Cancer‐Related Fever in Metastatic Prostate Cancer: A Case Report

ABSTRACT

Fever in cancer patients is often mistakenly attributed to infection, leading to unnecessary antibiotic use. Neoplastic fever, though well‐documented in hematologic malignancies, is rare in solid tumors, particularly prostate cancer. This case report presents an 81‐year‐old male with metastatic prostate cancer, who was admitted to Razi Hospital in Qaemshahr, Mazandaran, with persistent fever, chills, and urinary symptoms following radiotherapy. Despite broad‐spectrum antibiotics, the fever persisted, and extensive infectious workups yielded no identifiable source. The patient's condition was further complicated by hyponatremia, elevated inflammatory markers, and a negative initial blood culture. As the fever continued, oncological evaluation was initiated, leading to the diagnosis of neoplastic fever. Chemotherapy with docetaxel and zoledronic acid resulted in the resolution of fever, confirming the oncologic nature of the fever. This case underscores the importance of recognizing neoplastic fever in cancer patients with persistent fever of unknown origin, particularly when infectious causes have been excluded. Early oncologic intervention, rather than prolonged antibiotic therapy, can prevent unnecessary treatments and improve patient outcomes. This case highlights the need for a high index of suspicion in managing cancer patients with fever, especially in the absence of an infectious etiology.

Key Clinical Message

Neoplastic fever should be considered in cancer patients with persistent high‐grade fever unresponsive to broad‐spectrum antibiotics and without an identifiable infectious source. Early recognition after systematic exclusion of infection can prevent unnecessary antimicrobial escalation and facilitate timely initiation of tumor‐directed therapy, leading to rapid clinical improvement.

1. Introduction

Along with inflammation, fever is an important host‐protective response. It is one of the most frequent signs and symptoms in both inpatients and outpatients. The definition of fever varies arbitrarily based on its intended purpose. In some literature, fever is defined as a core temperature greater than 38.0°C (100.4°F), while other references classify fever as two successive elevations above 38.3°C. Fever is defined as a single oral temperature greater than 38.3°C in patients with neutropenia [1].

Neoplastic fever is common in patients with Hodgkin and non‐Hodgkin lymphoma, soft tissue sarcoma, acute or chronic leukemia, and renal cell carcinoma. Usually, there are no clinical characteristics of the fever. There is no specific origin of tumor‐associated fever in these patients and the main cause of tumor‐associated fever is not well understood, but it may result from factors such as drug treatment, tumor cell necrosis, or the release of various cytokines like interleukin 1 and 6 [2].

Prostate cancer is the most common malignancy after lung cancer in men worldwide, with early symptoms of frequent urination, difficulty urinating, and nocturia. In more advanced stages, back pain may also be observed due to bone metastasis [3]. However, fever and other inflammatory markers, which are considered paraneoplastic syndrome, are uncommon among people with prostate cancer. At initial diagnosis, fever is often mistaken for an infection, which can lead to futile antibiotic treatments [4].

In this article, we report a patient with prostate cancer who was admitted to the hospital with the chief complaint of fever following radiation therapy. Despite treatment with various antibiotics, the patient's fever remained elevated. We discuss the importance of considering cancer‐related fever in patients with cancer and fever of unknown origin.

2. Case Presentation/Examination

An 81‐year‐old man with previously diagnosed metastatic prostate adenocarcinoma presented with a two‐day history of fever, chills, weakness, and fatigue. He also reported anorexia, dysuria, urgency, nocturia, reduced urine output, and a one‐day history of watery dark stools without abdominal pain. He denied dyspnea, nausea, vomiting, or cough. The diagnosis of prostate cancer had been established by prostate biopsy, which revealed adenocarcinoma with a Gleason score of 4 + 5 = 9. Bone metastases were present at diagnosis, and the disease was classified as Stage IV (M1). His prostate‐specific antigen (PSA) level had increased from 240 ng/mL at diagnosis to 580 ng/mL at the time of admission. One month before hospitalization, he had received palliative pelvic radiotherapy (30 Gy in 10 fractions) for metastatic bone pain without any acute radiation‐related adverse effects. His medical history included prostate surgery 1 year earlier and cataract surgery. His regular medications consisted of oral iron and calcium supplements. The clinical timeline is summarized in Table 1.

TABLE 1.

Clinical timeline of the patient.

