What are the screening tests, tumor markers, chemotherapeutic agents, paraneoplastic syndromes, and electrolyte abnormalities associated with common malignancies in oncology?

Oncology: Screening, Tumor Markers, Chemotherapy, Paraneoplastic Syndromes, and Tumor Lysis Syndrome

Cancer Screening Tests for Common Malignancies

Average-risk adults should undergo screening for breast, cervical, colorectal, and lung cancers based on age-specific and risk-stratified protocols, while prostate cancer screening requires shared decision-making. 1

Breast Cancer Screening

• Mammography annually for women aged 45-54 years, with option to transition to biennial screening after age 55 1, 2
• Digital breast tomosynthesis (DBT) offers superior sensitivity and specificity compared to standard mammography, though access varies by population 2
• Clinical breast examination can be performed during cancer-related checkups 1

Cervical Cancer Screening

• Women aged 21-29: Cervical cytology (Pap test) every 3 years 1
• Women aged 30-65: Either cytology every 3 years OR cytology + hrHPV co-testing every 5 years 1
• Screening should continue in both HPV-vaccinated and unvaccinated women 1
• Women who have undergone total hysterectomy for benign reasons do not require screening 1

Colorectal Cancer Screening

Begin at age 45 for average-risk adults (recently lowered from age 50) and continue through age 75 1, 2

Two categories of tests exist:

Tests that primarily detect cancer:

• Annual high-sensitivity guaiac-based fecal occult blood test (gFOBT) or fecal immunochemical test (FIT) 1
• Multitarget stool DNA (mtsDNA) test every 3 years 1

Tests that detect cancer and advanced lesions:

• Colonoscopy every 10 years 1
• Flexible sigmoidoscopy every 5 years 1
• CT colonography (virtual colonoscopy) every 5 years 1
• Double-contrast barium enema every 5 years 1

Critical pitfall: Single-panel gFOBT performed in the medical office using a stool sample from digital rectal examination is NOT recommended due to very low sensitivity 1

Lung Cancer Screening

• Low-dose CT (LDCT) annually for adults aged 50-80 years with ≥20 pack-year smoking history who currently smoke or have quit within the past 15 years 1, 3
• Screening reduced lung cancer mortality in the National Lung Screening Trial (IRR 0.85, NNS 323 over 6.5 years) 3
• Harms include false-positive results (leading to 17 invasive procedures per 1000 screened), overdiagnosis (0-67%), and incidental findings (4.4-40.7%) 3

Prostate Cancer Screening

Shared decision-making is required; screening is not universally recommended 1

For men who choose screening after informed discussion:

• PSA testing with or without digital rectal examination (DRE recommended for men with hypogonadism due to reduced PSA sensitivity) 1
• PSA <2.5 ng/mL: Screen every 2 years 1
• PSA 2.5-4.0 ng/mL: Screen annually 1
• PSA ≥4.0 ng/mL: Consider referral for further evaluation 1
• Begin discussions at age 45-50 for average-risk men, age 40-45 for high-risk men (African American or strong family history) 4

Critical pitfall: PSA testing should NOT be performed in young adults (age <40-45) as it provides no benefit and leads to unnecessary anxiety and procedures 4

Cancers Without Routine Screening Recommendations

• Ovarian cancer: CA-125 and transvaginal ultrasound do NOT reduce mortality and lead to surgical interventions in women without cancer 1
• Testicular cancer: Insufficient evidence for routine physician or self-examination, though examination can be performed during cancer-related checkups 1, 4
• Skin cancer: Only recommended by select countries; not universally endorsed 5

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Tumor Markers

Tumor markers are primarily used for prognosis, treatment selection, and monitoring rather than screening, with most lacking sufficient sensitivity and specificity for population-based screening.

