An 83-year-old man—an ex-smoker with a history of hypertension, coronary artery disease, and multiple abdominal surgeries associated with a bowel perforation—was diagnosed with multiple low-grade transitional cell carcinomas over a 6-year period, with the first of these diagnosed when he was 73 years old. He underwent four transurethral resection of bladder tumor procedures during that time and received one treatment with intravesical mitomycin. A surveillance cystoscopy in year 7 showed high-grade noninvasive papillary urothelial carcinoma in the bladder trigone. A CT urogram showed a soft-tissue mass with diffuse enhancement in the lower pole of the left kidney, concerning for malignancy.
The patient underwent a ureteroscopy and stenting of the left ureter with resection of the mass, which was consistent with high-grade papillary urothelial carcinoma. He then received 6 treatments with intravesical bacillus Calmette–Guérin therapy. It is unclear why a nephroureterectomy was not performed at this time, given that this would have been standard of care.
Unfortunately, follow-up ureteroscopy performed 3 months later revealed a mass in the left renal pelvis. He underwent a left nephroureterectomy; final pathology was consistent with a high-grade urothelial carcinoma extending into the renal parenchyma, pathologic stage pT3NX. He did not receive adjuvant chemotherapy because he was not a candidate for cisplatin, due to an elevated creatinine level and his underlying cardiac disease. Surveillance cystoscopies were negative for the next year; however, in year 8, he was found to have a recurrence in the left renal pelvis, as well as new liver lesions. MRI of the abdomen showed multiple masses in the liver, with the largest measuring 4.9 cm × 4.4 cm (Figure 1). A positron emission tomography scan confirmed at least seven fluorodeoxyglucose-avid liver lesions. Biopsy of the liver demonstrated poorly differentiated carcinoma diffusely positive for GATA3 and CK7, with focal positivity for CK20, consistent with urothelial carcinoma.
As before, because of his elevated creatinine level and underlying cardiac disease, the patient was not a candidate for cisplatin. He received 6 cycles of gemcitabine and carboplatin. (While carboplatin has not been shown to improve overall survival in the adjuvant setting, it can be used in the metastatic setting for patients who are ineligible to receive cisplatin.) After he completed the 6 cycles, all liver lesions were nearly resolved, with the three remaining lesions measuring 0.6 cm, 0.8 cm, and 1.1 cm. However, a follow-up scan 2 months after completion of treatment showed growth of the hepatic lesions, with the largest measuring 2.6 cm (increased from 1.1 cm on the prior scan) (Figure 2).
The patient was then started on second-line atezolizumab. MRI of the abdomen after 4 cycles of atezolizumab showed a mixed response, with two of the liver lesions having shrunk (down to 1.4 cm from 2.0 cm, and to 1.3 cm from 2.6 cm) and one lesion having increased from 2.4 cm to 3.6 cm. Repeat MRI after 8 cycles showed further decreases in the size of the liver lesions—down to 1.2 cm, 0.6 cm, and 2.0 cm, respectively (Figure 3). Unfortunately, a chest CT scan performed at the same time showed multiple new bilateral lung nodules (a 1.3-cm nodule in the right upper lobe, a 1.9-cm nodule in the right middle lobe [Figure 4], a 1.0-cm nodule in the left upper lobe, and a 1.3-cm nodule in the left lower lobe).
Which of the following represents the next best step in management for this patient?
A. Cytotoxic chemotherapy
B. Stereotactic body radiotherapy for the lung lesions
C. Continuation of atezolizumab
Correct Answer: C
This case involves a patient with metastatic urothelial carcinoma receiving second-line therapy with atezolizumab, in whom imaging demonstrated progressive disease after he had completed 8 cycles of therapy. Urothelial carcinoma, also known as transitional cell carcinoma, is the sixth most common form of cancer in the United States. In 2017, there were approximately 80,000 new cases of bladder cancer and 17,000 deaths due to this disease.
Until recently, treatment for metastatic urothelial carcinoma was platinum-based chemotherapy, and the 5-year survival rate was dismal—only about 5%. However, there is no cytotoxic chemotherapy that has been approved by the US Food and Drug Administration (FDA) for second-line treatment of urothelial carcinoma. Studies with second-line agents such as single-agent taxanes have shown low response rates, considerable toxicities, and no survival benefit. Thus, Answer A is incorrect.
Immune checkpoint inhibitors were developed for second-line treatment of metastatic urothelial carcinomas since these tumors have the third highest mutation rate of all studied cancers, and because in both lung cancer and melanoma, high mutational burden has correlated with better responses to immune checkpoint blockade.[5,6] As part of the immune checkpoint system, programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1) play important roles in allowing tumor cells to evade the immune system, and both are highly expressed in many tumor types, including urothelial carcinoma. The binding of PD-1 to PD-L1 inhibits T-cell proliferation, production of cytokines, and cytotoxic activity—which leads to T-cell exhaustion. Antibodies against PD-1 and PD-L1 allow the T cells to remain active and able to recognize the tumor as foreign, with a resultant demonstration of antitumor activity. Atezolizumab (a monoclonal antibody to PD-L1) and nivolumab (a monoclonal antibody to PD-1) are both FDA-approved for second-line therapy in metastatic urothelial carcinoma, and a number of other agents are under investigation.
Because these agents work by activating the immune system, they can occasionally lead to edema and an influx of immune cells into the tumor, which can appear as tumor progression on imaging, based on the conventional criteria that are used to assess tumor response (Response Evaluation Criteria in Solid Tumors [RECIST]). Patients with melanoma treated with ipilimumab (a monoclonal antibody to cytotoxic T-lymphocyte–associated antigen 4), another immune checkpoint inhibitor, had an initial increase in tumor size prior to a decrease in tumor burden. Biopsy of these enlarging lesions showed inflammatory cells or necrosis. Similarly, tumor shrinkage in some patients is delayed until after the appearance of new lesions. These experiences led to the identification of the phenomenon of “pseudoprogression” that is seen in some patients treated with immune checkpoint inhibitors—and to the development of immune-related response criteria (irRC).
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