Thymoma: Pharmacological Management

Thymoma is a thymus gland cancer that is a type of thymic epithelial tumor, which also includes thymic carcinoma and neuroendocrine tumors (NETs).¹ Although thymomas are the most common type of thymic epithelial tumor, they are a rare type of thymus gland tumor, with an estimated incidence of 0.13 to 0.32 per 100,000 per year.² The incidence of thymoma is similar in male and females, and the mean age at diagnosis is 50 to 60 years. However, thymoma can be diagnosed in children and elderly patients.³ 

Thymoma symptoms are often nonspecific, such as chest pain, cough, or dyspnea.¹ 

In general, thymoma is less aggressive than thymic carcinoma.⁴ Management of thymoma can be complex because of its relatively rare and heterogeneous nature.¹ There is a lack of high-level evidence, so many recommendations for thymoma treatment are based on nonrandomized clinical trials, retrospective case series, and expert opinion.¹ 

The 2 main staging systems used for thymic epithelial tumors are the Masaoka-Koga stage classification and the TNM Classification of Malignant Tumors, 8th edition, which recently replaced the World Health Organization’s histologic classification system.⁴ 

Treatment of thymic epithelial tumors should be managed by a multidisciplinary team that includes oncologists, radiation oncologists, thoracic surgeons, neurologists, immunologists, and pathologists.⁴ The 5-year survival rate for patients with thymoma is approximately 80%, and a majority of patients with early-stage disease can be cured with surgical management with or without radiation therapy.⁴ 

Surgical Management of Thymoma

Surgical management is the treatment of choice for early-stage (stage I and stage II) thymoma due to the high rate of complete surgical resection of the tumor.¹ 

Median sternotomy is the standard surgical approach for thymoma resection. Data on minimally invasive techniques are lacking, and they are therefore not usually recommended for stage I or II disease and are discouraged in advanced disease.¹   

The goal of surgery is the complete excision of the entire lesion. This may require partial resection of adjacent structures, such as the pericardium, pleura, lung, phrenic nerve, and major vascular structures. However, resection of the bilateral phrenic nerve should be avoided due to respiratory morbidity.⁵ 

Radiation Therapy for Thymoma

Radiation therapy is not recommended for all patients with thymoma, such as those with stage I or II disease who have undergone complete resection of the tumor.³ 

Radiation therapy is recommended for patients with the following conditions⁵: 

• Unresectable disease
• Incompletely resected disease
• As adjuvant treatment for locally advanced disease 

The radiation dose depends on the indication and the completeness of surgical resection (Table 1).⁵ 

Table 1. Radiation Dose for Patients With Thymoma

Indication	Completeness of Surgical Resection	Dose
Definitive treatment	Unresectable disease	60 to 70 Gy
Adjuvant treatment	Clear or close margins	45 to 50 Gy
Microscopically positive resection margins	54 Gy
Gross residual disease	60 to 70 Gy
Palliative treatment	Any	Typical palliative doses (such as 8 Gy in a single fraction, 20 Gy in 5 fractions, or 30 Gy in 10 fractions) up to 60 to 70 Gy

Chemotherapy

Chemotherapy is recommended for patients with locally advanced, advanced, or recurrent thymoma. Chemotherapy is not recommended for patients who have no residual tumor (R0) or microscopic residual tumor (R1).^3,5 

Table 2. First-Line Combination Chemotherapy Regimens for Thymoma

Chemotherapy Regimen	Dose	Frequency
CAP*	Cyclophosphamide 500 mg/m2 Doxorubicin 50 mg/m2 Cisplatin 50 mg/m2	Every 3 weeks
CAP with prednisone	Cyclophosphamide 500 mg/m2 on day 1 Doxorubicin 20 mg/m2/d via continuous infusion on days 1-3 Cisplatin 30 mg/m2 on days 1-3 Prednisone 100 mg/d on days 1-5	Every 3 weeks
ADOC	Doxorubicin 40 mg/m2 on day 1 Cisplatin 50 mg/m2 on day 1 Vincristine 0.6 mg/m2 on day 3 Cyclophosphamide 700 mg/m2 on day 4	Every 3 weeks
PE	Cisplatin 60 mg/m2 on day 1 Etoposide 120 mg/m2/d on days 1-3	Every 3 weeks
Etoposide/ifosfamide/cisplatin	Etoposide 75 mg/m2 on days 1-4 Ifosfamide 1.2 g/m2 on days 1-4 Cisplatin 20 mg/m2 on days 1-2	Every 3 weeks

