Treatment of Small Cell Lung Cancer
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From the JAMA Network, this is JAMA Clinical Reviews, interviews and ideas about innovations in medicine, science, and clinical practice. Hello, and welcome to our listeners around the world. You're listening to the JAMA Clinical Reviews podcast. Thanks for joining us.

I'm your host, Dr. Karen Lasser, professor of medicine at Boston University and senior editor at JAMA. Today, I am joined by Dr. Anne Chang, who is an associate professor of medical oncology at Yale University School of Medicine, and will be speaking about small cell lung cancer. Welcome, Dr. Chang, to this JAMA podcast.

Thanks so much for having me. This is super exciting. Yes, it's an absolute pleasure to have you. So to begin with, how common is small cell lung cancer and what are the most common risk factors? So small cell lung cancer occurred in about 16,000 cases in 2024 in the U.S.,

The main risk factors for small cell are smoking. 95% of our patients have a smoking history, although some don't. And the never smokers or folks who don't smoke a lot do have a bit better prognosis.

And it seems like small cell lung cancer is pretty rare because in your review, you mentioned an incidence of 4.7 cases per 100,000 individuals in 2021 in the United States, correct? Yes. In 2021, there was incidence of 4.7 cases per 100,000 individuals in the U.S. And how does small cell lung cancer typically present?

Patients with small cell often have a cough or shortness of breath. Sometimes they can have hemoptysis or spit up blood. They can often have these symptoms for several months and may be diagnosed as having a URI or some sort of respiratory syndrome where they receive an antibiotic course and then their symptoms just don't get better. So persistence of the symptoms.

And one thing I thought was interesting in your review was that you said approximately 60% of patients are asymptomatic at presentation, correct? Right. So there are incidentalomas where patients are undergoing a CAT scan for other reasons, either preoperative or a CT of the coronaries, and there's an abnormality that is seen. In about 60% of the patients, you don't have a specific symptom.

That's interesting. And can you comment on the paraneoplastic syndromes that can present? Sure. Small cell lung cancer can present with paraneoplastic syndrome. Sometimes we can have most commonly low sodiums due to SIADH or symptom of inappropriate diuretic hormone secretion. But we can also have Cushing's as well as rarely Lambert-Eaton myasthenic syndrome where patients have neuromuscular weakness.

And what is the difference between limited-stage and extensive-stage small cell lung cancer? Limited-stage small cell lung cancer means that the disease, when it's diagnosed, is in a geometric area which can fit into a radiation portal. For example, just in the lung and the lymph nodes on the same side or...

Nowadays, because our abilities with radiation have improved, sometimes you can even have lymph nodes in the supraclavicular area, even bilaterally. As long as they fit within one radiation portal, there is the opportunity to give sterilizing radiation along with chemotherapy and immunotherapy, and that produces better outcomes.

And the extensive stage would be beyond that radiation field, correct? Right. So extensive stage small cell means that you have either disease that has spread to a different organ, such as the liver, adrenals, or brain, or bones, or that you have pleural disease or a malignant pleural effusion where you know that you can't irradiate every single microscopic cell. So.

Certainly. Now let's talk a little bit about treatment. What is considered first-line treatment for limited-stage small cell lung cancer?

The first-line treatment for limited stage has just changed, and that's one of the most exciting aspects of new developments in small cell. The Adriatic trial was a trial where patients with limited stage underwent the standard chemo radiation, and then after that, they received chemo.

consolidative immunotherapy with the drug Dervalumab for two years versus placebo. And the patients who received the Dervalumab did extremely well with the benefit of almost two years in overall survival compared to the patients who were on placebo. So that really has become our standard of care now. That's terrific. And what class of medication is Dervalumab?

Dervalumab is an immunotherapy. It's an anti-PDL1 agent. The idea behind it is that it tickles the immune system and teaches the immune system to recognize and prevent cancer cells from regrowing. Excellent. And now, what is first-line treatment for extensive stage small cell lung cancer?

