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From the Harry R. Horvitz Center for Palliative Medicine (World Health Organization demonstration project) and Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio, and Capital Hospice and Capital Palliative Care Consultants, Falls Church, Virginia.
Potential Financial Conflicts of Interest: None disclosed.
Requests for Single Reprints: Susan B. LeGrand, MD, Harry R. Horvitz Center for Palliative Medicine, Solid Tumor Oncology, Cleveland Clinic, Taussig Cancer Institute, 9500 Euclid Avenue R35, Cleveland, OH 44195; e-mail, firstname.lastname@example.org.
Current Author Addresses: Drs. LeGrand and Zama: Harry R. Horvitz Center for Palliative Medicine, Solid Tumor Oncology, Cleveland Clinic, Taussig Cancer Institute, 9500 Euclid Avenue R35, Cleveland, OH 44195.
Dr. Leskuski: 209 Gibson Street Northwest, Suite 202, Leesburg, VA 20176.
Although primary hyperparathyroidism is the most common cause of hypercalcemia, cancer is the most common cause requiring inpatient intervention. An estimated 10% to 20% of all patients with cancer have hypercalcemia at some point in their disease trajectory, particularly in advanced disease. Aggressive saline hydration and varying doses of furosemide continue to be the standard of care for emergency management. However, a review of the evidence for the use of furosemide in the medical management of hypercalcemia yields only case reports published before the introduction of bisphosphonates, in contrast to multiple randomized, controlled trials supporting the use of bisphosphonates. The use of furosemide in the management of hypercalcemia should no longer be recommended.
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TO THE EDITOR: LeGrand et al. (1) concluded, based upon their recent review of the literature, that furosemide has no role in the modern management of hypercalcemia. We take issue with this contention and note the fundamental limitations of their analysis.
Bisphosphonates attenuate bone calcium mobilization and address a major "“ but not the only "“ clinical contributor to hypercalcemia. Hypercalcemia may also result from increased gastrointestinal calcium uptake. Decreased renal excretion alone does not cause hypercalcemia, but it aggravates hypercalcemia from other causes. Volume contraction and dehydration due to natriuresis and nephrogenic diabetes insipidus, respectively, also amplify hypercalcemia of all causes. Furosemide's calciuric effect and its enhancement by volume expansion, however, are well established: natriuresis promotes calciuresis.
In our opinion, the authors' analysis neither demonstrated nor excluded therapeutic benefits for furosemide. That the therapy is "unproven" by systematic reviews does not invalidate a wealth of experimental and clinical data suggesting benefit (2-5). Indeed, the overwhelming majority of hypercalcemic patients detailed by the authors improved or normalized in response to calciuric therapy with furosemide(1). Our own clinical experience is similar, although the effectiveness of furosemide clearly depends upon adequate attention to volume status and fluid balance prior to and during therapy.
Bisphosphonates are not without significant adverse sequelae or expense, so alternative therapeutic options are needed for patients that cannot tolerate or afford them. We acknowledge the important role for bisphosphonates in the treatment of hypercalcemia, but we regard the monolithic contention that calciuric therapy has no utility in the treatment of hypercalcemia as both misplaced and unsupported by the data. The additive effects of bisphosphonates and calciuretic therapy are well suited for combination therapy, and we contend that furosemide remains an important tool in the well-prepared physician's therapeutic arsenal. The authors' anecdotal accounts of widespread nonadherence to recommended guidelines for concomitant saline administration suggests a need to educate clinicians in the proper use of furosemide therapy, rather than its dismissal.
This work reflects a recent trend in the literature that discounts fundamental physiologic principles and favors pure statistical considerations in determining "best" evidence. This article's selection for associated CME activities (http://cme.annals.org/) is also unfortunate, as this tacitly validates conclusions not fully supported by the data. The authors have, however, raised an important issue that can be best addressed by a well-designed randomized controlled trial comparing bisphosphonate therapy alone and in combination with calciuric therapy in carefully matched hypercalcemic patients.
1. LeGrand SB, Leskuski D, Zama I. Narrative review: Furosemide for hypercalcemia: An unproven yet common practice. Ann. Intern. Med. 2008;149:259-263.
2. Suki WN, Yium JJ, Von Minden M, Saller-Hebert C, Eknoyan G, Martinez-Maldonado M. Acute treatment of hypercalcemia with furosemide. N. Engl. J. Med. 1970;283(16):836-840.
3. Eknoyan G, Suki WN, Martinez-Maldonado M. Effect of diuretics on urinary excretion of phosphate, clacium, and magnesium in thyroparathyroidectomized dogs. J. Lab. Clin. Med. 1970;76(2):257-266.
4. Martinez-Maldonado M, Eknoyan G, Suki WN. Diuretics in nonedematous states: Physiological basis for the clinical use. Arch. Intern. Med. 1973;131:797-808.
5. Reyes AJ, Taylor SH. Diuretics in cardiovascular therapy: The new clinicopharmacological bases that matter. Cardiovasc. Drugs Ther. 1999;13:371-398.
The authors question our conclusion that furosemide has no role other than management of fluid overload although we are not alone in this conclusion (1-4). The fact that furosemide produces calciuris is not in question. The question is whether this translates into a practical therapy for malignant hypercalcemia. What we found was not a "wealth" but a paucity of evidence for the value of furosemide and no evidence to support the currently recommended doses. The other key element in the case reports was the intensity of monitoring to insure adequate rehydration and replacement of urine losses, something which is certainly not standard today and would add significantly to the cost of therapy. Only a third (not an "overwhelming majority) of patients normalized with duration of response not reported.
The letter writers overstate the toxicity of the single dose of bisphosphonates required for hypercalcemia. Toxicity is minimal, typically fever and in the acute setting administered inpatient so access to the medications is not an issue. The toxicity/cost issues noted are a concern for chronic rather than acute use. Delaying institution of bisphosphonates prolongs length of stay and might outweigh any cost advantage although comparison studies do not exist. Withholding bisphosphonates may result in rapid relapse once hydration is stopped particularly in a palliative setting when disease specific therapy may not exist.
While I agree that one could conduct a randomized trial of bisphosphonates +/- furosemide there are too many unanswered questions to ethically proceed. What dose of furosemide would one use? Based on what evidence? Would you conduct phase 1 trials to determine appropriate dose first? How would one determine adequate hydration on the furosemide arm, etc. There are many more critical things to research and newer therapies under evaluation as we continue to understand the cytokines involved in malignant hypercalcemia. Teach fluids and bisphosphonates, easy to learn and less potential for harm from over or underhydration.
1. Mundy GR, Guise TA. Hypercalcemia of malignancy. Am J Med. 1997; 103:134-45. [PMID: 9274897]
2. Sambandam K, Vijayan A. Fluid and electrolyte management. In: Cooper DH, Krainik AJ, Lubner SJ, Reno HEL, eds. Washington Manual of Medical Therapeutics. 32nd ed. Philadelphia: Lippincott Williams and Wilkins; 2007.
3. Luce JA. Oncologic emergencies. In: Wachter RM, Godman L, Hollander H, eds. Hospital Medicine. 2nd ed. Philadelphia: Lippincott Williams and Wilkins; 2005.
4. Agus ZS, Berensen JR. Treatment of hypercalcemia. UpToDate Online 16.1 2008. Accessed at www.uptodateonline.com on 28 May 2008
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