Episode #60 Current Perspectives on Treatment of Small Cell Lung Cancer with Dr. Jacob Sands

Dr. Albert Rizzo:
Welcome back to Lungcast, the monthly respiratory health podcast series from the American Lung Association and medical news site hcpive.com. I'm your host, Dr. Albert Rizzo, the chief medical officer of the American Lung Association.

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Cancer of the lung remains the number one cancer killer of men and women globally. In 2024, lung cancer was responsible for 1.8 million deaths, which is 18.7% of all cancer deaths.

There are two major categories of lung cancer: non-small cell and small cell lung cancer. Over the last two decades, we have seen advances in diagnosis and therapy, especially of non-small cell lung cancer, with the introduction of lung cancer screening that detects early-stage disease where survival is much more likely, and also with the explosion of targeted therapies and immunotherapy checkpoint inhibitors which have extended progression-free survival in many cases of non-small cell lung cancer.

However, small cell lung cancer, which represents about 15% of all lung cancers, has not seen similar successes. Small cell lung cancer is a highly aggressive lung cancer characterized by rapid growth and early metastasis, often spreading to other parts of the body like the brain, bones, and liver. Most patients are seen with advanced disease at the time of diagnosis, typically requiring multimodal treatment.

To discuss more deeply this cancer and to bring us some encouraging perspectives on the current state of therapies for small cell lung cancer is Dr. Jacob Sands. Dr. Sands is a thoracic medical oncologist at Dana-Farber Cancer Institute, where he also serves as associate chair of the Lowe Center for Thoracic Oncology and is assistant professor of medicine at Harvard Medical School.

He joined Dana-Farber Cancer Institute in 2017, where he sees individuals with lung cancer and leads the small cell lung cancer clinical research program. Dr. Sands has published several manuscripts on lung cancer, is leading many active clinical trials, and is a member of the National Comprehensive Cancer Network (NCCN) guidelines committee on small cell lung cancer and lung screening. Despite keeping busy with patients and these other duties, he finds time to act as a volunteer medical spokesperson for the American Lung Association.

Thank you for being with us today, Dr. Sands.

Dr. Jacob Sands:
So happy to be here. Thanks for having me.

Dr. Rizzo:
The staging and the terminology for small cell lung cancer differ a bit from non-small cell lung cancer, in which there's one to four stages that indicate early or advanced disease. Small cell lung cancer is divided into limited and extensive stages. Please review these definitions and the evaluations necessary to complete the staging.

Dr. Sands:
Yeah, so we do have stage I to stage IV, much like in non-small cell lung cancer, but more commonly and clinically we discuss this as limited and extensive stage. That’s really because when we’re thinking about treatment, the main decision point is: can this be encompassed within a tolerable radiation field or not?

Limited stage is really what can be encompassed within that tolerable radiation field, and extensive stage is when it’s spread outside of that. So when someone has disease within one lung and lymph nodes in the mediastinum, we’re generally able to treat that with chemoradiation.

Once it spreads beyond that, for example to the contralateral chest, to the liver, to the bones, to the brain, then we’re thinking of this as extensive stage. The way I often phrase it for patients is: limited stage means it’s limited enough that we can radiate the whole thing, and extensive stage means it’s spread too far for us to do that.

Dr. Rizzo:
And since you mentioned radiation, that does bring up a related question: what is the role of radiation therapy in small cell lung cancer compared to non-small cell lung cancer?

Dr. Sands:
In limited stage disease, the mainstay is chemoradiation — chemotherapy together with radiation — and there are studies that show the survival advantage with this combined approach. So that’s the standard of care in limited stage.

In extensive stage, historically, radiation hasn’t played as much of a role because the disease is too widespread. But there are exceptions. For example, if someone has an excellent response to systemic therapy and there’s one or two sites where the disease remains, we may use radiation in a more targeted way. Also, in the past there was a role for prophylactic cranial irradiation, or PCI, because small cell has such a propensity to spread to the brain.

That’s shifted some in recent years with the advent of better imaging like MRI surveillance, so we’re moving toward MRI surveillance as opposed to prophylactic cranial radiation in most cases.

Dr. Rizzo:
That brings up a great point — brain metastases are common in small cell. How do you approach brain imaging and monitoring?

Dr. Sands:
At the time of diagnosis, everyone should get an MRI of the brain. It’s really important because small cell can spread there early, and if we don’t look, we’ll miss it. CT of the brain just isn’t sensitive enough, so MRI is the standard.

For those who don’t have brain metastases at diagnosis, we do surveillance imaging — typically MRI every 3 months for the first year, then spacing it out if things are stable. That’s part of the reason PCI has shifted out of favor: with MRI surveillance, we can catch metastases early and treat them with stereotactic radiosurgery instead of whole-brain radiation, sparing patients the cognitive side effects.

Dr. Rizzo:
That’s very helpful. Shifting gears — let’s talk about systemic therapy. Historically, platinum-based chemotherapy has been the backbone of treatment. Can you walk us through the current landscape and how immunotherapy has changed things?