Time point	Clinical course	Investigations/Treatment
Two days before admission	Fever, chills, weakness, dysuria	—
Day 1	Temperature 39.5°C, tachycardia (107 bpm)	Empirical vancomycin + meropenem started; urine/stool cultures, Brucella serology, and PCT (0.1 ng/mL) obtained; all negative
Day 2–3	Persistent fever despite antibiotics	Amikacin added; echocardiography ruled out endocarditis; electrolyte imbalances corrected
Day 4	Persistent fever, no clinical response	Nuclear scan and CT confirmed diffuse bone metastases; linezolid and rifampin added
Day 5	Persistent fever, no clinical response	The blood culture result was negative
Day 8	Oncology consultation	Chemotherapy with docetaxel 80 mg IV and zoledronic acid 4 mg IV initiated
Day 10	Fever resolved; patient remained afebrile for 24 h; symptoms improved	—
Day 12	Discharged with oncology follow‐up	—

3. Methods

On admission, his axillary temperature was 39.5°C, and he had tachycardia with a heart rate of 107 bpm. Other vital signs, blood glucose levels, and oxygen saturation (96%) were within normal limits. No cardiac murmurs were auscultated, and lung sounds were clear. No skin lesions such as petechiae, purpura, or ecchymosis were observed. Given the clinical presentation, bloodstream infection (BSI) was initially suspected, and further investigations were performed. Laboratory findings revealed an elevated ESR (119 mm/h) and CRP (46 mg/L) along with hyponatremia (Na: 132 mEq/L). The patient's procalcitonin level was 0.1 ng/mL, below the 0.2 ng/mL cut off suggestive of systemic bacterial infection [5]. Urinalysis showed albuminuria (+) and blood trace. The blood culture was negative. Urine culture was negative. Stool examination showed no ova, cysts, or WBCs. Brucella serology (Wright & 2ME tests) was negative.

Radiation‐related inflammation or tissue injury was considered unlikely, as the fever developed 1 month after completion of radiotherapy, with no documented acute radiation‐related adverse effects. The patient had no respiratory symptoms; lung auscultation was unremarkable, and chest CT showed no ground‐glass opacities, consolidation, or other findings suggestive of radiation‐induced pneumonitis or tissue injury.

Empirical treatment was initiated with intravenous vancomycin and meropenem. Due to persistent fever, amikacin was added to the regimen. Given the prolonged fever and tachycardia, transthoracic and transesophageal echocardiography were performed, which ruled out infective endocarditis. The findings included an ejection fraction (EF) of 55%, mild mitral regurgitation (MR), moderate tricuspid regurgitation (TR), and no evidence of vegetation or abnormalities suggestive of endocarditis.

Daily monitoring of laboratory parameters showed persistent hyponatremia and hypokalemia, along with elevated blood urea levels. Electrolyte imbalances were corrected through IV fluid adjustments and potassium chloride (KCl) supplementation, leading to normalization of sodium and potassium levels.

Bone scintigraphy demonstrated a superscan pattern with diffuse, intense radiotracer uptake throughout the skeleton, consistent with widespread skeletal metastases (Figure 1). A non‐contrast abdominal and pelvic CT scan revealed multiple sclerotic metastatic lesions in the spine and pelvis without significant abnormalities in other abdominal or pelvic organs (Figure 2). Although the differential diagnosis of diffuse sclerotic skeletal lesions includes Paget's disease, osteoblastic metastases from other malignancies, and less commonly metabolic or hematologic disorders, the patient's known advanced prostate cancer, markedly elevated PSA level, and concordant imaging findings confirmed diffuse skeletal metastases secondary to prostate cancer.

FIGURE 1.

The scan shows multiple foci of increased radiotracer uptake throughout the skeleton. There is a faint visualization of the kidneys and a high ratio of bone to soft tissue activity.

FIGURE 2.

CT scan showed multiple sclerotic metastatic lesions in the spine and pelvis. No abnormalities were observed in other organs.

Despite negative initial investigations and a low PCT level, antimicrobial therapy was escalated because of persistent high‐grade fever and clinical instability. Due to technical limitations, the final blood culture result was unavailable until day 5; therefore, broad‐spectrum antimicrobial coverage was maintained while awaiting the result. Vancomycin was subsequently replaced with linezolid, and rifampin was added; however, the patient remained febrile, and no additional findings ultimately confirmed an infectious source.

4. Conclusions and Results (Outcome and Follow‐Up)

Due to persistent high‐grade fever, lack of an identifiable infectious source, failure of broad‐spectrum antimicrobial therapy, and progressive clinical deterioration, an oncology consultation was obtained. Although androgen deprivation therapy and androgen receptor signaling inhibitors (ARSI) are the standard first‐line treatment for metastatic prostate cancer, their slower onset of action made them less suitable for this critically ill patient. Therefore, docetaxel‐based chemotherapy (80 mg IV) together with zoledronic acid (4 mg IV) was initiated to achieve rapid reduction of tumor burden and control the presumed tumor‐driven inflammatory state.