Second-line chemotherapy agents recommended by the National Comprehensive Cancer Network (NCCN) for thymoma include⁵:

• Fluorouracil (5-FU) and leucovorin
• Gemcitabine with or without capecitabine
• Paclitaxel
• Pemetrexed

The following is a review of the chemotherapy agents used in first-line regimens for thymoma. 

Cyclophosphamide

Cyclophosphamide is an alkylating agent indicated for the treatment of malignant diseases. It works by decreasing tumor cell DNA synthesis by preventing DNA cross-linking.⁶ 

Dosage and Administration

Cyclophosphamide is administered intravenously (IV). It should be administered in the morning due to the need for increased fluid intake to avoid urinary tract toxicity.⁶ 

Antiemetics are recommended due to the high emetic risk of cyclophosphamide.⁷

See Table 2 for dosing of cyclophosphamide for thymoma. Infusion rate varies based on protocol. 

Adverse Reactions

The most common adverse drug reactions associated with cyclophosphamide include⁶:

• Hematopoietic (neutropenia)
• Gastrointestinal (nausea and vomiting, anorexia, abdominal pain, and diarrhea)
• Skin (alopecia, rashes, and changes in skin and nail pigmentation) 

Serious reactions associated with cyclophosphamide include⁶:

• Severe immunosuppression and infection
• Urinary and renal toxicity 
• Cardiotoxicity
• Pulmonary toxicity
• Veno-occlusive liver disease 

Patients should be monitored for signs of renal toxicity when undergoing treatment with cyclophosphamide. Cardiac function should be monitored, especially in patients with pre-existing risk factors.⁶ 

Drug Interactions

Cyclophosphamide is a prodrug activated by cytochrome P450 (CYP) enzymes.⁶ 

Cyclophosphamide has several drug interactions that may result in increased toxicity⁶: 

• Increased immunosuppression or hematologic toxicity with angiotensin-converting enzyme (ACE) inhibitors, natalizumab, paclitaxel, thiazide diuretics, and zidovudine 
• Increased cardiotoxicity with anthracyclines, cytarabine, pentostatin, cardiac region radiation therapy, and trastuzumab
• Increased pulmonary toxicity with amiodarone, granulocyte colony-stimulating factor (G-CSF), and granulocyte-macrophage colony-stimulating factor (GM-CSF)
• Increased nephrotoxicity with amphotericin B and indomethacin
• Increases in other toxicities with azathioprine, busulfan, protease inhibitors, and metronidazole  
• Increased risk of secondary malignancies with etanercept
• Increased thromboembolic complications with tamoxifen 

Both increased and decreased effects on warfarin have been reported among patients receiving cyclophosphamide; therefore, the patient’s international normalized ratio (INR) should be monitored closely.⁶ 

Cyclophosphamide may decrease concentrations of cyclosporine.⁶

Doxorubicin

Doxorubicin is an anthracycline topoisomerase inhibitor used off-label to treat thymoma.⁸ 

Dosage and Administration

The administration of antiemetics is recommended due to doxorubicin’s moderate emetic potential.⁷ 

Doxorubicin can be administered via IV push over 3 to 10 minutes or continuous infusion, depending on the protocol.⁸ See Table 2 for appropriate dosing. 

Dose reductions may be necessary for patients with hepatic impairment (elevated total bilirubin concentrations).⁸ 

Extravasation and tissue necrosis can also occur as a result of doxorubicin administration. During infusion, closely monitor for signs of extravasation and promptly discontinue if signs occur.⁸ 

The patient’s cumulative doxorubicin dose should be monitored. Cumulative doses of 300 mg/m² to 500 mg/m² have been reported to cause myocardial damage in 1% to 20% of patients.⁸ 

Adverse Reactions

The most common adverse reactions associated with doxorubicin include⁸:

• Gastrointestinal (nausea and vomiting)
• Skin (alopecia)
• Hematopoietic (leukopenia) 