The first-line treatment for extensive stage small cell lung cancer is chemotherapy with a platinum doublet in combination with an anti-PD-L1 agent such as atezolizumab or dervalumab. And for our generalist listeners, what is a platinum doublet?

A platinum doublet contains carboplatin plus etoposide and typically we give four cycles of these drugs every three weeks. So it's carboplatin and etoposide on day one, etoposide alone on days two and three, and then the immunotherapy also on day one. After four cycles of chemotherapy plus immunotherapy, then we do maintenance, immunotherapy,

every three weeks or every four weeks until the patient has side effects where it's not tolerated or if the patient has disease that progresses. And what is the prognosis for a patient diagnosed with limited stage versus extensive stage small cell lung cancer?

Well, for limited stage patients, the prognosis is at this point now has improved from a three-year overall survival of 27% to 30% in the past, now over 50% with the use of Dervalumab. So these patients can actually do quite well for almost five years, and that's the median overall survival. In comparison, the patients with extensive stage experience

disease have a median overall survival of only around 12 or 13 months. That being said, there are some patients who can do quite well even out to five years, the 12% overall survival with one of the trial agents. That's very different from prior to immunotherapy where unfortunately patients really didn't make it much longer than out to five years.

And what is the role of palliative care in patients with small cell lung cancer? Palliative care is a really important part of the care that we give. In extensive stage small cell, we are giving therapy to palliate symptoms and not to cure the patient specifically because usually the disease has spread to other organs.

So being able to palliate symptoms, to talk about goals of care, and to improve quality of life is something that each oncologist does. But we also refer to our palliative care colleagues. And in fact, there is data that shows that even just a palliative care referral for patients with lung cancer can actually help to improve survival.

Yeah, I thought it was interesting in your review that you said all patients diagnosed with small cells should establish care with a palliative care team, correct? Yes. I think that palliative care is an extra layer of support for the patients that is available to them. So if it's available in the area that the patients live or they have access to that, it should definitely be used.

Sure. And when do you encourage patients to enroll in clinical trials? I encourage all my patients to enroll in clinical trials. I think that this is key, especially for small cell lung cancer, which is an area of need. This is how we have trials that can improve lives, improve quality of life, and reduce symptoms. And there are so many really super exciting trials coming up.

where we are able to, for example, allow patients access to cutting-edge technologies ahead of the time that potentially they might be able to access it after FDA approval. I think clinical trials are also another level of care in terms of having a whole other set of eyes in the research staff, you know, communicating and talking to our patients and making sure that they're feeling good.

Sure. So it sounds like all patients should consider clinical trials, but especially those with relapse, correct? I think all patients should consider clinical trials, even at diagnosis. Certainly at relapse, this has been a way to offer patients more tools for combating their disease.

But also at time of diagnosis, there are often trials or at time of maintenance after their initial chemo immunotherapy, there are lots of opportunities for them to participate in trials. Great. Well, this has been super helpful. Is there anything else generalists should know about small cell lung cancer that we haven't talked about?

Yeah. Small cell lung cancer in the past has sort of been treated as one size fits all. These are small blue cells that are rapidly dividing and we just treat with chemotherapy, immunotherapy and radiation if possible. But now our understanding is changing.

of the biology of small cell, where we're now starting to understand that it's not just one size fits all, that there are actually subtypes and that we might be able to target potentially one subtype with one drug versus another drug for another subtype. That's something that has really led to a lot of advances in non-small cell lung cancer. And so I think that our understanding of small cell lung cancer is improving, allowing us to develop more therapeutics for our patients.

That's great. That's exciting to hear. I'm Dr. Karen Lasser. I've been speaking today with Dr. Ann Chang from the Yale University School of Medicine about small cell lung cancer. You can find a link to the article in this episode's description. This episode was produced by Daniel Musisi at the JAMA Network.

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