Dr. Sands:
Yeah, so for decades the standard first-line therapy for extensive stage small cell lung cancer was platinum plus etoposide — that was it. And we knew from decades of research that while responses were often dramatic initially, the durability just wasn’t there. The median progression-free survival was only around 5 months.

The big advance came in 2019, when trials showed that adding immunotherapy — checkpoint inhibitors like atezolizumab or durvalumab — to chemotherapy improved overall survival. So now the standard first-line therapy is platinum plus etoposide plus immunotherapy, followed by immunotherapy maintenance.

It’s not a cure, but it is a meaningful step forward. We’re seeing median overall survival improve from about 10 months to 12–13 months. That might sound modest, but in small cell lung cancer that’s a significant advance, and importantly, there are patients who have longer-term benefit, which we really hadn’t seen before.

Dr. Rizzo:
You mentioned immunotherapy, which is now part of first-line treatment. Are there any biomarkers that help determine who benefits from immunotherapy in small cell lung cancer, similar to what we see in non-small cell lung cancer?

Dr. Sands:
That’s a great question. Unfortunately, unlike non-small cell where PD-L1 expression or tumor mutational burden can help guide us, in small cell lung cancer we don’t have reliable biomarkers yet. The clinical trials showed benefit across subgroups regardless of PD-L1 expression. So at this point, the recommendation is to use chemo plus immunotherapy for essentially all patients with extensive stage disease, unless there’s a contraindication.

Dr. Rizzo:
So there’s no biomarker selection — it’s just standard across the board.

Dr. Sands:
Exactly. We’re hopeful that ongoing research into molecular subtypes of small cell will eventually give us more personalized approaches, but we’re not there yet.

Dr. Rizzo:
Let’s talk about relapse, because as you mentioned, most patients respond to initial therapy, but relapses are common. What are the treatment options in the relapse setting?

Dr. Sands:
Right. Unfortunately, relapse is the rule, not the exception. How we treat depends on how long it’s been since the patient completed first-line therapy.

• If relapse occurs within 6 months, we call that “platinum-resistant.” Those patients tend to have more aggressive disease and poorer prognosis.

• If relapse occurs after 6 months, we call that “platinum-sensitive,” and we can consider rechallenging with platinum-based chemo.

For platinum-resistant disease, options include agents like lurbinectedin, which was FDA-approved in 2020 for relapsed small cell lung cancer. It has activity, though the response rates are modest — around 20%. Topotecan is another option, though it’s not well tolerated by everyone. And of course, clinical trials are always strongly encouraged in this setting.

Dr. Rizzo:
You mentioned lurbinectedin — can you explain how that’s used and what its impact has been?

Dr. Sands:
Sure. Lurbinectedin is an alkylating agent that interferes with transcription in tumor cells. It was approved based on a phase II trial that showed a response rate around 35% in previously treated patients, particularly in those who were more than 6 months out from initial therapy.

In practice, I’d say it’s better tolerated than topotecan, and for many patients it’s become the preferred second-line option. That said, the durability of responses is still limited — the median progression-free survival is just a few months. So again, we emphasize clinical trial enrollment whenever possible.

Dr. Rizzo:
What about immunotherapy beyond the first-line setting? Is there any role?

Dr. Sands:
That’s a tricky one. Early on, there was enthusiasm about single-agent immunotherapy, and drugs like nivolumab and pembrolizumab even had accelerated FDA approvals in the relapsed setting. But subsequent trials failed to confirm the benefit, and those approvals were withdrawn.

So today, immunotherapy really has its role in the frontline setting combined with chemo, but not as a single agent after progression.

Dr. Rizzo:
That makes sense. Let’s touch on supportive care, because small cell lung cancer often presents with high symptom burden. What are some of the key issues you address with your patients?

Dr. Sands:
Yes, supportive care is critical. Patients often present with bulky mediastinal disease, leading to cough, shortness of breath, sometimes superior vena cava syndrome. We need to be very proactive with symptom management. Radiation can be used palliatively for things like airway obstruction or painful bone metastases.

Also, brain metastases are common, so neurologic symptoms need to be taken seriously. Fatigue, weight loss, and paraneoplastic syndromes like SIADH or Lambert-Eaton can complicate the picture.

So it’s really a team effort with palliative care, nutrition, social work — making sure patients and families are supported throughout.

Dr. Rizzo:
That’s such an important point. Even as we make advances in therapy, the supportive care and quality-of-life aspects are just as vital.

Dr. Rizzo:
We’ve touched on chemotherapy, immunotherapy, and relapse treatment. Let’s shift to clinical trials and emerging therapies. What are some of the promising directions in research for small cell lung cancer?

Dr. Sands:
There’s a lot of excitement right now in trying to move beyond the “one-size-fits-all” approach. Historically, we treated all small cell the same way, but recent research has shown there are molecular subtypes based on transcription factors — ASCL1, NEUROD1, POU2F3, and YAP1.