Doxorubicin-induced cardiotoxicity can be acute or delayed. Left ventricular ejection fraction (LVEF) should be monitored before, during, and after treatment with doxorubicin.⁸

Serious infections and septic shock can occur due to doxorubicin-induced myelosuppression.⁸ 

Drug Interactions  

Doxorubicin is metabolized by P-glycoprotein and CYP450 enzymes CYP2D6 and CYP3A4. Concomitant use of inducers or inhibitors of these enzymes should be avoided.⁸  

Cardiotoxic medications, such as trastuzumab, should also be avoided during doxorubicin therapy to avoid an increased risk of cardiac dysfunction.⁸ 

Cisplatin

Cisplatin is a platinum-based agent that inhibits DNA synthesis.⁹ 

Dosage and Administration

Pretreatment hydration and antiemetic treatment are recommended to prevent nephrotoxicity and severe nausea and vomiting, respectively.⁹ 

Cisplatin is typically administered by IV over at least 1 hour.¹⁰ See Table 2 for dosing. 

During infusion of cisplatin, patients should be closely monitored for hypersensitivity and infusion reactions.⁹

Dose modifications may be required for patients with decreased creatinine clearance, myelosuppression, or neuropathy.⁹ 

Adverse Reactions 

Common adverse reactions associated with cisplatin include⁹:

• Nephrotoxicity
• Peripheral neuropathy
• Nausea and vomiting
• Myelosuppression
• Ototoxicity 

Drug Interactions 

Nephrotoxic and ototoxic drugs may have an additive effect in patients undergoing treatment with cisplatin. Kidney and hearing function should be closely monitored with concomitant administration with nephrotic or ototoxic drugs, such as aminoglycosides or vancomycin.⁹ 

Vincristine

Vincristine is a vinca alkaloid chemotherapy agent that inhibits microtubule formation, preventing cell division.¹¹ 

Dosage and Administration 

To reduce the risk of potential and fatal medication errors, vincristine should be administered by IV over 5 to 10 minutes in a minibag or other flexible container with compatible solution and not via a syringe.^11,12 

See Table 2 for dosing information. 

Patients should be monitored for extravasation during infusion of vincristine. If extravasation occurs, the infusion should be stopped, and any remaining medication should be given into another vein.¹¹ 

Dose modifications may be necessary for patients with hepatotoxicity (bilirubin >3 mg/dL) or neurotoxicity adverse drug reactions.¹¹ 

Adverse Reactions

Potential adverse reactions associated with vincristine include¹¹:

• Neurologic (sensory impairment, paresthesia, neuritic pain, motor difficulties, convulsions, ototoxicity, and vertigo)  
• Gastrointestinal (constipation or diarrhea, abdominal cramps, weight loss, nausea and vomiting, oral ulcers, and intestinal perforation)
• Genitourinary (polyuria, dysuria, and urinary retention) 
• Cardiovascular (hypertension or hypotension) 
• Endocrine (inappropriate antidiuretic hormone secretion)
• Skin (alopecia and rashes) 
• Pulmonary (acute shortness of breath and severe bronchospasm) 
• Infusion reactions (hypersensitivity reactions) 

Close neurologic monitoring should occur during treatment with vincristine. Neurologic side effects are typically dose-related and usually start with sensory impairment and then progress to motor difficulties.¹¹ 

Drug Interactions 

An additive effect may be seen when vincristine is concomitantly administered with other neurotoxic drugs. Caution and close patient monitoring should occur.¹¹ 

Simultaneous oral or IV administration of vincristine and phenytoin may decrease phenytoin levels and induce seizures.¹¹ 

Caution should be used when administering vincristine with CYP3A4 inhibitors like itraconazole. 

Drugs known to cause urinary retention (such as anticholinergics, opioids, benzodiazepines, nonsteroidal anti-inflammatory drugs [NSAIDs], and calcium channel blockers) should be avoided as much as possible for the first few days after administration. The risk of urinary retention is increased in older patients.^11,13 

Caution should be used with concomitant administration of other ototoxic medications, such as platinum-containing chemotherapy agents.¹¹ 

Etoposide

Etoposide is a topoisomerase inhibitor that inhibits DNA synthesis in cancer cells.¹⁴ 

Dosage and Administration

Etoposide is administered via IV infusion over a period of up to 3.5 hours. Etoposide should not be administered via a bolus injection. Nausea and vomiting are usually mild to moderate; therefore, pretreatment with antiemetics may be necessary.⁷ Patients should be monitored for extravasation during infusion.¹⁴ 

See Table 2 for dosing. 

