Urothelial Carcinoma: Muscle-Invasive and Metastatic Disease

Case Continued

The patient remains on pembrolizumab every 3 weeks as per protocol with regular surveillance imaging. His disease stabilizes as the nodule in his liver and the retroperitoneal lymph nodes, all representing metastatic disease, became slightly smaller in size without evidence of any new disease. He continues to follow up closely with his genitourinary oncologist, undergoing regular surveillance and imaging every 3 months without evidence of disease progression.

Approximately 12 months into therapy, the patient notices a nonproductive cough with progressive and rapidly worsening shortness of breath. He is noted to be hypoxic with oxygen saturation levels to 79% in clinic and is sent immediately to the emergency department by his oncologist. Diffuse bilateral reticular opacities are noted on chest radiograph. Non-contrast CT scan demonstrates diffuse ground-glass opacities consistent with acute respiratory distress syndrome–pattern pneumonitis. He is admitted to the intensive care unit.

The patient is aggressively treated with high-flow nasal oxygen supplementation, intravenous steroids, and empiric antibiotics. He slowly improves on high-dose steroids (methylprednisolone 1 mg/kg/day) without requiring intubation or infliximab therapy and is discharged home in stable condition after 10 days. Oral steroid therapy is continued with a long taper over 6 weeks. In the setting of his grade 3 pneumonitis, pembrolizumab is discontinued and the patient is scheduled for a follow-up appointment with his oncologist to discuss next steps.

• In addition to pneumonitis, what other toxicities should you monitor for in patients treated with an immune checkpoint inhibitor?
• Is this patient a candidate to receive immunotherapy again in the future?

Treatment Toxicities

As use of immune checkpoint inhibitors has become more prevalent, the medical community has become increasingly aware of various immune-related adverse effects (irAE) associated with these drugs. These toxicities can be seen in virtually any organ system, and even vague complaints that arise years after therapy initiation should be treated with a high level of suspicion. The most commonly affected organ systems include the skin, gastrointestinal (GI) tract, lungs, liver, and endocrine system, although all other organ systems can be involved (Table 3) and toxicities appear to be similar across individual drugs.

The American Society of Clinical Oncology recently published a complete set of recommendations to guide clinicians on appropriate treatment strategies for each manifestation of immunotherapy-related toxicity.⁵⁶ The details of these recommendations largely fall outside the purview of this article, but the mainstays of management are worth noting. These include high-dose systemic glucocorticoids, along with supportive care and cessation of immunotherapy in grade 3 or 4 toxicities. Infliximab is frequently recommended as an adjunct in severe or refractory cases.

Chemotherapy-related toxicities, on the other hand, are well-described and tend to be more familiar to patients and clinicians (Table 3). Classic MVAC, which has now been largely replaced by ddMVAC, was notoriously difficult to tolerate. It was known for a high rate of serious (grade 3 or 4) myelosuppressive complications as well as frequent GI toxicities. These complications include neutropenia (57%), stomatitis (10%), and nausea and vomiting (6%).²³ ddMVAC with growth factor support is much better tolerated than classic MVAC. Prominent complaints with ddMVAC still can include nausea, GI distress, mucositis, and fatigue, but the incidence of myelosuppressive complications in particular has markedly decreased. GC is largely well tolerated, with minimal nausea and manageable myelotoxicity, but it is associated with an increased risk of venous thromboembolism.³⁸