Criteria Used to Diagnose Small Cell Lung Cancer

Jared Weiss, MD: Hello, and thank you for joining this OncLive® webinar titled “Updates in Small Cell Lung Cancer: Treating Relapsed Disease.” I’m Jared Weiss. I’m a medical oncologist who focuses on thoracic cancers and cancers of the head and neck, and I run a joint section of thoracic and head and neck oncology at UNC Lineberger Comprehensive Cancer Center [at the University of North Carolina School of Medicine in Chapel Hill, North Carolina]. I’m joined by Dr Carl Gay, also a thoracic head and neck medical oncologist and an associate professor at [The University of Texas] MD Anderson Cancer Center [in Houston, Texas]. Welcome.

The treatment of small cell lung cancer continues to evolve as we learn how to incorporate new agents and improve the use of established agents. Through our discussion, we hope to review the landscape of small cell lung cancer and factors that make it an aggressive disease, to compare and contrast the first-line therapy options, to obtain insight on strategies for monitoring patient response to treatment, and to discuss second-line therapy options and indicators to change therapy. Let’s begin. Dr Gay, start by showing an overview of the landscape of small cell lung cancer, incident rates, and risk factors.

Carl M. Gay, MD, PhD: In terms of risk factors for small cell lung cancer, unlike non–small cell lung cancer, the etiology of small cell lung cancer is relatively straightforward, so the vast majority of patients have a history of not just smoking but heavy smoking. You’re looking at upward of 95% of patients who will have a heavy smoking history. That’s evolving a bit as our targeted therapies become more effective as small cell lung cancer transformation from driver mutation. Driven adenocarcinoma is emerging as a real entity, but still, if you have a patient that carries a diagnosis of small cell lung cancer without a history of smoking, you want to make sure you have a repeat pathologic review of that at this point in time.

Jared Weiss, MD: Yes, that’s my practice as well. If it really is small cell [lung cancer], then that’s the 1 incidence where I am sequencing small cells for exactly the reason that you described. We think of these as resistant change, but I have seen a de novo diagnosis of small cell [lung cancer] in a never-smoker who had EGFR transformed before selection pressure from TKI [tyrosine kinase inhibitor]. But that’s not our typical presentation. What’s our more typical presentation?

Carl M. Gay, MD, PhD: The typical presentation is rapid onset of symptoms. These are usually patients who present with pulmonary symptoms, often cough or shortness of breath. These are often centrally located tumors, so they develop symptoms there rapidly. But because the disease metastasizes early on in the process, you also see systemic symptoms like weight loss; bony pain if they have bone metastasis, which is common; and various other symptoms that might be related to the sites of the distant metastasis, liver, brain, adrenal glands, etc. These are not patients who you’ve scanned for a pulmonary nodule 5 years ago and they’ve had a slow-growing evolving tumor that you’re going to finally biopsy. These are patients who say, “I felt fine 3 months ago, and now I’m in the hospital on the border of going to the ICU [intensive care unit] and in desperate need of systemic therapy.”

Jared Weiss, MD: In the tobacco belt, a lot of our diagnoses are through the emergency department [ER] with fairly acute pulmonary symptoms just as you described, and we often end up giving cycle 1 in patients far out of proportion to other cancers.

Carl M. Gay, MD, PhD: We have the same—1 of the interesting challenges with designing clinical trials around small cell lung cancer is exactly that. Many trials require cycle 1 day 1 to be given on protocol, and these are patients who are often treated emergently in the ER or even the ICU in some cases, so it’s an interesting challenge for somebody who designs trials for small cell lung cancer.

Jared Weiss, MD: Maybe we can blame our slow progress over the past several decades on that, taking ownership for failure to understand biology until recently. Patients are in the office or in the emergency department. How are we or our emergency department, internal medicine, or pulmonary colleagues working these patients up? How do they get from shortness of breath to X-stage small cell lung cancer?

Carl M. Gay, MD, PhD: There’s not a lot of nuisance to staging small cell lung cancer. Once you have a confirmed pathologic diagnosis of small cell lung cancers, so if you have a mass that gets biopsied and returns consistent with small cell carcinoma, every patient deserves a PET [positron emission tomography] scan, if not a CT of the chest, abdomen, and pelvis and bone scan as well as an MRI of the brain. These patients are at very high risk for having distant metastasis. Two-thirds or more are going to have extensive-stage disease at diagnosis, so they need to be staged as such.

Jared Weiss, MD: All of us in academia worship at an altar of biomarkers. At MD Anderson, what are the cutting-edge biomarkers for small cell [lung cancer]?

Carl M. Gay, MD, PhD: We certainly lag in non–small cell and that arena. Most of the folks following us will be aware that there are no standard biomarkers integrated into the care for patients with small cell lung cancer. That said, some clinical trials are integrating them. There’s a biomarker called Schlafen-11 that has been shown to be predictive of several things, most notably PARP inhibitor sensitivity. There’s an ongoing cooperative group study where the patients are randomized only if they’re Schlafen-11 positive. There are some other biomarkers that are another experimental arena: DLL3 expression for DLL3-targeted therapies, NIK expression for ROR kinase inhibition, as well as the recent appreciation of the transcriptional subtypes that lie within the small cell lung cancer landscape. We and certainly others are working on CLIA [chemiluminescent immunoassay]–validated assays to be able to use those for select patients or at least retrospectively review outcomes for patients on trials.

Jared Weiss, MD: I’m very impressed by that work. For those who aren’t familiar, transcription profiling shows these 4 distinct biologics, and they’re rather distinct. I was joking earlier about our progress being a lack of biological understanding until recently. These transcription subtypes to me are a legitimate promise that we’re getting there and heading toward subtyping this heterogeneity. It’s not applicable to current practice, as Dr Gay has directly stated, but I have real hope that these are going to make a difference. I’m impressed by that work. In the span of 5 years, we’re going to see therapies that are more or less effective in groups and hopefully speeding of drug design as a consequence.

Unfortunately, in the current time for standard practice, there’s nothing. PD-L1, in particular, is not helpful for telling us whom to treat. There we are for now. For anyone who’s still a trainee, on your board is technically the same TNM [tumor, node, metastasis] system used for non–small cell [lung cancer]. But I’m with Dr Gay and nearly 100% of lung cancer doctors in using this simple extensive-stage or limited-stage system. It’s so practical. You’re limited-stage if you can incorporate everything into 1 acceptable radiation portal; everything else is extensive-stage. What I love about our small cell system is that we use it in practice, as compared with many of the other staging systems. Dr Gay and I both treat head and neck, where the staging system doesn’t cut off to tell you what to do. What’s nice is that if you’re limited-stage, you’re doing chemo-rads [chemotherapy and radiation]; if you’re extensive stage, you’re doing a systemic regimen, which we’re going to talk about. I like that about the small cell system. It’s 1 of the few that does that cleanly for you, where it’s practical. I did just see 2 new patients with small cell [lung cancer], and they both asked me the same questions that every newly diagnosed patient asks: “What’s the prognosis here?”

Carl M. Gay, MD, PhD: Unfortunately, that’s a very difficult conversation to have out of the gate because even with some of the improvements that we’re going to talk about later in terms of systemic therapy options, the prognosis remains very poor. That’s all comers regardless of the stag—in particular for extensive-stage patients where the overall survival even with the addition of immunotherapy is bordering on about a year or maybe a month or 2 longer than that. It’s a little better in limited stage. If you look at 5-year overall survival for patients across all stages, you’re getting close to 5%, which is really dismal, especially compared with the strides that we’ve made in non–small cell lung cancer.

Transcript edited for clarity.