Dosage adjustments may be needed for patients with renal impairment.¹⁴ 

Adverse Reactions

Neutropenia is the most common adverse drug reaction associated with etoposide treatment.¹⁴ 

Other possible side effects associated with etoposide include¹⁴:

• Myelosuppression
• Gastrointestinal (nausea and vomiting, abdominal pain, dysphagia)
• Ocular (transient cortical blindness, optic neuritis)
• Skin (abnormal pigmentation, radiation recall dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis)  
• Neurologic (seizure and abnormal taste) 
• Hepatotoxicity 
• Secondary leukemias 
• Infusion reactions (hypersensitivity reactions) 

Drug Interactions 

Concomitant use of etoposide with warfarin can result in increased INR; therefore, close monitoring is required.¹⁴ 

Ifosfamide

Ifosfamide is an alkylating agent that inhibits protein and DNA synthesis in cancer cells.¹⁵ 

Dosage and Administration

Pretreatment with mesna, hydration, and an antiemetic is recommended for prophylaxis of hemorrhagic cystitis, nausea, and vomiting.¹⁵ 

Ifosfamide is administered by a slow IV infusion lasting at least 30 minutes to reduce the risk of hypotension. See dosing in Table 2. Patients should be monitored closely for infusion reactions, as anaphylaxis reactions have occurred in patients receiving ifosfamide.¹⁵ 

Dose adjustment may be necessary for patients with renal impairment.¹⁵ 

Adverse Reactions 

The most common adverse reactions associated with ifosfamide include¹⁵:

• Alopecia
• Nausea and vomiting
• Leukopenia
• Anemia
• Central nervous system (CNS) toxicity
• Hematuria
• Infection 

Serious adverse reactions associated with ifosfamide include¹⁵:

• Myelosuppression
• CNS toxicity resulting in encephalopathy and death
• Nephrotoxicity resulting in renal failure 
• Pulmonary toxicity 
• Cardiotoxicity, including arrhythmias
• Anaphylaxis 

Drug Interactions 

Concomitant use of CYP3A4 inducers or inhibitors could result in increased ifosfamide toxicity or decreased efficacy, respectively.¹⁵ 

Hormone Therapy

Hormone therapy with octreotide is an option for patients with advanced thymoma and an octreotide-positive nucleotide scan who are not eligible to receive additional chemotherapy.^3,5 

Octreotide 

Octreotide is a second-line treatment option for advanced, recurrent, or unresectable thymic tumors in patients with octreotide-avid disease as determined by nuclear medicine scan.^5,16.17

Octreotide mimics the action of the naturally occurring hormone somatostatin. It acts as a potent inhibitor of growth hormone, glucagon, and insulin.¹⁷ Somatostatin receptors are often expressed in thymic tumors. Treatment with the somatostatin analog octreotide can result in tumor size reduction and remission in some patients.¹⁸ 

Octreotide may be given with or without corticosteroids, such as prednisone.⁵

Dosage and Administration

Octreotide is administered subcutaneously or intramuscularly.¹⁶

The dosage of octreotide administered subcutaneously is 500 µg 3 times daily for up to 1 year.¹⁸

The dosage of the long-acting release formulation of octreotide administered intramuscularly for patients with thymoma is 30 mg every 2 weeks for up to 24 weeks. If administered with prednisone, the recommended dosage is 0.6 mg/kg/d.¹⁷ 

The dose of octreotide may need to be adjusted for patients with renal or hepatic impairment.¹⁶ 

Patients should be monitored for infusion reactions, as anaphylaxis reactions have occurred.¹⁶ 

Adverse Reactions

The most common (more than 20% of patients) adverse reactions associated with octreotide include¹⁶:

• Cholelithiasis
• Diarrhea
• Abdominal pain
• Flatulence 
• Back pain
• Fatigue 
• Headache
• Nausea
• Dizziness 