Fever resolved within 2 days of initiating chemotherapy, and the patient's symptoms improved. The final diagnosis was neoplastic fever associated with metastatic prostate cancer. The diagnosis was established by exclusion, based on Chang's criteria, including persistent fever despite broad‐spectrum antimicrobial therapy, negative blood, urine, and stool cultures, negative serologic and imaging studies for infection, and active malignancy. Previous low‐dose palliative radiotherapy (30 Gy in 10 fractions) was considered an unlikely cause because no acute radiation‐related adverse effects had occurred. Although an NSAID challenge test was not performed, the prompt resolution of fever following tumor‐directed therapy further supported the diagnosis. The patient was discharged with oncology follow‐up. The patient remained afebrile after chemotherapy, with no recurrence of fever during the available follow‐up period. He completed the planned course of chemotherapy and subsequently continued hormonal therapy. The patient remained alive and clinically stable during approximately 1 year of follow‐up. This case highlights the importance of considering neoplastic fever in cancer patients with persistent fever after exclusion of infection to avoid unnecessary antibiotic use and delays in initiating appropriate anticancer therapy.

5. Discussion

In this report, we present a case of prolonged fever in a patient with metastatic prostate cancer, where distinguishing between infectious and non‐infectious causes posed a significant clinical challenge. Initially, based on the patient's symptoms—including fever, tachycardia, and elevated CRP and ESR—a preliminary diagnosis of bloodstream infection (BSI) was considered. However, the patient's lack of response to antibiotics, along with further investigations, ruled out an infectious etiology. Subsequently, the fever gradually subsided following the initiation of chemotherapy, suggesting its non‐infectious, cancer‐related nature.

Neoplastic fever and cancer‐associated systemic inflammatory syndrome (SIS) are closely related but distinct clinical entities [6]. Both are believed to result from tumor‐induced production of pro‐inflammatory cytokines, including interleukin (IL)‐1, IL‐6, tumor necrosis factor‐α (TNF‐α), and interferon‐γ [7]. This systemic inflammatory response is observed in some patients with advanced malignancies, and failure to recognize it can lead to cancer progression [8]. SIS represents a broader systemic inflammatory state characterized by constitutional symptoms, elevated inflammatory markers, metabolic disturbances, and progressive functional decline [9], whereas neoplastic fever is a specific paraneoplastic manifestation defined by persistent fever after exclusion of infectious and other non‐neoplastic causes. Therefore, neoplastic fever should be regarded as one manifestation of cancer‐associated systemic inflammation rather than synonymous with SIS [6].

Mauri et al. described prostate cancer‐associated SIS as a rare paraneoplastic syndrome characterized by fever, fatigue, night sweats, weight loss, anemia, elevated inflammatory markers, and extensive bone metastases [10]. In contrast, our patient presented with persistent fever as the sole predominant manifestation and did not exhibit the broader systemic features typically seen in SIS. This clinical pattern is more consistent with neoplastic fever than with a full systemic inflammatory syndrome [11].

Differentiating between neoplastic fever and infectious fever in cancer patients remains a crucial clinical challenge. Both conditions can increase C‐reactive protein (CRP) and erythrocyte sedimentation rate (ESR), making it difficult to distinguish between them [12]. In our case, despite elevated CRP levels, the fever was not of infectious origin. However, an important distinguishing factor is procalcitonin (PCT) levels, which can help differentiate infectious from non‐infectious causes. A 2024 study on febrile cancer patients demonstrated that PCT levels were significantly higher in the BSI group compared to the neoplastic fever (NBI) group, confirming its diagnostic value [4]. In our case, a PCT level of 0.1 suggested a non‐infectious etiology.

A hallmark feature of neoplastic fever is its resistance to antibiotics and its resolution with anticancer therapies. A case report by Tae Hoon Oh described a patient with prolonged fever unresponsive to antibiotics, whose symptoms completely resolved following chemotherapy with docetaxel [13]. Similarly, a 2020 study by Thiago Hota reported that a prostate cancer patient, after ruling out infectious causes, was treated with docetaxel, leading to fever resolution [4]. A comparable treatment approach was adopted for our patient, where the fever decreased and was ultimately controlled following chemotherapy initiation.

Author Contributions

Masoud Maboudi: conceptualization, data curation, formal analysis, project administration, resources, supervision, writing – review and editing. Maryam Montazeri: data curation, methodology, validation, writing – review and editing. Sara Ghandi: formal analysis, visualization, writing – original draft, writing – review and editing. Moozhan Mofidi: visualization, writing – original draft.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not‐for‐profit sectors.

Consent

I confirm that written informed consent was obtained from the patient for participation in this study. The patient has been fully informed about the nature of the study, the procedures involved, and any potential risks or benefits. The patient's consent was voluntarily given, and they understood their rights. This written consent has been collected in accordance with the journal's patient consent policy. I will retain the original written consent form and will provide it to the Publisher if requested.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.