticosteroids inadvanced cancer patients: Two case reports. J Pain Symptom Manage 19(4):309-317, 2000.

8. Brennan MJ: Corticosteroids in the treatment of solid tumors. Med Clin North Am 57(5):1225-1239,1973.

9. Alexanian R, Yap BS, Bodey GP: Prednisone pulse therapy for refractory myeloma. Blood62(3):572-577, 1983.

10. Norfolk DR, Child JA: Pulsed high-dose oral prednislone in relapsed or refractory multiplemyeloma. Hematol Oncol 7(1)61-68, 1989.

11. Friedenberg WR, Kyle RA, Knospe WH, et al: High-dose dexamethasone for refractory or relapsingmultiple myeloma. Am J Hematol 36(3):171-175, 1991.

12. Alexanian R, Barlogie B, Dixon D: High-dose glucocorticoid treatment of resistant myeloma. Ann

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Intern Med 105(1):8-11, 1986.

13. Newcome SR: Case reports: Continuous corticosteroids for refractory poorly differentiatedlymphocytic lymphoma. Am J Med Sci 312(3):136-137, 1996.

14. Minton MJ, Knight RK, Rubens RD, et al: Corticosteroids for elderly patients with breast cancer.Cancer 48(4):883-887, 1981.

15. Mercer PM, Ebbs SR, Fraser SC, et al: Trial of aminoglutethimide vs hydrocortisone as second-linehormone treatment of advanced breast cancer. Eur J Surg Oncol 19(3):254-258, 1993.

16. Tannock I, Gospodarowicz M, Meakin W, et al: Treatment of metastatic prostatic cancer withlow-dose prednisone: Evaluation of pain and quality of life as pragmatic indices of response. J ClinOncol 7(5):590-597, 1989.

17. Tannock IF, Osoba D, Stockler MR, et al: Chemotherapy with mitoxantrone plus prednisone orprednisone alone for symptomatic hormone-resistant prostate cancer: A Canadian randomized trialwith palliative end points. J Clin Oncol 14(6):1756-1764, 1996.

18. Sartor O, Weinberger M, Moore A, et al: Effect of prednisone on prostate-specific antigen inpatients with hormone-refractory prostate cancer. Urology 52(2):252-256, 1998.

19. Rich WM, Abdulhayoglu G, DiSaia PJ: Methylprednisolone as an antiemetic during cancerchemotherapy—A pilot study. Gynecol Oncol 9(2):193-198, 1980.

20. Lee BJ: Methylprednisolone as an antiemetic. N Engl J Med 304(8):486, 1981.

21. Aapro MS, Alberts DS: Dexamethasone as an antiemetic in patients treated with cisplatin. N EnglJ Med 305(9):520, 1981.

22. Cassileth PA, Lusk EJ, Torri S, et al: Antiemetic efficacy of dexamethasone therapy in patientsreceiving cancer chemotherapy. Arch Intern Med 143(7):1347-1349, 1983.

23. Metz CA, Freedman RS, Magrina JF: Methylprednisolone in cisplatinum induced nausea andemesis: A placebo-controlled trial. Gynecol Oncol 27(1):84-89, 1987.

24. Parry H, Martin K: Single-dose IV dexamethasone—an effective anti-emetic in cancerchemotherapy. Cancer Chemother Pharmacol 28(3):231-232, 1991.

25. Markman M, Sheidler V, Ettinger DS, et al: Antiemetic efficacy of dexamethasone. Randomized,double-blind, crossover study with prochlorperazine in patients receiving cancer chemotherapy. NEngl J Med 311(9):549-552, 1984.

26. Kirkbride P, Bezjak A, Pater J, et al: Dexamethasone for the prophylaxis of radiation-inducedemesis: A National Cancer Institute of Canada Clinical Trials Group phase III study. J Clin Oncol18(9):1960-1966, 2000.

27. Smith DB, Newlands ES, Rustin GJ, et al: Comparison of ondansetron and ondansetron plusdexamethasone as antiemetic prophylaxis during cisplatin-containing chemotherapy. Lancet338(8765):487-490, 1991.

28. Roila F, Tonato M, Cognetti F, et al: Prevention of cisplatin-induced emesis: A double-blindmulticenter randomized crossover study comparing ondansetron and ondansetron plusdexamethasone. J Clin Oncol 9(4):675-678, 1991.

29. Hesketh PJ, Harvey WH, Harker WG, et al: A randomized, double-blind comparison of intravenousondansetron alone and in combination with intravenous dexamethasone in the prevention ofhigh-dose cisplatin-induced emesis. J Clin Oncol 12(3):596-600, 1994.