Possible serious adverse reactions associated with octreotide include¹⁶:

• Gallbladder abnormalities
• Hypoglycemia or hyperglycemia
• Hypothyroidism 
• Cardiac arrhythmia 
• Bradycardia 
• Other cardiac conduction abnormalities

Patients should be monitored for serious adverse events such as gallbladder abnormalities and should undergo monitoring of glucose and thyroid levels.¹⁶ 

Drug Interactions

Octreotide may have an effect on the absorption of orally administered drugs and may decrease blood levels of certain drugs.¹⁶

Dosage adjustments may be necessary for the following drugs¹⁶:

• Hypoglycemic agents
• β-blockers
• Calcium channel blockers
• Agents that control fluid and electrolyte balance
• Cyclosporine 

Additionally, octreotide may decrease the clearance of drugs metabolized by some CYP450 enzymes, especially CYP3A4. Clinicians are advised to monitor therapy closely when administering concomitantly with other drugs with a low therapeutic index, such as quinidine or terfenadine.¹⁶ 

Octreotide may increase the bioavailability of bromocriptine.¹⁶ 

Targeted Therapy

Targeted therapy is a type of precision medicine that targets specific proteins that affect how cancer cells grow and spread.  

Although targeted therapy has become the standard of care for many types of cancer, it has only shown a modest effect in the treatment of thymoma.¹⁹ There is a lack of known targets and drugs that are active against those targets.²⁰ 

Treatment with the following types of targeted therapy is not indicated in patients with thymoma¹⁹:

• Anti-epidermal growth factor receptor (anti-EGFR) or anti-insulin-like growth factor (anti-IGFR) drugs
• Antiangiogenic agents 
• cKIT inhibitors
• Epigenetic drugs 

Everolimus

Everolimus is a mammalian target of rapamycin (mTOR) inhibitor that has antiproliferative and antiangiogenic properties. It is indicated for the treatment of renal cell carcinoma and subependymal giant cell astrocytoma.²¹ A phase 2 trial found that everolimus may be beneficial in patients with thymoma progression after pretreatment with platinum-based chemotherapy.²² 

Dosage and Administration

The dosage of everolimus for thymoma treatment is 10 mg/d orally as a tablet or suspension until disease progression or unacceptable toxicity.²² Everolimus should be taken with a full glass of water at the same time each day. It can be administered with or without food but should remain consistent. Everolimus tablets should not be crushed or chewed. Patients unable to swallow tablets whole should use the oral suspension.²¹ 

The manufacturer recommends an everolimus dosage of 5 mg/d or temporary interruption for patients with severe adverse reactions. Dosage adjustments may also be necessary in the following cases²¹:

• Patients with hepatic impairment (dose decrease)
• Concomitant use of CYP3A4 or P-glycoprotein inhibitors (dose decrease)
• Concomitant use of CYP3A4 inducers (dose increase)

Adverse Reactions

The most common adverse reactions associated with everolimus include²¹:

• Stomatitis
• Infections
• Asthenia
• Fatigue
• Cough
• Diarrhea
• Upper respiratory tract infection
• Pyrexia
  

Serious treatment-related adverse events in thymoma clinical trials included hepatotoxicity, neutropenia, metabolic disorders, and fatal pneumonitis.²²

Drug Interactions

Everolimus is a substrate of CYP3A4 and P-glycoprotein; therefore, caution is needed for the simultaneous use of other substrates, inhibitors, or inducers of these enzymes.²¹ 

CYP3A4 and P-glycoprotein inhibitors (such as ketoconazole, erythromycin, or verapamil) may increase blood concentrations of everolimus, thereby increasing toxicity. Concomitant use of strong inhibitors should be avoided with everolimus.²¹ 

CYP3A4 inducers (such as rifampin) may decrease blood concentrations of everolimus, thereby decreasing efficacy. Concomitant use with St John’s wort should be avoided.²¹ 

Sunitinib 

Sunitinib is a kinase inhibitor with antitumor and antiangiogenic properties. Sunitinib inhibits multiple tyrosine kinases, including vascular endothelial growth factor (VEGF).²³ VEGF is often overexpressed in thymomas, and it is associated with tumor invasiveness.²⁴ 

