Kirstine K Søgaard, Dóra Körmendiné Farkas, Michelle Z Leisner, Sigrun Alba Johannesdottir Schmidt, Timothy L Lash, Henrik Toft Sørensen
Fever of Unknown Origin and Incidence of Cancer.
Clin Infect Dis. 2022 Sep 29;75(6):968-974. doi: 10.1093/cid/ciac040.
Abstract/Text
BACKGROUND: Diagnostic tools for determining causes of fever of unknown origin (FUO) have improved over time. We examined if cancer incidence among these patients changed over a 20-year period.
METHODS: Population-based cohort study using nationwide Danish registries. We identified individuals diagnosed with FUO (1998-2017) to quantify their excess risk of cancer compared with the general population. Follow-up for cancer started 1 month after FUO. We computed absolute risks and standardized incidence ratios (SIRs) of cancer, and mortality rate ratios adjusted for age, sex, and cancer stage.
RESULTS: Among 6620 patients with FUO (46.9% male; median age: 39 years), 343 were diagnosed with cancer (median follow-up: 6.5 years). The 1- to <12-month risk was 1.2%, and the SIR was 2.3 (95% CI, 1.8-2.9). The increased 1- to <12-month SIR was mainly due to an excess of Hodgkin lymphoma (SIR = 41.7) non-Hodgkin lymphoma (SIR = 16.1), myelodysplastic syndrome/chronic myeloproliferative diseases (SIR = 6.0), lower gastrointestinal cancer (SIR = 3.3), and urinary tract cancer (SIR = 2.9). Beyond 1-year follow-up, malignant melanoma, hepatobiliary tract/pancreatic cancer, and brain/CNS/eye cancer were diagnosed more often than expected. The 1- to <12-month cancer SIR attenuated over time, and for the 2013-2017 period we found no excess risk. Patients diagnosed with cancer ≤1 year after FUO had similar mortality to cancer patients without this diagnosis.
CONCLUSIONS: Patients with FUO have a higher 1- <12-month cancer SIR; thereafter, the incidence for most cancers equals that of the general population. Decreasing SIRs over time suggests improvements in the initial diagnostic workup for FUO.
© The Author(s) 2022. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.
E Toussaint, E Bahel-Ball, M Vekemans, A Georgala, L Al-Hakak, M Paesmans, M Aoun
Causes of fever in cancer patients (prospective study over 477 episodes).
Support Care Cancer. 2006 Jul;14(7):763-9. doi: 10.1007/s00520-005-0898-0. Epub 2006 Mar 10.
Abstract/Text
GOALS OF WORK: The aim of this study was to determine the causes of fever among cancer patients.
METHODS: All febrile cancer patients were followed up prospectively. Clinical, microbiological and radiological documentations were performed. Aetiologies of fever, type of tumour, site of infection, type of microorganism and outcome were assessed and compared between neutropenics and non-neutropenics.
RESULTS: Four hundred and seventy-seven episodes were evaluated. Infection, non-infectious causes and fever of unknown origin represented 67, 23 and 10%, respectively. The respiratory tract is the most frequently involved site in infection (29%), and in microbiologically documented infections, Gram-negative bacilli were predominant. The tumour itself (27%) or an invasive procedure (17%) were the main causes of non-infectious febrile episodes. Mortality from infection was higher among non-neutropenic (11.1%) than neutropenic patients (4.3%).
CONCLUSION: Fever in cancer patients remains a challenge, and the differentiation between infectious and non-infectious causes at onset of fever is very difficult. Despite all the prophylactic measures, infection is still the principal cause. However, the infection-related mortality is low either in neutropenic or non-neutropenic patients.
J C Chang, H M Gross
Utility of naproxen in the differential diagnosis of fever of undetermined origin in patients with cancer.
Am J Med. 1984 Apr;76(4):597-603.
Abstract/Text
The clinical utility of naproxen as an antipyretic agent was examined in the differential diagnosis of fever of undetermined origin in patients with cancer. Twenty-two patients with cancer and fever of undetermined origin for more than seven days were treated with naproxen to control fever when there was no evidence of infection after a careful initial evaluation, and in most cases, after failure of antibiotic therapy. In final analysis, none of five patients with infectious fever had responses to naproxen. In contrast, 14 of 15 patients with neoplastic fever showed a prompt, complete, and sustained lysis of fever within 24 hours after the initiation of naproxen treatment, and the patients also showed symptomatic improvement. One patient with neoplastic fever who did not have a response to naproxen had lysis of fever after the removal of necrotic tumor tissue. Two patients with fever from connective tissue disease had a partial lysis of fever in response to naproxen. These data suggest that naproxen specifically produces the lysis of neoplastic fever and, therefore, is a useful agent in assisting in the differential diagnosis of infectious fever and neoplastic fever in patients with cancer and fever of undetermined origin.
Steven Vanderschueren, Daniël C Knockaert, Willy E Peetermans, Herman J Bobbaers
Lack of value of the naproxen test in the differential diagnosis of prolonged febrile illnesses.
