The demise of Susan Wojcicki, the former CEO of YouTube, has drawn attention to the devastating impact of lung cancer, a disease that continues to challenge oncologists.

Lung cancer is the leading cause of cancer-related deaths in the United States, responsible for 1 in 5 cancer fatalities, largely due to late detection at advanced, less treatable stages.

American Cancer Society. Key Statistics for Lung Cancer. January 29, 2024.

Non-small cell lung cancer (NSCLC) is the most common type, accounting for 80%–85% of cases, while small cell lung cancer (SCLC) makes up 10%–15%.

American Cancer Society. Key Statistics for Lung Cancer. January 29, 2024.

Among these, SCLC is the most rapidly aggressive, with untreated cases having a median survival of just 8 to 16 weeks.

PDQ Adult Treatment Editorial Board. Small Cell Lung Cancer Treatment (PDQ®): Health Professional Version. 2024 Jun 27. In: PDQ Cancer Information Summaries [Internet]. Bethesda (MD): National Cancer Institute (US). 2002.

  At diagnosis, only one-third of SCLC cases are limited to the thorax, mediastinum, or supraclavicular lymph nodes, while the majority, categorized as extensive-stage (ES-SCLC), have already spread beyond these regions.

American Cancer Society. Small Lung Cancer Stages. January 29, 2024.

Response to treatment

Researchers in Cancer Medicine report that ES-SCLC often relapses within a year of treatment despite an initial response.

Hart L, Ogbonnaya A, Boykin K, et al. Burden of chemotherapy-induced myelosuppression among patients with extensive-stage small cell lung cancer: A retrospective study from community oncology practices. Cancer Medicine. 2023;12(8):10020–10030.

First-line chemotherapy combines platinum-based drugs (carboplatin or cisplatin) with etoposide, with alternatives like topotecan and lurbinectedin being second-line drugs. Carboplatin is favored for its more favorable toxicity profile

Regardless of the regimen, all chemotherapies are associated with dose-limiting side effects, such as hair loss, mouth sores, appetite changes, nausea, vomiting, and gastrointestinal disturbances, which are expected and managed symptomatically. However, severe hematological and neurological toxicities, albeit rare, can be fatal. They are often addressed reactively rather than proactively.

Myelosuppression

According to board-certified oncologist and hematologist Dr. Daniel Landau, aggressive treatment of ES-SCLC  “allows the healthy cells to repopulate.” However, he warns, “These chemotherapies are compared to dropping a bomb. Killing both good and bad cells and then waiting and hoping the good cells repopulate.”

“The (hematopoietic) bone marrow cells are part of these (good) cells,” he adds, noting their dysfunction leads to myelosuppression.  

Myelosuppression is defined by the following thresholds: neutropenia (ANC <1,000 cells/μL), anemia (hemoglobin <8.0 g/dL), thrombocytopenia (platelets <50,000/μL), lymphopenia (WBC <2,000/μL), and leukopenia (lymphocytes <500/μL).

Hart L, Ogbonnaya A, Boykin K, et al. Burden of chemotherapy-induced myelosuppression among patients with extensive-stage small cell lung cancer: A retrospective study from community oncology practices. Cancer Medicine. 2023;12(8):10020–10030.

A 2023 retrospective study from the US involving 1,239 ES-SCLC patients found that 98.6% experienced at least one episode of myelosuppression, with 62.1% having grade ≥3 events in at least one lineage. Other studies report that 56.6%–64.1% of ES-SCLC patients undergoing chemotherapy experience grade ≥3 myelosuppressive events. 

Myelosuppression increases infection risk, causes bruising and bleeding from low platelets, and leads to fatigue from reduced RBCs, often requiring delayed chemotherapy or lower doses to "give the bone marrow a chance to make new cells," says Dr. Landau.

Chemoimmunotherapy-induced toxicity

Dr. Landau warns, “Immunotherapy is designed to 'fire up' the immune system and allow our body's immune system to behave more aggressively. Sometimes, the 'fired up' immune cells attack things they shouldn't,” like other hematological cells. “If this occurs, immunotherapy may need to be stopped or interrupted," he says.