Dosage and Administration

The dosage of sunitinib for the treatment of thymoma is 50 mg oral capsule once daily in a 6-week cycle of 4 weeks of treatment followed by 2 weeks without treatment until tumor progression or unacceptable toxicity.^23,24 Sunitinib can be taken with or without food.²³

Dosage adjustments may be necessary for treatment-related renal or hepatic toxicity.^23,24 

Adverse Reactions 

The most common adverse reactions associated with sunitinib include²³:

• Gastrointestinal (diarrhea or constipation, mucositis/stomatitis, nausea and vomiting, dyspepsia, abdominal pain, altered taste, and anorexia)
• Cardiovascular (hypertension and edema)
• Skin (rash, hand-foot syndrome, skin discoloration, dry skin, and hair color changes)
• Other (headache, back pain, arthralgia, extremity pain)
• Pulmonary (cough and dyspnea)
• Endocrine (thyroid dysfunction)
• Bleeding 
• Fever
• Fatigue and asthenia 

Serious adverse events that may require sunitinib dose adjustments or discontinuation include²³:

• Hepatotoxicity, including liver failure 
• Cardiac toxicity, including LVEF decline and heart failure
• Prolonged QT interval and torsades de pointes
• Hemorrhagic events 
  

Patients should be monitored for signs of heart failure, thyroid dysfunction, and hypertension, with treated as needed.²³ 

Periodic cardiac electrocardiogram and monitoring of blood electrolytes should be considered for potential arrhythmias.²³ 

Drug Interactions

Sunitinib is a CYP3A4 substrate; therefore, administration with CYP3A4 inhibitors and inducers is not recommended. If concomitant administration with a CYP3A4 inhibitor or inducer is unavoidable, a dose decrease or increase, respectively, may be required.²³ 

Caution should be used when administering sunitinib with other QT-prolonging agents and antiarrhythmics.²³  

Immunotherapy

The thymus is a lymphatic organ responsible for several immune functions, such as T-cell maturation and the induction of self-tolerance.²⁵ Up to 40% of patients with thymoma also have an autoimmune disorder, most commonly myasthenia gravis.²⁶ 

The utility of immunotherapy may be limited by the high incidence of autoimmune conditions with thymoma. The risks and benefits of immunotherapy are influenced by the key role the thymus gland plays in immunity.^25,26 

The programmed death-ligand 1 (PD-L1) — a target of immune checkpoint inhibitors — is expressed in 23% to 92% of thymomas.¹⁹ This fact has led to the investigation of immunotherapy to treat advanced thymoma. However, current clinical trials for immunotherapies exclude patients with autoimmune disorders.²⁶

Pembrolizumab

Pembrolizumab is an immune checkpoint inhibitor indicated for the treatment of several cancers. It is a monoclonal antibody that reverses T-cell suppression and induces an antitumor response by inhibiting PD-1.²⁷ Some types of thymoma have high PD-1 ligand expression, making PD-1 a possible target for thymoma treatment.⁴ 

Pembrolizumab has been studied in patients with advanced thymoma whose disease progresses after platinum-based chemotherapy.²⁸ However, NCCN guidelines do not recommend pembrolizumab for thymoma due to the high rate of immune-related adverse events.⁵ 

Dosage and Administration

Pembrolizumab is administered via IV infusion over 30 minutes.²⁷ 

The recommended dosage of pembrolizumab for thymoma treatment is 200 mg IV every 3 weeks for up to 24 months or until disease progression, death, or unacceptable toxicity.²⁸ 

Patients undergoing treatment with pembrolizumab should be monitored closely for infusion-related reactions.²⁷ 

Adverse Reactions

The most common adverse reactions associated with pembrolizumab include²⁷:

• Gastrointestinal (decreased appetite, diarrhea or constipation, nausea, and abdominal pain)
• Skin (pruritus and rash)
• Pulmonary (cough and dyspnea)
• General (fatigue, musculoskeletal pain, and pyrexia)

Severe or fatal immune-mediated adverse reactions can occur in any organ system or tissue, including^26,27:

• Pneumonitis
• Colitis
• Hepatitis
• Endocrinopathies 
• Nephritis 
• Myasthenia gravis 

Patients with thymoma may be more likely to experience serious immune-mediated adverse drug reactions, including myocarditis, myositis, or myasthenia gravis.²⁶ 

The manufacturer recommends monitoring liver enzymes, creatinine, and thyroid function at baseline and regularly during treatment with pembrolizumab.²⁷

Drug Interactions

The manufacturer does not list any known drug interactions with pembrolizumab.²⁷ 

Monitoring Considerations

Clinicians should consider personalized monitoring parameters based on treatment selection and individual patient factors before, during, and after thymoma treatment. 

