8.5 Complications of Cancer & Its Treatment

1. Immune Checkpoint Inhibitor Toxicity

Checkpoint inhibitors release the brakes on T cells, and the resulting immune-related adverse events can involve any organ. They are the fastest-growing source of oncology questions on internal medicine examinations because patients present to general internists and emergency departments, not to oncology clinics.

Three principles govern management:

1. Timing is variable. Events may begin within weeks or months after therapy has stopped. A patient who received pembrolizumab four months ago and now has diarrhea still has drug-attributable colitis until proven otherwise.
2. Treatment is immunosuppression, not symptom control. Grade 2 or higher events require corticosteroids (typically prednisone 1 to 2 mg/kg), escalating to infliximab, mycophenolate or other agents if refractory. Treating checkpoint-inhibitor colitis with loperamide alone risks perforation.
3. Infection must be excluded before immunosuppression — C. difficile in colitis, viral hepatitis in hepatitis, and pneumonia in suspected pneumonitis.

Endocrine events are the exception to the reversibility rule. Corticosteroids do not restore thyroid or pituitary function; these patients need lifelong hormone replacement, and the checkpoint inhibitor is often continued once replacement is established. In contrast, colitis, pneumonitis and hepatitis usually require holding or permanently discontinuing the drug.

Adrenal insufficiency from hypophysitis is the diagnosis not to miss. Fatigue, nausea, hyponatremia and hypotension in a patient on immunotherapy warrant a morning cortisol. Give glucocorticoid before levothyroxine if both deficits are present, to avoid precipitating adrenal crisis.

2. Cardiotoxicity

Risk rises steeply above a cumulative anthracycline dose threshold and with concurrent trastuzumab, prior chest radiation, hypertension and pre-existing cardiac disease. Management of declining ejection fraction follows standard heart failure therapy with renin-angiotensin blockade and beta-blockade.

Other cardiac toxicities: 5-fluorouracil and capecitabine cause coronary vasospasm with chest pain and ischemic ECG changes; tyrosine kinase inhibitors cause hypertension and QT prolongation; VEGF inhibitors cause hypertension, proteinuria, arterial thrombosis and impaired wound healing.

3. Chemotherapy-Induced Peripheral Neuropathy

A dose-limiting, often permanent toxicity, and a major determinant of long-term quality of life.

No agent prevents it. Dose reduction or discontinuation is the only effective intervention, and duloxetine has the best evidence for established painful neuropathy. Gabapentinoids and tricyclics are used but with weaker support.

Vincristine must never be given intrathecally — it is uniformly fatal — and must be avoided or used with extreme caution in Charcot-Marie-Tooth disease.

4. Nausea, Vomiting and Gastrointestinal Toxicity

Prophylaxis matched to emetogenic risk, given before treatment, is the principle. Rescue-only dosing is inferior and is a common wrong answer.

Anticipatory nausea is a conditioned response occurring before the infusion; it responds to benzodiazepines and behavioral therapy, not to additional anti-emetics. Delayed emesis beyond 24 hours is characteristic of cisplatin and is prevented by NK1 antagonists and dexamethasone.

Mucositis — pain and ulceration from rapid epithelial turnover, worst with 5-fluorouracil, methotrexate and radiation. Managed with oral care, analgesia, and evaluation for superimposed candidal or herpetic infection.

Diarrhea — irinotecan causes an early cholinergic diarrhea during infusion (treated with atropine) and a late secretory diarrhea (treated with high-dose loperamide). Always distinguish chemotherapy-related diarrhea from C. difficile and from checkpoint-inhibitor colitis, because the treatments are opposite.

Constipation from vincristine, opioids and 5-HT3 antagonists requires a scheduled bowel regimen.

5. Cancer Pain

Managed by mechanism as well as severity.

• Around-the-clock long-acting opioid with a short-acting breakthrough dose for continuous pain, with breakthrough dosing at roughly 10 to 20% of the total daily dose.
• Bone pain responds to NSAIDs, radiation to a symptomatic site, and bone-modifying agents.
• Neuropathic pain requires an adjuvant — duloxetine, gabapentinoid or tricyclic; opioids alone are less effective.
• Constipation prophylaxis is mandatory with every opioid prescription; tolerance does not develop to it.
• Never combine a partial agonist or mixed agonist-antagonist with a full agonist, which precipitates withdrawal.
• Meperidine is avoided because normeperidine accumulates and causes seizures.

6. Paraneoplastic Syndromes

Ectopic ACTH differs from pituitary Cushing syndrome: it produces marked hypokalemic metabolic alkalosis and hyperpigmentation with rapid onset and often without the classic cushingoid habitus, because there has not been time to develop it.

Lambert-Eaton myasthenic syndrome shows improvement in strength with repeated effort and an incremental response on high-frequency repetitive nerve stimulation, the opposite of myasthenia gravis, and warrants a search for small cell lung cancer.

7. Lymphedema and Radiation Toxicity

Lymphedema — an enumerated blueprint topic — follows nodal dissection or regional irradiation, most commonly after axillary surgery for breast cancer. It is managed with complete decongestive therapy: manual lymphatic drainage, compression garments, exercise and meticulous skin care. Cellulitis is the major complication, and recurrent episodes worsen the lymphedema, creating a cycle. Diuretics are ineffective. Late-onset or rapidly worsening lymphedema warrants evaluation for recurrent disease or angiosarcoma.

Radiation toxicity is divided into acute and late effects:

• Acute (during or shortly after treatment): dermatitis, mucositis, esophagitis, diarrhea, cystitis, fatigue — generally reversible.
• Late (months to years): fibrosis, xerostomia, radiation pneumonitis (typically 1 to 6 months after thoracic radiation, responsive to corticosteroids), constrictive pericarditis, accelerated coronary disease, hypothyroidism after neck irradiation, bowel strictures and chronic proctitis, and second malignancies including sarcoma and, after mantle irradiation, breast cancer.

Radiation recall — an inflammatory reaction in a previously irradiated field precipitated by later chemotherapy — is a distinctive phenomenon worth recognizing.