Genomic Tests with Strong Recommendations (Category 1)

The following genomic tests received strong recommendations with high-level evidence 1:

Screening/Diagnostic:

• Lynch syndrome screening for colorectal cancer (microsatellite instability testing) 1
• 1p/19q deletion for glioma diagnosis and prognosis 1

Prognostic:

• Oncotype DX for breast cancer (21-gene recurrence score) 1
• RET mutation for thyroid cancer 1

Pharmacogenomic:

• KRAS mutation for colorectal cancer (predicts anti-EGFR therapy response) 1
• EGFR mutation for non-small cell lung cancer (predicts tyrosine kinase inhibitor response) 1
• ALK rearrangement for non-small cell lung cancer 1
• BRAF mutation for melanoma and colorectal cancer 1
• HER2 amplification for breast cancer (predicts trastuzumab response) 1

Additional Genomic Tests with Favorable Recommendations (Category 2)

• UGT1A1 for colorectal cancer (predicts irinotecan toxicity) - FDA cleared 1
• BCR-ABL for chronic myeloid leukemia 1
• FLT3, NPM1, CEBPA mutations for acute myeloid leukemia 1
• PML-RARA for acute promyelocytic leukemia 1

Traditional Serum Tumor Markers

• PSA (prostate-specific antigen): Used for prostate cancer screening with shared decision-making, not for routine screening in young adults 1, 4
• CA-125: NOT recommended for ovarian cancer screening due to lack of mortality benefit 1
• CEA (carcinoembryonic antigen): Used for colorectal cancer monitoring, not screening 1
• AFP (alpha-fetoprotein): Used for hepatocellular carcinoma and germ cell tumors 1

Important caveat: Most genomic tests (71%) were commented on by NCCN, with concordance of recommendations across organizations at only 67%, indicating ongoing evolution of evidence 1

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Chemotherapeutic Agents: Classes, Examples, and Common Side Effects

Chemotherapy remains the cornerstone of cancer treatment, with myelosuppression being the most common dose-limiting toxicity across most classes. 1

Alkylating Agents

Mechanism: Cross-link DNA strands, preventing replication

Examples:

• Cyclophosphamide 6
• Ifosfamide
• Cisplatin
• Carboplatin

Most common side effects of cyclophosphamide:

• Myelosuppression (neutropenia most significant) - correlates with reduced resistance to infections 6
• Hemorrhagic cystitis and bladder toxicity (hematuria, cystitis ulcerative, bladder necrosis) 6
• Nausea and vomiting 6
• Alopecia 6
• Cardiotoxicity (cardiac failure, cardiomyopathy, myocarditis, pericarditis) 6
• Pulmonary toxicity (interstitial lung disease, pneumonitis, pulmonary fibrosis) 6
• Infertility (ovarian failure, testicular atrophy, azoospermia) 6
• Secondary malignancies (acute leukemia, myelodysplastic syndrome, bladder cancer) 6

Critical drug interactions:

• Increased cardiotoxicity when combined with anthracyclines, cytarabine, pentostatin, or cardiac radiation 6
• Increased pulmonary toxicity when combined with amiodarone or G-CSF/GM-CSF 6
• Increased hematotoxicity when combined with paclitaxel (administer cyclophosphamide before paclitaxel) 6

Antimetabolites

Mechanism: Interfere with DNA/RNA synthesis by mimicking normal metabolites

Examples:

• 5-Fluorouracil (5-FU)
• Methotrexate
• Gemcitabine
• Cytarabine

Most common side effects:

• Myelosuppression 1
• Mucositis
• Diarrhea
• Hand-foot syndrome (with 5-FU)

Anthracyclines

Mechanism: Intercalate DNA and inhibit topoisomerase II

Examples:

• Doxorubicin
• Epirubicin
• Daunorubicin

Most common side effects:

• Myelosuppression 1
• Cardiotoxicity (dose-dependent cardiomyopathy and heart failure) 1, 6
• Alopecia
• Nausea and vomiting
• Red discoloration of urine

Taxanes

Mechanism: Stabilize microtubules, preventing mitotic spindle formation

Examples:

• Paclitaxel 7
• Docetaxel

Most common side effects of paclitaxel:

• Myelosuppression (neutropenia in 78% of patients) 7
• Peripheral neuropathy (60% of patients, 3% severe) - dose-dependent and increases with cumulative dose 7
• Hypersensitivity reactions (41% of patients, <2% severe) despite premedication 7
• Alopecia 7
• Cardiovascular effects (hypotension 12%, bradycardia 3%, arrhythmias ~1%) 7
• Myalgia and arthralgia 7

Critical warnings:

• Peripheral neuropathy is dose-dependent and improves within several months of discontinuation 7
• Pre-existing neuropathy from prior therapies is NOT a contraindication 7
• When combined with cisplatin, neurotoxicity increases significantly (87% vs 52% with cyclophosphamide/cisplatin) 7
• Increased hematotoxicity when paclitaxel is given after cyclophosphamide - administer paclitaxel first 6, 7