Am J Med. 2003 Nov;115(7):572-5.
Abstract/Text
J C Chang
Neoplastic fever. A proposal for diagnosis.
Arch Intern Med. 1989 Aug;149(8):1728-30.
Abstract/Text
Jason A Zell, Jae C Chang
Neoplastic fever: a neglected paraneoplastic syndrome.
Support Care Cancer. 2005 Nov;13(11):870-7. doi: 10.1007/s00520-005-0825-4. Epub 2005 Apr 29.
Abstract/Text
Neoplastic fever, a paraneoplastic syndrome caused by cancer itself, represents a diagnostic challenge for the clinician and is an important issue in supportive oncology. Timely recognition of this febrile condition by differentiating it from other cancer-associated fevers, such as infection and drug reaction, is essential for effective patient management. Although the pathophysiology of neoplastic fever is not well understood, it is suspected to be cytokine mediated. In clinical practice, when a patient with cancer presents with unexplained fever, extensive diagnostic studies are needed to differentiate neoplastic fever from nonneoplastic fever. Only after excluding identifiable etiologies of fever can the diagnosis of neoplastic fever be suspected. According to our experience, the naproxen test is a safe and useful test in differentiating neoplastic fever from infectious fever in patients with cancer. In addition, naproxen and other nonsteroidal anti-inflammatory drugs have been effective in the management of neoplastic fever and offer a significant palliative benefit for the patient.
J C Chang, H M Gross
Neoplastic fever responds to the treatment of an adequate dose of naproxen.
J Clin Oncol. 1985 Apr;3(4):552-8. doi: 10.1200/JCO.1985.3.4.552.
Abstract/Text
Twenty-one patients with neoplastic fever due to malignancy were treated with naproxen. A prompt and complete lysis of fever was obtained in 20 patients within 12 hours when an adequate dose of naproxen was given, and a sustained normal temperature was maintained in all responding patients while receiving naproxen except for one in whom a low grade fever recurred. Lysis of fever usually was followed by excessive sweating and subjective symptomatic improvement. However, when naproxen was discontinued in ten patients, febrile state to the pretreatment level recurred in seven patients within three days. This observation suggests naproxen has a definite and effective antipyretic activity against neoplastic fever although it may recur as the drug is discontinued. Naproxen may be a useful adjunctive agent in patients with neoplastic fever for a short-term symptomatic relief.
J C Chang
Antipyretic effect of naproxen and corticosteroids on neoplastic fever.
J Pain Symptom Manage. 1988 Summer;3(3):141-4.
Abstract/Text
Hongliang Zhang, Yuyong Wu, Zhongqiu Lin, Xiaobin Zhong, Taotao Liu, Zhenguang Huang, Yufang Yang
Naproxen for the treatment of neoplastic fever: A PRISMA-compliant systematic review and meta-analysis.
Medicine (Baltimore). 2019 May;98(22):e15840. doi: 10.1097/MD.0000000000015840.
Abstract/Text
BACKGROUND: The effect of naproxen on the treatment of neoplastic fever is still unclear. A systematic review and meta-analysis were performed to investigate the effect of naproxen in the treatment of cancer fever or suspicion. Besides, the latest and most convincing evidence was provided for the earlier use of naproxen in treating cancer patients with fever of unknown origin.
METHODS: A literature review was conducted to identify all published studies on the naproxen for the treatment of neoplastic fever. Electronic databases (eg, PUBMED, EMBASE and the Cochrane Library) were searched until October 2018. Data were extracted, and the risk of bias was assessed by 2 authors independently. Standard meta-analyses on the rate of successful treatment were conducted using a random-effects model, and relative risks were calculated with 95% confidence intervals (CIs).
RESULTS: A total of 15 studies, recruiting 582 participants, were included, which were 1 randomized controlled trial (RCT), 1 non-RCT, 3 cross-sectional studies, and 10 case-series studies. The result of our meta-analysis revealed that the success rate on the treatment of neoplastic fever using naproxen was 94.1% (95% CI: 87.6%-97.3%). The success rate of the suspected neoplastic fever was 79.8%; for fever of unknown origin, it also reached 67.7%. In this meta-analysis, the success rate was 98.1% (95% CI: 95.0%-99.3%) in the dosage of 250 mg twice a day. Besides, a small dose of 125 mg naproxen, 375 mg twice a day and 250 mg 3 times a day were also useful. The result of the subgroup analysis revealed that the difference was not statistically significant in the treatment success rate for solid tumors and hematologic malignant.
CONCLUSIONS: The result of our meta-analysis suggested that naproxen exhibited a highly successful rate for the treatment of neoplastic fever. Besides, naproxen was also satisfactory in improving symptoms of suspected neoplastic fever and fever of unknown origin. The earlier use of naproxen might be able to mitigate cancer patient's suffering and enhanced their quality of life. These findings, however, rely primarily on observational data and should be interpreted rigorously. Further well-conducted trials are required to assess naproxen for the treatment of neoplastic fever.