Before and During Treatment

The American Society of Clinical Oncology (ASCO®) recommends that all patients should be screened for chronic or past hepatitis B virus infection prior to undergoing systemic cancer treatment to evaluate the reactivation risk.²⁹

All patients with childbearing potential should be screened for pregnancy and counseled on pregnancy prevention and planning. All systemic thymoma treatments other than octreotide can cause fetal harm.^{6,8,9,11,14-16,21,23,27}

Baseline tests for most treatment regimens for thymoma should include the following^{6,8,9,11,14-16,21,23,27}:

• Physical examination including blood pressure 
• Complete blood count with differential
• Kidney function test
• Liver function tests 
• Blood chemistry 
• Thyroid function
• LVEF
• Audiology and vestibular tests 
• Neurologic testing 

Some therapies require ongoing monitoring before each round of treatment or as needed to detect nephrotoxicity, hepatic toxicity, neurotoxicity, ototoxicity, or cardiac toxicity.^{6,8,9,11,14-16,21,23,27}

Patients receiving oral therapy, such as everolimus or sunitinib, should be evaluated for adherence via patient interviews or blood serum levels.^21,23 

During Infusion

Chemotherapy, targeted therapies, and immunotherapies should be administered by healthcare professionals with experience in these treatment modalities. Infusion-related reactions or anaphylactic reactions can happen with any infusion. Patients should also be observed for signs of extravasation, especially when administering doxorubicin, vincristine, and etoposide.^{6,8,9,11,14-16,21,23,27}

After Treatment

Patients need ongoing monitoring after thymoma treatment ends to watch for signs of secondary malignancies and other adverse drug reactions.^{6,8,9,11,14-16,21,23,27} 

Patients should be monitored for signs of cardiac toxicity, such as arrhythmias and heart failure, for several years after treatment with doxorubicin, ifosfamide, and sunitinib. Octreotide may worsen existing heart failure.^8,15,16,23 

Premenopausal patients who receive chemotherapy should be monitored for amenorrhea and early menopause.^{6,8,9,11,14,15} 

Considerations for Specific Populations 

The majority of patients with thymoma are aged between 50 and 60 years; however, thymoma can occur in pediatric or geriatric populations.^3,4 

Pediatrics

Thymoma is very rare in the pediatric population, but cases have been reported. A review of the Surveillance, Epidemiology, and End Results (SEER) Program registry from 1973 to 2008 identified 23 patients with thymoma.³⁰ 

Surgery is also considered the mainstay of therapy for pediatric patients. Radiation doses may differ based on the child’s age.³¹ 

Anthracycline-based chemotherapy regimens are preferred for children with advanced or unresponsive thymoma.³² Chemotherapy agents that have been successful in pediatric patients include doxorubicin, cyclophosphamide, etoposide, cisplatin, ifosfamide, and vincristine. Other systemic therapies for childhood thymoma include octreotide and sunitinib.³¹ 

The safety and efficacy of etoposide, ifosfamide, octreotide, and everolimus have not been established for the pediatric population.^14-16,21 The safety and efficacy of pembrolizumab in pediatric patients have been established for some types of cancers.²⁷ Animal studies suggest that sunitinib may be harmful to the pediatric population.²³ 

Other thymoma treatments may be associated with increased risks for some adverse reactions, including^6,8,9,11,16:

• Cyclophosphamide (altered development of secondary sexual characteristics and increased risk of early menopause in female patients) 
• Doxorubicin (increased risk of developing late cardiac dysfunction) 
• Cisplatin (increased incidence of ototoxicity [incidence between 40% and 60%])
• Vincristine (increased risk of liver damage, paralytic ileus, and neurologic side effects such as convulsions)
• Octreotide (increased risk of hypoxia, necrotizing enterocolitis, and death, especially in children younger than 2 years of age)

