Neoplastic Fever: Pathophysiology, Clinical Features, And Diagnostic Assessment

August 13, 2014

By David Kudlowitz, MD

Peer Reviewed

Neoplastic fever (aka tumor fever) is a challenging yet essential clinical diagnosis. In fevers of unknown origin, studies estimate that the incidence of neoplastic fever is anywhere from 7 to 31% [1, 2, 3]. In the febrile patient with malignancy, tumor fever is the most common cause of non-infectious pyrexia (41%) [4]. While leukemia, lymphoma, sarcoma, atrial myxoma, renal cell carcinoma, and liver metastases are the most common culprits, neoplastic fever has been reported in several other cancer types [5, 6, 7]. The process of making this diagnosis can cause a patient significant morbidity, anxiety, and frustration. This review will focus on the pathophysiology, clinical features, and diagnostic assessments we have to pinpoint this cancer related disorder.


The pathophysiology of neoplastic fever is not completely understood, however, cytokines are known to be the key players. These endogenous pyrogens induce prostaglandin E2, which in turn causes hypothalamic set point surge, and fever. IL-1, TNF, IL-2, IL-6, IL-12, or interferon may be elevated with neoplasm or infection [8]. While the cause of elevated cytokines during infection is precipitated by pathogens, the trigger in cancer is unclear. One study found that activation of Il-1? was induced by mutated RAS [9]. Another possibility includes inflammation secondary to ulceration or necrosis caused by the tumor itself. A key player in this cytokine jumble is IL-6. High levels of IL-6 are seen in Hodgkin’s Lymphoma, Diffuse Large Cell Lymphoma, and CLL. IL-6 is associated with B-symptoms and has prognostic value in these three cancer types, as well as renal cell carcinoma [10, 11, 12, 13, 14]. Notably, in Diffuse-Large Cell Lymphoma, the independent factor that most correlates with complete remission and disease free survival is IL-6 serum level [15].

Clinical Features

The clinical features of fever caused by malignancy are different than those caused by infection. While the temperatures are usually high (above 40 degrees Celsius), the signs and symptoms are muted when compared to infectious pyrexia. The fevers are generally not associated with rigors, chills, tachycardia, or hypotension. Notably, the fever is not relieved by acetaminophen [16].

Usually chemotherapy, blood transfusion, drug reaction, and radiation induced pyrexia can been ruled out based on signs and symptoms, time course, and duration; however, ruling out occult infection is not as straight forward. All patients with known malignany and fever require a full infectious work up. After 1-2 weeks of continuous fever without positive culture data or response to antibiotics, alternative infectious etiologies should be considered including less common fungal, viral, and parasitic organisms. Neoplastic fever is only considered when other diagnoses have been thoroughly excluded.

Diagnostic Assessment: Does Naproxen Lyse Neoplastic Fever?

In an attempt to successfully diagnose this disorder and provide patients with relief from regular fevers, several studies have examined naproxen and its role in tumor fever lysis. Clinical studies completed in the 1980s by Chang and Gross had affirmative results. The first study examined 22 cancer patients with fever. The patients had a variety of malignancies, including leukemia, lymphoma, primary lung, melanoma, and colon. All patients received naproxen 250 mg twice daily. Of the 22 patients, 15 were clinically diagnosed with neoplastic fever, 5 had infection, and 2 had connective tissue disorders (in addition to cancer). Of the 15 with neoplastic fever, 14/15 had lysis of fever within 24 hours of naproxen treatment; none of the patients with infection or rheumatologic disease responded to naproxen. The striking elements of this study are that naproxen was: successful in lysis in 93% of neoplastic fever patients, effective within 24 hours, and specific to neoplastic fever (no response in patients with infection) [17]. Similar results were seen in the 1985 study – 20/21 patients with neoplastic fever had lysis within 24 hours after starting naproxen [18]. A presentation by Chang, published in 1987, showed that in 68 cancer patients with pyrexia, 50 had neoplastic fever with 46/50 responders (it is unclear if the patients included in this presentation were also part of his previous two studies). Of the infectious patients, only 1/13 had a partial response to naproxen [19]. Of note, these three studies included patients with neutropenic fever and naproxen was just as successful (although there was higher incidence of infection in these patients). In 1995, another clinical study was performed in patients with advanced gynecologic malignancy and suspected neoplastic fever. This investigation had 10/12 naproxen responders (1 of the non-responders was found to have culture negative bacteremia) [xx]. Other NSAIDs, such has rofecoxib, indomethicin, ibuprofen, and diclofenac have been as effective as naproxen in fever lysis [21, 22, 23].