Platinum Compounds

Mechanism: Form DNA cross-links

Examples:

• Cisplatin
• Carboplatin
• Oxaliplatin

Most common side effects:

• Myelosuppression (especially carboplatin) 1
• Nephrotoxicity (cisplatin)
• Peripheral neuropathy (cisplatin, oxaliplatin)
• Ototoxicity (cisplatin)
• Nausea and vomiting

Topoisomerase Inhibitors

Mechanism: Inhibit topoisomerase enzymes, preventing DNA unwinding

Examples:

• Irinotecan
• Topotecan
• Etoposide

Most common side effects:

• Myelosuppression 1
• Diarrhea (irinotecan)
• Nausea and vomiting

Vinca Alkaloids

Mechanism: Inhibit microtubule formation

Examples:

• Vincristine
• Vinblastine
• Vinorelbine

Most common side effects:

• Peripheral neuropathy (vincristine)
• Myelosuppression (vinblastine, vinorelbine) 1
• Constipation

Maintaining Dose Intensity

Myelosuppression (grades 3-4 neutropenia, anemia, thrombocytopenia) is the primary cause of unplanned dose reductions and treatment delays 1

• Approximately 50% of patients with early-stage breast cancer and non-Hodgkin's lymphoma receive <85% relative dose intensity (RDI) 1
• More than half of RDI reduction is unplanned and associated with myelosuppression 1
• Maintaining RDI is crucial for survival in curative settings (early-stage breast cancer) and optimal outcomes in non-curative settings 1
• Current trends show more myelosuppressive regimens are being used for early-stage disease where survival benefits are possible 1

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Paraneoplastic Syndromes

Paraneoplastic syndromes are systemic effects of cancer that occur at sites distant from the tumor or its metastases, caused by tumor secretion of hormones, cytokines, or immune-mediated mechanisms.

Endocrine Paraneoplastic Syndromes

Syndrome of Inappropriate Antidiuretic Hormone (SIADH):

• Most commonly associated with small cell lung cancer
• Causes hyponatremia and water retention
• Hyponatremia is a recognized complication that can occur with various malignancies 6

Cushing Syndrome (Ectopic ACTH):

• Small cell lung cancer, carcinoid tumors
• Causes hyperglycemia, hypertension, hypokalemia, metabolic alkalosis

Hypercalcemia of Malignancy:

• Squamous cell lung cancer, breast cancer, multiple myeloma, renal cell carcinoma
• Caused by PTHrP secretion or osteolytic metastases
• Presents with confusion, constipation, polyuria, kidney stones

Hypoglycemia:

• Hepatocellular carcinoma, sarcomas
• Caused by IGF-2 secretion

Neurologic Paraneoplastic Syndromes

Lambert-Eaton Myasthenic Syndrome:

• Small cell lung cancer
• Proximal muscle weakness that improves with repeated use
• Caused by antibodies against presynaptic calcium channels

Paraneoplastic Cerebellar Degeneration:

• Ovarian cancer, breast cancer, small cell lung cancer, Hodgkin lymphoma
• Subacute onset of ataxia, dysarthria, nystagmus
• Anti-Yo, anti-Hu, anti-Tr antibodies

Encephalomyelitis:

• Small cell lung cancer
• Anti-Hu antibodies
• Encephalopathy is reported with cyclophosphamide 6

Peripheral Neuropathy:

• Various malignancies
• Chemotherapy-induced peripheral neuropathy is common with taxanes (60% with paclitaxel), platinum agents, and vinca alkaloids 7

Hematologic Paraneoplastic Syndromes

Thrombocytosis:

• Lung cancer, gastrointestinal cancers, ovarian cancer
• Increased risk of thrombosis

Anemia:

• Chronic disease anemia common in many cancers
• Severe anemia (Hb <8 g/dL) occurs in 16% of chemotherapy patients 7

Disseminated Intravascular Coagulation (DIC):

• Acute promyelocytic leukemia, adenocarcinomas (especially pancreatic, prostate, lung)
• DIC is reported with cyclophosphamide 6

Thromboembolism (Trousseau Syndrome):

• Pancreatic cancer, lung cancer, gastric cancer
• Migratory thrombophlebitis
• Venous thrombosis and pulmonary embolism reported with cyclophosphamide 6

