Dr Anne Chiang Discusses Considerations in SCLC Treatment: Benefits vs Side Effects, and Quality of Life

Anne Chiang, MD, PhD, is an associate professor of medicine in the Section of Medical Oncology at Yale School of Medicine, specializing in thoracic oncology, with a background in translational research in metastasis; she has extensive experience in clinical practice in both academic and community settings. In addition, Chiang is the deputy chief medical officer and chief integration officer for Smilow Cancer Hospital, where she has helped build the SCH Network and spearhead both quality initiatives as well as clinical research. Her clinical focus at Yale is lung cancer, with focus on heading the small cell lung cancer program, and her own research concerns testing novel agents and combinations in both small cell (SCLC) and non-small cell lung cancer. Chiang spoke with The American Journal of Managed Care® (AJMC®) about monitoring patients with SCLC, developing treatments for patients who relapse, and the importance of patient-reported outcomes (PROs). This interview has been lightly edited for clarity.

AJMC®: Typically, if the cancer is caught early enough, small cell lung cancer (SCLC) is responsive to initial therapy. However, some patients do relapse following that primary therapy. How do you monitor patients for the potential for relapse after their primary therapy?

Chiang: So typically, with patients who have extensive stage [ES-SCLC] and are on maintenance therapy after completing chemotherapy, we will monitor with scans every 2-3 months.For limited stage [LS-SCLC] patients, after completing treatment, we will do scans once every 3 to 4 months during in years 1 and 2. In year 3, we shift to scans every 6 months; in year 5, if they haven't relapsed, then we’d go to annual scans. And certainly, communication lines are open— any new symptoms or issues that patients have, such as new persistent shortness of breath or pain, would prompt earlier evaluation including imaging if needed. Surveillance imaging usually includes MRI brain and CAT scan of chest, abdomen, and pelvis.MRI brain is key because so many of these patients do have central nervous system relapse.

AJMC®: When a patient does end up relapsing, what are some of the factors that you consider when you are looking at that patient in their relapse state, in trying to select a new regimen for them to follow that primary therapy?

Chiang: There are several factors that I consider when determining a new regimen for patients who have relapsed, including performance status. This refers to whether a patient can function and perform activities of daily living.It’s important to make sure that patients can tolerate treatment with chemotherapy and to have a discussion about the benefits versus the side effects and impact on quality of life.Specifically, it’s crucial to discuss the patient’s goals of care and the option of best supportive care if appropriate.

Another important factor is platinum-sensitivity of the tumor.Typically, the first line regimen includes a platinum chemotherapy, e.g. carboplatin or cisplatin).If the patients response to such a first line treatment is 6 months or greater, then the recommendation is to retreat with the original regimen. If the patient relapses within 6 months, then the NCCN guidelines recommend using an option such as lurbinectidin or topotecan (oral or IV), the only two FDA-approved options for relapsed disease.

For patients that relapse in the brain, it is important to use treatments that are able to penetrate the blood brain barrier, for example taxanes, topotecan or temozolomide.The trial leading to lurbinectidin FDA approval unfortunately did not include patients with brain metastases.

We need to do develop better treatment options for patients, and that’s why clinical trials should be considered at every point in a patient’s journey.I try to have clinical trial options available for patients if possible to develop additional tools to manage their disease and improve their outcome. 

AJMC®: You touched on the issue of quality of life, and I'd like to ask you about patient reported outcomes. These are commonly used tools in things like clinical trials, but do you have experience using something like a patient reported outcome in your treatment, or in the research of small cell lung cancer? Can you expand upon that?

Chiang: I’ve worked on aspects of Patient reported outcomes [PROs], for example working through barriers and feasibility of collecting PROs in a pilot implementation of distress screening in one clinic.Subsequently, we also participated in a large multi-institutional grant from the Patient-Centered Outcomes Research Institute—implementing PRO collection within multiple clinics at Yale/Smilow—that was quite successful.Although these studies were not limited to lung cancer patients, the results are important for small cell lung cancer, a disease that is largely treated by systemic therapy.As such, accurate and timely reporting of side effects directly from the patient can help with symptoms management and adherence so patients can stay on therapy longer and get the benefit of the therapy for their disease response.

