In an adult (≥18 years) with known or suspected cancer presenting with unexplained weight loss of ≥5 % of body weight over 6–12 months and persistent fatigue, which laboratory tests and imaging studies should be ordered to evaluate tumor‑related, treatment‑related, and metabolic causes?

Laboratory and Imaging Evaluation for Cancer-Related Weight Loss and Fatigue

Order a complete blood count with differential, comprehensive metabolic panel, and thyroid-stimulating hormone (TSH) as the essential initial laboratory tests for any cancer patient presenting with ≥5% weight loss and persistent fatigue. 1

Core Laboratory Panel

The following tests form the foundation of your evaluation and should be ordered immediately:

• Complete blood count (CBC) with differential to assess for anemia (compare current hemoglobin/hematocrit with end-of-treatment values if available), evaluate white blood cell and platelet counts, and identify treatment-related cytopenias 1

• Comprehensive metabolic panel to assess electrolytes, hepatic function (aminotransferases, alkaline phosphatase, gamma-glutamyl transpeptidase), renal function (creatinine, BUN), and detect metabolic derangements that commonly cause fatigue 1, 2

• Thyroid-stimulating hormone (TSH) to screen for hypothyroidism, which frequently develops after cancer treatment and presents with fatigue and weight changes 1, 3

• Erythrocyte sedimentation rate (ESR) or C-reactive protein to evaluate for systemic inflammation, infection, or occult malignancy 4, 2

Additional Laboratory Tests Based on Clinical Context

If initial screening suggests endocrine dysfunction or if fatigue is severe, expand your evaluation:

• Morning cortisol and ACTH (drawn around 8 AM, before any steroid administration) to evaluate for adrenal insufficiency, particularly in patients who received immunotherapy or have multiple pituitary hormone deficiencies 3

• Free T4 and thyroid peroxidase (TPO) antibodies if TSH is abnormal, to characterize thyroid dysfunction and identify autoimmune thyroiditis 3

• Fasting glucose and hemoglobin A1C to screen for diabetes mellitus, which causes fatigue and may develop after certain cancer treatments (steroids, immunotherapy) 3

• Vitamin D, vitamin B12, and iron studies (ferritin, iron, TIBC) to identify nutritional deficiencies contributing to fatigue 4

• Albumin and lactate dehydrogenase (LDH) as markers of nutritional status and tumor burden 2

Critical Timing and Sequencing Considerations

A critical pitfall: If both adrenal insufficiency and hypothyroidism are identified, you must always start corticosteroids before initiating thyroid hormone replacement to avoid precipitating an adrenal crisis 3

Laboratory testing should be driven by symptom severity and clinical context rather than reflexive ordering—abnormal results alter management in only ~5% of fatigued patients when initial screening is normal 4

Imaging Studies for Disease Recurrence Evaluation

When weight loss and fatigue raise concern for cancer recurrence or progression, imaging should be guided by:

• Review of systems to identify localizing symptoms that suggest specific sites of recurrence 1

• Risk stratification based on original cancer stage, pathologic factors, and treatment history 1

• Abdominal ultrasonography or CT scan as first-line imaging for patients with isolated weight loss, as digestive system malignancies account for 54% of cancers presenting this way 2

• MRI of the sella with pituitary cuts if ≥1 pituitary hormone deficiency is identified (particularly TSH or ACTH deficiency) combined with headache, suggesting hypophysitis from immunotherapy 3

Assessment of Treatable Contributing Factors

Beyond laboratory testing, systematically evaluate these factors that commonly cluster with fatigue:

• Pain assessment and management, as pain correlates strongly with fatigue severity 1

• Emotional distress screening using the two-question depression screen: (1) "In the last month, have you often felt dejected, sad, depressed or hopeless?" and (2) "In the last month, did you experience significantly less pleasure than usual with things you normally like to do?" If positive, administer PHQ-9 3

• Sleep disturbance evaluation (present in 30-75% of cancer patients with fatigue), including assessment for sleep apnea that may develop after treatment affecting the upper airway, body composition changes, or hormonal alterations 1, 4

• Medication review for persistent use of sleep aids, opioids, antiemetics, or other sedating medications 1

• Nutritional assessment documenting caloric intake changes, impediments to eating, and recent weight trajectory 1

• Activity level and deconditioning status, as physical inactivity perpetuates fatigue 1

• Alcohol and substance use screening 1

When to Refer for Specialist Evaluation

Refer to appropriate specialists when:

• Endocrinologic abnormalities require comprehensive evaluation beyond TSH screening 1, 3
• Multiple pituitary hormone deficiencies are identified 3
• Cardiac, pulmonary, or renal dysfunction contributes to symptoms 1
• Fatigue remains unresolved despite addressing identified treatable factors 1

Evidence-Based Management Priorities

The strongest evidence supports addressing treatable factors before attributing symptoms solely to cancer-related fatigue:

• Weight loss at cancer presentation independently predicts worse outcomes (hazard ratio 1.43-1.63), shorter survival, increased chemotherapy toxicity, and reduced treatment tolerance 5

• Patients with cancer and weight loss receive 18% less chemotherapy due to dose-limiting toxicity (particularly hand-foot syndrome and stomatitis), directly impacting survival 5

• Structured physical activity programs (150 minutes of moderate aerobic exercise plus 2-3 strength training sessions weekly) have Category 1 evidence for reducing cancer-related fatigue and should be initiated unless contraindicated 1, 4

Common Pitfalls to Avoid

• Do not repeat normal laboratory tests without new clinical indications—this rarely changes management 4
• Do not overlook the timing of cortisol/ACTH testing—these must be drawn in the morning around 8 AM before steroid administration 3
• Do not start thyroid replacement before corticosteroids if both deficiencies coexist 3
• Do not attribute all symptoms to "cancer-related fatigue" without systematically excluding treatable medical causes 1
• Do not underestimate the prognostic significance of weight loss—median survival is only 2 months in patients with cancer presenting with isolated involuntary weight loss 2