Insights on the differences between limited-stage and extensive-stage small-cell lung cancer and recent progress made with combination chemotherapy plus immunotherapy.
Jared Weiss, MD: We are supposed to stage small cell lung cancer by the same TNM [tumor, nodes, metastases] system that is used for non–small cell lung cancer. Indeed, that system will give a more granular prognosis than the system we all actually use. The problem is prognosis isn’t as helpful in clinical practice as a system that tells you what to do. The simpler system of limited versus extensive stage is what’s used in clinical practice. The definition here is simple. Limited stage is if all the disease can be encompassed in a single radiation portal, and everything else is extensive-stage disease. Most limited-stage disease is treated with chemoradiotherapy with a goal of cure, and most extensive-stage disease is treated with carboplatin, etoposide, and a PD-L1 inhibitor.
The prognosis of these diseases is of course different. We treated limited-stage disease with a goal of cure. Unfortunately, we don’t get there as often as we’d like. We probably cure about a quarter of our patients, and this results in a median survival of only about 30 months. Of course, extensive-stage disease has a more adverse prognosis that’s about half of that with a median survival of 15 or 20 months. The demographics of small cell are unique. These tend to be patients with a heavy smoking history. That’s the biology of patients with small cell lung cancer. They’re more likely to be elderly, and they’re more likely to be male. Thinking about the presentation of small cell, this is a very aggressive disease; this is a disease where you need to diagnose it early, you need to treat it early. In fact, probably about 30% of presentations at my institution are inpatient, typically through the emergency department, typically with dramatic shortness of breath. And because treatment works, it works quite dramatically, quickly, it’s very important to recognize and treat early.
What do these presentations look like? Shortness of breath is certainly the most common. Small cell likes to present centrally in the chest where it can clip off airways, leading to shortness of breath, cough, and pneumonia. It can also cause pain, of course, wherever it metastasizes, and it’s famous for paraneoplastic syndromes. It can suppress blood counts in and of itself. It causes hypercalcemia in 5% or 10% of our patients. Hypercalcemia is manifested as anorexia, nausea, vomiting, constipation, lethargy. But in the modern world where everyone gets a blood test on the way in to the emergency department, this often manifests as a laboratory test result. Small cell causes SIADH [syndrome of inappropriate antidiuretic hormone secretion], which manifests as anorexia, nausea, and vomiting, and occurs in about 10% of patients. And again, in the modern world where everyone gets labs rather quickly, it manifests as low sodium on a blood test.
Small cell lung cancer causes a variety of neurologic syndromes, the most common and famous of these is the Lambert-Eaton myasthenic syndrome, or LEMs. But it also can cause a variety of others more rarely: cerebellar ataxia, sensory neuropathy, limbic encephalitis, encephalomyelitis, and a variety of long-named, easy-to-trip-over neurologic syndromes that are rare. There’s a very long list of things that rarely happen. Hypercoagulability, as with any malignancy, small cell is with non–small cell lung cancer in being very high up on that list. And hypertrophic pulmonary osteoarthropathy, most commonly seen as digital clubbing in our patients, but it can happen as a symmetric painful arthropathy in any joint. I often see ankles, knees, wrists, and elbows.
Stephen V. Liu, MD: The historic standard for extensive-stage small cell lung cancer has been platinum plus etoposide chemotherapy. This regimen was first explored in the 1970s and became the clear standard of care in the mid-1980s. And it’s effective initially. Response rates are high, north of 60%. You can see complete responses, and the benefit is seen relatively quickly. It’s also pretty well tolerated. While there is myelosuppression, patients generally feel better with treatment and not worse. The problem is that responses are not durable, they are very transient. The median progression-free survival is on the order of about 4 months, and that’s from the start of therapy. Most patients are progressing either during or shortly after completing their initial induction chemotherapy.
Survival with chemotherapy alone has hovered around the 8-to-10-month range, and there have been repeated efforts to improve upon those first-line outcomes that have really failed. Dozens of phase 3 trials over many decades have not improved overall survival. It wasn’t until the introduction of chemoimmunotherapy that we saw improvements. With adding more agents, with alternating agents back and forth, looking at maintenance strategies, early second-line therapy, we were able to improve response rates, and at times make modest improvements in progression-free survival. But the only studies that impacted survival overall was the addition of immunotherapy to chemotherapy, seen first with IMpower133 and then with CASPIAN.
Transcript Edited for Clarity