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30. Ahn MJ, Lee JS, Lee KH, et al: A randomized double-blind trial of ondansetron alone vs incombination with dexamethasone vs in combination with dexamethasone and lorazepam in theprevention of emesis due to cisplatin-based chemotherapy. Am J Clin Oncol 17(2):150-156, 1994.

31. Italian Group For Antiemetic Research: Ondansetron + dexamethasone vs metoclopramide +dexamethasone + diphenhydramine in prevention of cisplatin-induced emesis. Lancet340(8811):96-99, 1992.

32. Levitt M, Warr D, Yelle L, et al: Ondansetron compared with dexamethasone and metoclopramideas antiemetics in the chemotherapy of breast cancer with cyclophosphamide, methotrexate, andfluorouracil. N Engl J Med 328(15):1081-1084, 1993.

33. Jones AL, Hill AS, Soukop M, et al: Comparison of dexamethasone and ondansetron in theprophylaxis of emesis induced by moderately emetogenic chemotherapy. Lancet338(8765):483-487, 1991.

34. The Italian Group for Antiemetic Research: Dexamethasone, granisetron, or both for theprevention of nausea and vomiting during chemotherapy for cancer. N Engl J Med 332(1):1-5, 1995.

35. Goedhals L, Heron JF, Kleisbauer JP, et al: Control of delayed nausea and vomiting withgranisetron plus dexamethasone or dexamethasone alone in patients receiving highly emetogenicchemotherapy: A double-blind, placebo-controlled, comparative study. Ann Oncol 9(6):661-666,1998.

36. Breier S, Lebedinsky C, Ayaviri C, et al: Long-term weekly paclitaxel over 1-hour infusion withde-escalated premedication. A phase II trial report (abstract 523). Breast Cancer Res Treat57(1):124, 1999.

37. Latreille J, Gelmon KA, Hirsh V, et al: Phase II trial of docetaxel with dexamethasonepremedication in patients with advanced non-small-cell lung cancer: The Canadian experience.Invest New Drugs 16(3):265-270, 1998.

38. Hainsworth JD, Burris HA, 3rd, Greco FA: Weekly administration of docetaxel (Taxotere):Summary of clinical data. Semin Oncol 26(3 suppl 10):19-24, 1999.

39. Borgelt B, Gelber R, Kramer S, et al: The palliation of brain metastases: Final results of the firsttwo studies by the Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys 6(1):1-9, 1980.

40. Kofman S, Al E: Treatment of cerebral metastases from breast carcinoma with prednisolone.Jama 163:1473-1476, 1957.

41. French L, Galicich J: The use of steroids for control of cerebral edema. Clin Neurosurg10:212-223, 1964.

42. Vecht CJ, Hovestadt A, Verbiest HB, et al: Dose-effect relationship of dexamethasone onKarnofsky performance in metastatic brain tumors: A randomized study of doses of 4, 8, and 16 mgper day. Neurology 44(4):675-680, 1994.

43. Loblaw DA, Laperriere NJ: Emergency treatment of malignant extradural spinal cord compression:An evidence-based guideline. J Clin Oncol 16(4):1613-1624, 1998.

44. Ushio Y, Posner R, Posner JB, et al: Experimental spinal cord compression by epidural neoplasm.Neurology 27(5):422-429, 1977.

45. Ushio Y, Posner R, Kim JH, et al: Treatment of experimental spinal cord compression caused byextradural neoplasms. J Neurosurg 47(3):380-390, 1977.

46. Greenberg HS, Kim JH, Posner JB: Epidural spinal cord compression from metastatic tumor:Results with a new treatment protocol. Ann Neurol 8(4):361-366, 1980.

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47. Delattre JY, Arbit E, Thaler HT, et al: A dose-response study of dexamethasone in a model ofspinal cord compression caused by epidural tumor. J Neurosurg 70(6):920-925, 1989.

48. Sorensen S, Helweg-Larsen S, Mouridsen H, et al: Effect of high-dose dexamethasone incarcinomatous metastatic spinal cord compression treated with radiotherapy: A randomised trial. EurJ Cancer 30A(1):22-27, 1994.

49. Vecht CJ, Haaxma-Reiche H, van Putten WL, et al: Initial bolus of conventional vs high-dosedexamethasone in metastatic spinal cord compression. Neurology 39(9):1255-1257, 1989.

50. Maranzano E, Latini P: Effectiveness of radiation therapy without surgery in metastatic spinalcord compression: Final results from a prospective trial. Int J Radiat Oncol Biol Phys 32(4):959-967,1995.

