What causes pleural effusions in patients undergoing chemotherapy?

Causes of Pleural Effusions During Chemotherapy

Primary Mechanisms

Pleural effusions during chemotherapy occur through three distinct mechanisms: direct malignant pleural involvement (most common), chemotherapy-induced cardiotoxicity causing cardiogenic pulmonary edema, and paradoxical tumor lysis with transient effusion formation despite treatment response.

1. Malignant Pleural Involvement (Most Common)

The overwhelming majority of pleural effusions during chemotherapy represent progression or persistence of malignant pleural disease rather than treatment complications:

• Direct pleural invasion by the primary tumor or metastatic disease causes approximately 10% of all pleural effusions, with lung cancer accounting for one-third of all malignant pleural complications 1
• Lymphatic obstruction from tumor infiltration or enlarged mediastinal lymph nodes blocks pleural fluid drainage, particularly common in lymphoma and breast cancer 1
• Vascular endothelial growth factor (VEGF) secretion by tumors promotes both angiogenesis and increased vascular permeability, driving fluid accumulation in the pleural space 1

2. Chemotherapy-Induced Cardiotoxicity

Certain chemotherapy agents directly damage the myocardium, leading to heart failure and cardiogenic pleural effusions:

• Anthracyclines (doxorubicin, daunorubicin) are the most common cause of chemotherapy-related cardiac dysfunction resulting in pleural effusions, especially in patients with preexisting cardiovascular risk factors 2
• Cyclophosphamide can cause acute cardiac dysfunction and subsequent pulmonary edema with pleural effusions 3, 2
• Dasatinib (tyrosine kinase inhibitor for CML) causes pulmonary hypertension in approximately 5% of patients, which can progress to right heart failure and pleural effusions if untreated 2
• Methotrexate, procarbazine, and bleomycin are documented causes of drug-related pulmonary injury that may present with pleural effusions 3

3. Paradoxical Effusion with Tumor Response

A rare but important phenomenon where pleural effusions develop or worsen despite tumor shrinkage:

• Tumor lysis during effective chemotherapy can paradoxically cause transient pleural effusions that resolve within 2-3 weeks while the tumor continues to respond 4
• This occurs in a small subset of non-small cell lung cancer patients receiving chemotherapy, with positive cytology for cancer cells in the fluid despite overall tumor reduction 4
• The effusions improve spontaneously without treatment interruption, distinguishing this from disease progression 4

4. Lymphangitic Carcinomatosis

• Gastric, breast, lung, and pancreatic cancers most commonly cause pulmonary lymphangitic spread, presenting with progressive dyspnea and cough due to lymphatic obstruction and interstitial edema that can be accompanied by pleural effusions 2

Critical Diagnostic Distinctions

When evaluating pleural effusions during chemotherapy, distinguish between:

• Disease progression (most common): Persistent or worsening effusion with tumor growth on imaging
• Treatment-related cardiotoxicity: New or worsening effusion with echocardiographic evidence of reduced ejection fraction or pulmonary hypertension
• Paradoxical tumor lysis: Transient effusion appearing within days of chemotherapy initiation, with concurrent tumor shrinkage on imaging 4

Management Approach Based on Mechanism

For Malignant Effusions in Chemotherapy-Responsive Tumors

Systemic chemotherapy should be initiated or continued as the primary treatment for pleural effusions from small-cell lung cancer, breast cancer, and lymphoma, as these respond better to systemic therapy than local interventions 1, 3:

• Small-cell lung cancer requires systemic chemotherapy as first-line treatment, with pleurodesis reserved only when chemotherapy is contraindicated or has failed 3
• Breast cancer should receive hormonal therapy or cytotoxic chemotherapy first, as malignant effusions from breast cancer respond better to systemic treatment than other tumor types 3
• Lymphoma warrants systemic chemotherapy as primary treatment, with local interventions considered only for symptomatic relief in recurrent effusions 1, 3

For Chemotherapy-Induced Cardiotoxicity

• Dasatinib-induced pulmonary hypertension: Withhold dasatinib, switch to alternative tyrosine kinase inhibitors, and consider sildenafil, endothelin antagonists, or calcium channel blockers with monthly echocardiographic follow-up 2
• Anthracycline cardiotoxicity: Manage heart failure with standard therapies; consider therapeutic thoracentesis for symptomatic relief while optimizing cardiac function 3

For Symptomatic Relief During Ongoing Treatment

• Therapeutic thoracentesis provides temporary relief while systemic therapy takes effect, removing no more than 1.5L during a single procedure to prevent re-expansion pulmonary edema 1, 3
• Avoid pleurodesis in chemotherapy-responsive tumors until systemic therapy has been attempted, as it may be unnecessary if the effusion resolves with tumor response 1, 3

Important Pitfalls to Avoid

• Do not assume all effusions during chemotherapy represent disease progression—paradoxical effusions with tumor response can occur and resolve spontaneously 4
• Do not delay systemic chemotherapy in favor of local treatment for effusions from small-cell lung cancer, breast cancer, or lymphoma, as systemic therapy is more effective 1, 3
• Monitor for cardiotoxicity in patients receiving anthracyclines or dasatinib, as early detection allows for treatment modification before irreversible cardiac damage occurs 2
• Intrapleural chemotherapy (cisplatin/cytarabine) appears inferior to existing sclerosing agents for effusion control and cannot be recommended for standard management 5, 6, 7