Geriatrics

Geriatric patients tend to be more likely to have comorbidities, such as kidney and liver dysfunction, that could affect the efficacy or excretion of a medication.^{6,8,9,11,14-16,21,23,27} 

Some systemic thymoma treatments — including doxorubicin, etoposide, everolimus, and sunitinib — show no evidence of differences in the geriatric population.^8,14,21,23 Patients in the geriatric population may be more susceptible to adverse events associated with some treatments, including^6,9,11,15,27:

• Cyclophosphamide (increased risk of hepatic, renal, or cardiac dysfunction)
• Cisplatin (increased risk of hematologic adverse events, peripheral neuropathy, and nephrotoxicity) 
• Vincristine (increased risk of urinary retention)
• Ifosfamide (increased frequency of hepatic, renal, and cardiac side effects)
• Pembrolizumab (increased risk of all adverse events) 

Providers should consider conservative dosing for the above medications in geriatric patients, with close monitoring for adverse events.^6,9,11,15,27 

Pregnancy 

Due to potential fetal harm, female patients should avoid pregnancy during thymoma treatment and for several months after treatment. Male patients with female partners of reproductive potential should also avoid fathering a child while undergoing systemic treatment and for several months afterward. Patients of reproductive potential should be counseled on effective contraception methods.^{6,8,9,11,14-16,21,23,27}  

There are no studies of octreotide in pregnant women, although animal studies suggest that octreotide does not cause fetal harm. However, this drug should only be used in pregnancy if clearly needed.¹⁶ 

Lactation 

Current systemic thymoma treatments are either found in breast milk or there are no data. Due to the potential harm to an infant, breastfeeding is not recommended during maternal thymoma treatment.^{6,8,9,11,14-16,21,23,27} It is unknown whether octreotide is present in human breast milk; therefore, caution is advised when breastfeeding while taking this drug.¹⁶ 

Infertility 

As chemotherapy treatment for thymoma can cause infertility in male and female patients, they should be counseled about the possibility of infertility and family planning before treatment.^{6,8,9,11,14,15} 

Renal Impairment

The following thymoma treatments may require dose reductions or close monitoring in patients with renal impairment^6,9,15,16,23:

• Cyclophosphamide 
• Cisplatin 
• Ifosfamide 
• Octreotide 
• Sunitinib 

Hepatic Impairment

The following thymoma treatments may require dose reduction or close monitoring in patients with hepatic impairment^{6,8,11,15,16,21,23}:

• Cyclophosphamide 
• Doxorubicin 
• Vincristine  
• Ifosfamide 
• Octreotide 
• Everolimus
• Sunitinib 

Thymoma Treatment Guidelines 

A number of organizations have created guidelines to assist in clinical decision-making for patients with thymoma: 

• The NCCN Clinical Practice Guideline in Oncology for Thymomas and Thymic Carcinomas is available here (updated in 2022).⁵
• Thymic Epithelial Tumours: ESMO Clinical Practice Guidelines for Diagnosis, Treatment and Follow-up is available here (published in 2015).³
• Thymoma and Thymic Carcinoma in Children and Adolescents: The Expert/Partner Diagnostic and Therapeutic Recommendations is available here (published in 2021).³²
• GOECP/SEOR Radiotherapy Guidelines for Thymic Epithelial Tumours is available here (published in 2021).¹ 

References

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29. Hwang JP, Feld JJ, Hammond SP, et al. Hepatitis B virus screening and management for patients with cancer prior to therapy: ASCO provisional clinical opinion update. J Clin Oncol. 2020;38(31):3698-3715. doi:10.1200/JCO.20.01757

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Author Bio

Amanda Jacob, PharmD, earned a Bachelor of Science degree in biology from the University of Texas at Austin in 2009 and a Doctor of Pharmacy degree from the University of Texas College of Pharmacy in 2014. She has worked as a community pharmacist for 8 years and is a member of the American Society of Consultant Pharmacists. Amanda is passionate about empowering people to take charge of their health and improving health literacy.