Of the papers written by Chang and Gross, it is unclear if they were using new patients for all of their trials or if they used repetitive data. These studies are limited by their small sample sizes, narrow geographic range, and higher prevalence of neoplastic fever than reported in other literature. [4] The validity of these trials is also limited by the fact that an exceptional amount has changed in cancer treatment since the 1980’s.

Furthermore, not all studies of naproxen have been positive. A retrospective study of one hospital looked at 290 patients over a 10-year period with prolonged unexplained fever. Of these patients, 72 received naproxen, 11 of whom had neoplastic fevers, 66 with nonneoplastic fever. On review, there was no statistically significant difference in Naproxen response between neoplastic and nonneoplastic fever groups (6/11 for neoplastic fever patients and 25/66 in non-neoplastic disease; 55% vs. 38%, p=0.5)24though this study was not designed with the power to detect a difference between neoplastic and non-neoplastic fever groups.

Despite the limitations of the literature, naproxen may aid in the diagnostic workup of neoplastic fever and provide symptomatic relief from pyrexia in patients with malignancy. 25Other diagnostic and treatment methods, such as ESR/CRP trending and corticosteroids have been investigated, but have not demonstrated a role in the management of neoplastic fever [24, 25].


Neoplastic fever is an important consideration in patients with fever of unknown origin or with known malignancy. Other causes, including infection, must be thoroughly excluded before making the diagnosis. Although these patients have intractable fevers, their signs and symptoms are generally milder than those patients with pyrexia secondary to a pathogen. Some studies have shown Naproxen and NSAIDs to cause defervescence in neoplastic fever and not infectious fever, although these studies were small, geographically limited, and poorly powered. In a patient with fever suspected to be secondary to malignancy without a contraindication to NSAIDs, administering several doses of naproxen to attempt lysis of fever, even while on antibiotics, may have clinical and diagnostic utility.

Dr. David Kudlowitz is an Internal Medicine Resident at NYU Langone Medical Center

Peer reviewed by Theresa Ryan, MD, Oncology Medicine, NYU Langone Medical Center

Image courtesy of Wikimedia Commons


1. Horowitz HW. Fever of unknown origin or fever of too many origins? The New England Journal of Medicine 2013;368(3):197–199.

2. Vanderschueren S, Knockaert D, Adriaenssens T, et al. From prolonged febrile illness to fever of unknown origin: the challenge continues. Arch Intern Med 2003;163:1033-41.

3. Bleeker-Rovers CP, Vos FJ, de Kleijn EMHA, et al. A prospective multicenter study on fever of unknown origin: the yield of a structured diagnostic protocol. Medicine (Baltimore) 2007;86:26-38.

4. Toussaint E, Bahel-Ball E, Vekemans M, Georgala A, Al-Hakak L, Paesmans M, Aoun M. Causes of fever in cancer patients (prospective study over 477 episodes). Supportive Care in Cancer 2006;14(7):763–769.

5. Bodel P. Generalized perturbations in host physiology caused by localized tumors. Tumors and fever. Ann N Y Acad Sci 1974;230:6–13.

6. Browder AA, Huff JW, Petersdorf RG. The Significance of Fever in Neoplastic Disease. Annals of Internal Medicine 1961;55(6):932-942.

7. Boggs, DR and Frei E. Clinical studies of fever and infection in cancer. Cancer 1960;13(6):1240–1253.;2-9/abstract

8. Kurzrock R. The role of cytokines in cancer-related fatigue. Cancer 2001;92(6 Suppl):1684–1688.

9. Beaupre DM, Talpaz M, Marini FC, Cristiano RJ, Roth JA, Estrov Z, et al. Autocrine Interleukin-1? Production in Leukemia Evidence for the Involvement of Mutated RAS6. Cancer Research 1999:59(12):2971–2980.