Dermatologic Paraneoplastic Syndromes

Acanthosis Nigricans:

• Gastric adenocarcinoma
• Hyperpigmented, velvety skin in body folds

Dermatomyositis:

• Ovarian, lung, pancreatic, gastric cancers
• Proximal muscle weakness, heliotrope rash, Gottron papules

Sweet Syndrome (Acute Febrile Neutrophilic Dermatosis):

• Acute myeloid leukemia
• Painful erythematous plaques, fever, neutrophilia

Renal Paraneoplastic Syndromes

Membranous Nephropathy:

• Solid tumors (lung, colon, breast)
• Nephrotic syndrome

Minimal Change Disease:

• Hodgkin lymphoma
• Nephrotic syndrome

Rheumatologic Paraneoplastic Syndromes

Hypertrophic Osteoarthropathy:

• Non-small cell lung cancer
• Digital clubbing, periostitis, arthritis

Polymyalgia Rheumatica:

• Hematologic malignancies
• Proximal muscle pain and stiffness

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Tumor Lysis Syndrome: Electrolyte Abnormalities

Tumor lysis syndrome (TLS) occurs when rapid tumor cell death releases intracellular contents into the bloodstream, causing life-threatening metabolic derangements, most commonly in hematologic malignancies with high tumor burden or rapidly proliferating solid tumors. 6

Classic Electrolyte Abnormalities (The "Tetrad")

Hyperuricemia:

• Caused by massive purine release from tumor cell DNA breakdown
• Uric acid can precipitate in renal tubules causing acute kidney injury
• Most characteristic finding of TLS

Hyperkalemia:

• Released from intracellular compartment (high intracellular K+ concentration)
• Most immediately life-threatening abnormality - can cause fatal cardiac arrhythmias
• Requires urgent treatment with calcium gluconate, insulin/glucose, and dialysis if severe

Hyperphosphatemia:

• Released from tumor cell nucleic acids and phospholipid membranes
• Can precipitate with calcium causing calcium phosphate deposition in tissues

Hypocalcemia:

• Secondary to hyperphosphatemia (calcium binds to excess phosphate)
• Can cause tetany, seizures, QT prolongation, and cardiac arrhythmias
• Often symptomatic when severe

Secondary Metabolic Consequences

Acute Kidney Injury:

• Results from uric acid and calcium phosphate precipitation in renal tubules
• Exacerbated by volume depletion
• Can progress to acute renal failure requiring dialysis 6

Metabolic Acidosis:

• From renal dysfunction and cellular breakdown
• Worsens hyperkalemia

Risk Factors for TLS

High-risk malignancies:

• Acute lymphoblastic leukemia
• Acute myeloid leukemia (especially with high WBC count) 1
• High-grade lymphomas (Burkitt lymphoma)
• Chronic lymphocytic leukemia with bulky disease

Patient factors:

• Pre-existing renal dysfunction 6
• High tumor burden
• Elevated baseline LDH or uric acid
• Volume depletion

Treatment factors:

• Cyclophosphamide and other cytotoxic drugs can induce tumor lysis syndrome 6
• Initiation of highly effective chemotherapy in sensitive tumors

Prevention and Management

Prophylaxis (before chemotherapy):

• Aggressive IV hydration (maintain urine output >2 mL/kg/hr)
• Allopurinol (xanthine oxidase inhibitor) to prevent uric acid formation
• Rasburicase (recombinant urate oxidase) for high-risk patients - rapidly degrades existing uric acid

Monitoring:

• Electrolytes, calcium, phosphate, uric acid, LDH, creatinine every 4-6 hours initially
• Continuous cardiac monitoring for hyperkalemia
• Urine output monitoring

Treatment of established TLS:

• Continue aggressive hydration
• Rasburicase for severe hyperuricemia
• Treat hyperkalemia urgently (calcium gluconate, insulin/glucose, sodium polystyrene sulfonate, dialysis)
• Avoid calcium supplementation unless symptomatic hypocalcemia (can worsen calcium phosphate precipitation)
• Hemodialysis for refractory electrolyte abnormalities or acute kidney injury

Critical pitfall: Do NOT give calcium for asymptomatic hypocalcemia in the setting of hyperphosphatemia, as this will worsen calcium phosphate precipitation and tissue deposition 6