The hope is that these subtypes can eventually guide therapy. For example, certain subtypes may be more sensitive to DLL3-targeted therapy. DLL3 is a protein expressed on most small cell lung cancer cells but not in normal tissue, making it an appealing target. There’s ongoing work with bispecific T-cell engagers and antibody–drug conjugates directed against DLL3.

Dr. Rizzo:
I remember earlier attempts with DLL3 didn’t pan out, right?

Dr. Sands:
Correct. The original DLL3-targeted antibody–drug conjugate, rovalpituzumab tesirine, showed initial promise but ultimately failed in phase III because of toxicity and lack of survival benefit. But newer DLL3-targeted agents seem to be more tolerable and effective, so that area is reemerging.

Dr. Rizzo:
Besides DLL3, are there other targeted strategies being studied?

Dr. Sands:
Yes. PARP inhibitors are being evaluated, especially in combination with other therapies, because small cell often has defects in DNA damage repair. There are also studies looking at combining immunotherapy with other checkpoint targets like TIGIT and LAG-3. And then there’s interest in epigenetic modulators — drugs that can reprogram small cell biology to make it more susceptible to treatment.

Another area is cellular therapies, like CAR T-cells, though those are still in very early stages for small cell.

Dr. Rizzo:
That’s fascinating. It sounds like we’re finally getting to a place where small cell lung cancer research is catching up with what we’ve seen in non-small cell over the past decade.

Dr. Sands:
Yes, exactly. For a long time, small cell was neglected in research. But with better molecular understanding and new drug platforms, there’s real momentum now.

Dr. Rizzo:
Let’s talk about the patient journey. When you first meet a patient with small cell lung cancer, how do you frame the discussion about prognosis and goals of treatment?

Dr. Sands:
That’s always a delicate but important conversation. I tell patients that small cell lung cancer is an aggressive cancer, but it is also very responsive to treatment — often dramatically so, at least initially. So we do expect symptoms to improve quickly once therapy starts.

At the same time, I’m upfront that cures are rare in extensive stage disease, and even in limited stage, the relapse rate is high. So I emphasize both the importance of treatment and the need to plan for supportive care, clinical trials, and maintaining quality of life.

It’s a balance of honesty about the challenges and hope about the progress being made.

Dr. Rizzo:
Do you involve palliative care early on?

Dr. Sands:
Yes. We know from studies in lung cancer that early palliative care improves outcomes — not just quality of life but even survival. So I strongly encourage palliative care involvement from the time of diagnosis. It’s not about giving up; it’s about adding an extra layer of support for patients and families.

Dr. Rizzo:
That’s a great way to put it. Before we start to wrap up, let’s touch briefly on prevention and screening. Small cell is strongly linked to smoking. How does smoking cessation fit into your care plan?

Dr. Sands:
It’s huge. Quitting smoking at any stage improves outcomes — it reduces treatment complications, lowers the risk of second cancers, and improves survival. So I always counsel patients and connect them with resources like smoking cessation programs.

On screening, low-dose CT is primarily designed to detect non-small cell, but it can also pick up small cell earlier than we would otherwise. So patients who meet screening criteria — typically 50 to 80 years old with a significant smoking history — should absolutely be screened. That’s our best chance to catch small cell at a limited stage where it’s potentially curable.

Dr. Rizzo:
As we close, what would you say are the biggest unmet needs in small cell lung cancer today?

Dr. Sands:
I’d highlight three. First, we need better therapies for relapsed disease — that’s where patients have the fewest options and the worst outcomes. Second, we need biomarkers to personalize therapy, so we’re not treating everyone the same way. And third, we need to continue focusing on quality of life and supportive care, making sure patients are living as well as possible while we push the science forward.

Dr. Rizzo:
If you look ahead five to ten years, are you optimistic that we’ll see meaningful changes in survival for these patients?

Dr. Sands:
I am. We’re already seeing incremental improvements with immunotherapy in the frontline setting. The science around molecular subtypes and new targets like DLL3 gives me real hope that we’ll have more effective, personalized options soon. I think the future for small cell will look much different than it has in the past.

Dr. Rizzo:
That’s encouraging to hear. Before we finish, is there one message you’d like patients, families, or clinicians listening today to take away from this conversation?

Dr. Sands:
Yes — I’d say don’t lose hope. Small cell lung cancer has historically been difficult to treat, but research is accelerating, and new treatments are on the horizon. In the meantime, make sure patients are supported holistically, get connected with palliative care early, and always ask about clinical trials.

Dr. Rizzo:
Excellent advice. Dr. Sands, thank you so much for joining us today and for sharing your insights.

Dr. Sands:
Thank you — it’s been a pleasure.

Dr. Rizzo:
And thanks to our listeners for tuning in to Lungcast, the monthly podcast from the American Lung Association in partnership with HCP Live. You can find this and other episodes on your favorite streaming platforms. Be sure to subscribe to stay updated on new episodes.

Until next time, I’m Dr. Albert Rizzo.