10. Seymour JF, Talpaz M, Cabanillas F, Wetzler M, Kurzrock R. Serum interleukin-6 levels correlate with prognosis in diffuse large-cell lymphoma. Journal of Clinical Oncology1995;13(3):575–582.

11. Seymour JF, Talpaz M, Hagemeister FB, Cabanillas F, Kurzrock R. Clinical correlates of elevated serum levels of interleukin-6 in patients with untreated Hodgkin’s disease. The American Journal of Medicine 1997;102(1):21–28.

12. Fayad L, Keating MJ, Reuben JM, O’Brien S, Lee BN, Lemer S, Kuzrock R. Interleukin-6 and interleukin-10 levels in chronic lymphocytic leukemia: correlation with phenotypic characteristics and outcome. Blood 2001;97(1):256–263.

13. Blay JY, Negrier S, Combaret V, Attali S, Goillot E, Merrouche Y, et al. Serum level of interleukin 6 as a prognosis factor in metastatic renal cell carcinoma. Cancer Research 1992;52(12):3317–3322.

14. Tran TT, Liu Y, Zurita A, Lin Y, Baker-Neblett KL, et al. Prognostic or predictive plasma cytokines and angiogenic factors for patients treated with pazopanib for metastatic renal-cell cancer: a retrospective analysis of phase 2 and phase 3 trials. Lancet Oncology 2012;13(8):827–837.

15. Preti HA, Cabanillas F, Talpaz M, Tucker SL, Seymour JF, Kurzrock R. Prognostic value of serum interleukin-6 in diffuse large-cell lymphoma. Annals of Internal Medicine 1997;127(3):186–194.

16. Zell JA and Chang JC. Neoplastic fever: a neglected paraneoplastic syndrome. Supportive Care in Cancer 2005;13(11):870–877.

17. Chang JC and Gross HM. Utility of naproxen in the differential diagnosis of fever of undetermined origin in patients with cancer. The American Journal of Medicine 1984;76(4):597–603.

18. Chang JC and Gross HM. Neoplastic fever responds to the treatment of an adequate dose of naproxen. Journal of Clinical Oncology 1985;3(4):552–558.

19. Chang JC. How to differentiate neoplastic fever from infectious fever in patients with cancer: usefulness of the naproxen test. Heart Lung 1987;16:122–127 .

20. Economos K, Lucci JA, Richardson B, Yazigi R, Miller DS. The effect of naproxen on fever in patients with advanced gynecologic malignancies. Gynecologic Oncology 1995;56(2):250–254.

21. Tsavaris N, Zinelis A, Karabelis A, Beldecos D, Bacojanis C, Milonacis N, et al. A randomized trial of the effect of three non?steroid antiinflammatory agents in ameliorating cancer?induced fever. Journal of Internal Medicine 1990;228(5):451–455.

22. Kathula SK, Shah K, Polenakovik H, Koduri J. Cyclo-oxygenase II inhibitors in the treatment of neoplastic fever. Supportive Care in Cancer 2003;11(4):258–259.

23. Lusch CJ, Serpick AA, Slater L. Antipyretic effect of indomethacin in patients with malignancy. Cancer 1968;21(4):781–786.

24. Vanderschueren S, Knockaert DC, Peetermans WE, Bobbaers HJ. Lack of value of the naproxen test in the differential diagnosis of prolonged febrile illnesses. The American Journal of Medicine 2003;115(7):572–575.

25. Alsirafy SA, Mesidy El SM, Abou-Elela EN, Elfaramawy YI. Naproxen test for neoplastic fever may reduce suffering. Journal of Palliative Medicine 2011;14(5):665–667.

26. Kallio R, Bloigu A, Surcel HM, Syrjala H. C-reactive protein and erythrocyte sedimentation rate in differential diagnosis between infections and neoplastic fever in patients with solid tumours and lymphomas. Support Care Cancer 2001;9:124–128.

27. Chang JC. Antipyretic effect of naproxen and corticosteroids on neoplastic fever. Journal of Pain and Symptom Management 1988;3(3):141–144.



Leave a Reply

Your email address will not be published. Required fields are marked *