51. Byrne TN: Spinal cord compression from epidural metastases. N Engl J Med 327(9):614-619,1992.

52. Maranzano E, Latini P, Beneventi S, et al: Radiotherapy without steroids in selected metastaticspinal cord compression patients. A phase II trial. Am J Clin Oncol 19(2):179-183, 1996.

53. Moertel CG, Schutt AJ, Reitemeier RJ, et al: Corticosteroid therapy of preterminal gastrointestinalcancer. Cancer 33(6):1607-1609, 1974.

54. Bruera E, Roca E, Cedaro L, et al: Action of oral methylprednisolone in terminal cancer patients: Aprospective randomized double-blind study. Cancer Treat Rep 69(7-8):751-754, 1985.

55. Hanks GW, Trueman T, Twycross RG: Corticosteroids in terminal cancer—a prospective analysisof current practice. Postgrad Med J 59(697):702-706, 1983.

56. Needham PR, Daley AG, Lennard RF: Steroids in advanced cancer: Survey of current practice.Bmj 305(6860):999, 1992.

57. Twycross R: Corticosteroids in advanced cancer. BMJ 305(6860):969-970, 1992.

58. Watanabe S, Bruera E: Corticosteroids as adjuvant analgesics. J Pain Symptom Manage9(7):442-445, 1994.

59. Bruera E: Current pharmacological management of anorexia in cancer patients. Oncology6(1):125-130; discussion 32, 37, 1992.

60. Willox JC, Corr J, Shaw J, et al: Prednisolone as an appetite stimulant in patients with cancer. BrMed J (Clin Res Ed) 288(6410):27, 1984.

61. Loprinzi CL, Goldberg RM, Burnham NL: Cancer-associated anorexia and cachexia. Implicationsfor drug therapy. Drugs 43(4):499-506, 1992.

62. Loprinzi CL, Ellison NM, Goldberg RM, et al: Alleviation of cancer anorexia and cachexia: Studiesof the Mayo Clinic and the North Central Cancer Treatment Group. Semin Oncol 17(6 suppl 9):8-12,1990.

63. Lai YL, Fang FM, Yeh CY: Management of anorexic patients in radiotherapy: A prospectiverandomized comparison of megestrol and prednisolone. J Pain Symptom Manage 9(4):265-268, 1994.

64. Percival RC, Yates AJ, Gray RE, et al: Role of glucocorticoids in management of malignanthypercalcaemia. Br Med J (Clin Res Ed) 289(6440):287, 1984.

65. Kristensen B, Ejlertsen B, Holmegaard SN, et al: Prednisolone in the treatment of severemalignant hypercalcaemia in metastatic breast cancer: A randomized study. J Intern Med

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232(3):237-245, 1992.

66. Gilson AJ, Sahn SA: Reactivation of bleomycin lung toxicity following oxygen administration. Asecond response to corticosteroids. Chest 88(2):304-306, 1985.

67. Jensen JL, Goel R, Venner PM: The effect of corticosteroid administration on bleomycin lungtoxicity. Cancer 65(6):1291-1297, 1990.

68. White DA, Stover DE: Severe bleomycin-induced pneumonitis. Clinical features and response tocorticosteroids. Chest 86(5):723-728, 1984.

69. Chang AY, Kuebler JP, Pandya KJ, et al: Pulmonary toxicity induced by mitomycin C is highlyresponsive to glucocorticoids. Cancer 57(12):2285-2290, 1986.

70. Vander Els NJ, Miller V: Successful treatment of gemcitabine toxicity with a brief course of oralcorticosteroid therapy. Chest 114(6):1779-1781, 1998.

71. Flombaum CD, Schroy P, Watson R, et al: Treatment of acute obstructive renal failure withhigh-dose methylprednisolone. Arch Intern Med 145(1):58-61, 1986.

72. Mackey JR, Wood L, Nabholtz J, et al: A phase II trial of triamcinolone hexacetanide forsymptomatic recurrent malignant ascites. J Pain Symptom Manage 19(3):193-199, 2000.

73. Abner A: Approach to the patient who presents with superior vena cava obstruction. Chest 103(4suppl):394S-397S, 1993.

74. Rothwell BR, Spektor WS: Palliation of radiation-related mucositis. Spec Care Dentist 10(1):21-25,1990.

75. Leborgne JH, Leborgne F, Zubizarreta E, et al: Corticosteroids and radiation mucositis in head andneck cancer. A double-blind placebo-controlled randomized trial. Radiother Oncol 47(2):145-148,1998.

76. Lowenthal RM, Jestrimski KW: Corticosteroid drugs: Their role in oncological practice. Med J Aust144(2):81-85, 1986. Source URL: http://www.diagnosticimaging.com/review-article/corticosteroids-advanced-cancer

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