AJMC®: What aspects do you find in small cell lung cancer or in those treatments, like you mentioned, things like chemotherapy, do you find have the largest impact on a patient's quality of life? Are there certain side effects that are just really undesirable for certain patients? Or are certain aspects of the disease itself that really trouble patients and their quality of life?

Chiang: Small cell is a disease that is characterized by rapid proliferation and growth. Often patients may have symptoms of bulky disease, such as difficulty breathing due to obstruction of airways, or of disease spread to other organs, such as painful bony metastatic lesions. It is crucial for these patients to get urgent evaluation and treatment. Often, we start these patients with chemotherapy while they are initially diagnosed in the hospital, rather than wait to treat in the outpatient setting. Patients can sometimes get relief from symptoms quickly, even within the first few weeks.If patients present with disease in the brain metastases and are asymptomatic, then we will treat them first with chemotherapy.Chemo does penetrate the blood brain barrier and can work to shrink disease quickly and help relieve patients of the symptoms.

What other things impinge on their quality of life? There are disease-related symptoms, but there are also treatment-related symptoms. With chemotherapy, you can have fatigue, lowering of blood counts, increased risk of infection, and GI effects such as nausea or change in bowels.For many of these symptoms, we have tools to help prevent or treat them. Fatigue is one symptom that is still hard to treat. There are also side effects from immunotherapy that are very specific and different from chemotherapy. Overall, immunotherapy is tolerated very well, but serious inflammation of organs can occur 3-5% percent of the time, for example, of the lungs causing shortness of breath, or of the colon causing diarrhea.The good news is that immunotherapy-related toxicities all respond very well to steroids, but it’s important to recognize signs and intervene promptly.

AJMC®: You spoke of the progress as immunotherapy has become an option. However, as we look at small cell lung cancer, particularly compared to non-small cell lung cancer, there’s been a slower progression of new therapies coming to market. Lurbinectedin, as you mentioned earlier, is a new player, but in other diseases, we're seeing many more new therapies in the same timeframe. In your opinion, what is the reason for the relative lag in innovation in small cell lung cancer?

Chiang: Well, small cell lung cancer differs from non-small cell in that most tumors do not express the protein PD-L1, which serves as a biomarker for immunotherapy. This doesn’t mean that immunotherapy is not effective for small cell, just that there are differences.We may need to tickle the immune system with an additional agent in order to activate the tumor microenvironment for a better response to immunotherapy.

Still, progress in small cell lung cancer is definitely starting to accelerate. Since 2019, the FDA has approved 2 immunotherapy drugs (atezolizumab and durvalumab) each in combination with chemotherapy in the front-line setting, lurbinectedin for relapsed disease and approval, and trilaciclib for supportive care use to lower rates of myelosuppression.

What's also really exciting is that we're starting to have a better understanding of small cell biology. We are starting to understand that small cell lung cancer is heterogeneous, that there are, for example, molecular subtypes of small cell that may have therapeutic vulnerabilities. In other words, if a patient has subtype A, they could be more susceptible to an agent targeting subtype A in the future. There was a recent study that showed that patients with the “inflamed” molecular subtype I had more benefit from immunotherapy in combination with chemo than chemo alone.

AJMC®: You mentioned the identification of those molecular subtypes. Are there any other therapies or advances coming in the near future that have you excited in the area of small cell lung cancer?

Chiang: Looking at the landscape of drugs in development, there are some that are really promising. One new class of drugs is antibody-drug conjugates, where a chemotherapy molecule is tethered to an antibody that specifically recognizes the tumor cell.Thus, the chemo is like a missile that goes directly to the tumor to kill it, with hopefully more potency and less toxicity than standard chemotherapy.There are also bispecific antibodies that recognize the tumor and help to direct the immune response specifically to cancer cells.There is continuing interest in biomarker-driven research, for example, a current cooperative trial treats patients with the schlafen11 biomarker (predicting for response to DNA-damaging agents) with immunotherapy with or without PARP inhibitors.More and more clinicians and researcher are interested and involved in small cell research, so it's a very exciting time.

AJMC®: Do you have any closing thoughts that you'd like to share with our audience in the realm of small cell lung cancer?

Chiang: I think that we need to continue to do all we can to understand the disease and to find treatments for it, by offering access to clinical trials to all our patients.In addition, we want to support our patients’ journeys through their disease and to help mitigate the impact of cancer on not only their physical and emotional health, but their social and economic circumstances.