Anemia 

Board-certified surgical oncologist Dr. Sandeep Nayak states, “Anemia can significantly impact a patient's ability to tolerate treatment.” However, anemia is not solely a consequence of therapy but can also result from the cancer itself.

Dr. Daniel Landau notes, "ES-SCLC can cause anemia on its own. This is a cancer that can often invade the bone marrow. As this occurs, the bone marrow cannot produce its normal cells.” Approximately 38% of lung cancer patients exhibit anemia independent of treatment, and it has emerged as an independent poor prognostic factor for patients.

Kang HS, Shin AY, Yeo CD, et al. Clinical significance of anemia as a prognostic factor in non-small cell lung cancer carcinoma with activating epidermal growth factor receptor mutations. Journal of Thoracic Disease. 2020;12(5):1895–1902.

The underlying mechanism in ICI-induced autoimmune hemolytic anemia may involve decreased Treg-mediated immune suppression and B-cell activation.

Kroll MH, Rojas-Hernandez C, Yee C. Hematologic complications of immune checkpoint inhibitors. Blood. 2022;139(25):3594–3604.

Thrombocytopenia

Thrombocytopenia accounts for nearly 30% of all hematological immune-related adverse events from ICIs, and ITP is associated with poorer survival rates than other immune reactions.

Qiu G, Li S, Li B, et al. Immune thrombocytopenia in a small cell lung cancer patient treated with atezolizumab: a case report. Translational Lung Cancer Research. 2022;11(11):2346–2355.

Dr. Nayak explains, “Severe thrombocytopenia can lead to bleeding in critical organs like the brain, which is a life-threatening complication.”

In a Translational Lung Cancer Research report, Dr. Nobuhiko Seki from the Division of Medical Oncology, Teikyo University School of Medicine, explains that chemotherapy-induced thrombocytopenia follows a predictable cycle of platelet count drop and recovery with every chemotherapy cycle, whereas sudden severe drops likely indicate immunotherapy-induced thrombocytopenia.

Qiu G, Li S, Li B, et al. Immune thrombocytopenia in a small cell lung cancer patient treated with atezolizumab: a case report. Translational Lung Cancer Research. 2022;11(11):2346–2355.

Neutropenia

Dr. Nayak highlights neutropenia as the gravest form of myelosuppression, stating, “Beyond the obvious increased risk of bacterial infections, neutropenic patients are also susceptible to fungal and viral infections, which can be particularly challenging to treat.” He adds, “Even a low-grade fever in a neutropenic patient (febrile neutropenia) should be considered a medical emergency.” 

Dr. Landau notes, "Sometimes, we give a shot of [filgrastim] to help boost the number of white blood cells." Trilaciclib is an FDA-approved agent that proactively prevents overall myelosuppression, not just single lineage cytopenias, making it a valuable option for consideration in treatment discussions. Standard interventions like filgrastim, RBC, and platelet transfusions only address specific blood cell lineages but don't protect the bone marrow stem cells, making them more like bandaids on bullet holes.

Thrombosis

The hypercoagulable state caused by both cancer and its treatment leads to venous thromboembolism (VTE) in 4.1% of SCLC patients.

Dimakakos E, Livanios K, Vathiotis I, et al. Risk Factors for Venous Thromboembolism in Patients With Small Cell Lung Cancer. Anticancer Research. 2021;41(3):1523–1528.

Other less common but serious treatment-related side effects include:

• ICI-induced myocarditis with a reported incidence of less than 1% but a mortality rate of up to 50%.

  Bi H, Ren D, Wang Q, et al. Immune checkpoint inhibitor-induced myocarditis in lung cancer patients: a case report of sintilimab-induced myocarditis and a review of the literature. Annals of Palliative Medicine. 2021;10(1):793–802.

   

• Peripheral neuropathy secondary to platinum drugs results in tingling, numbness, and pain, often necessitating dose adjustments and symptomatic management.

  American Cancer Society. Chemotherapy for Small Cell Lung Cancer. June 6, 2024. 

   

• Cytokine release syndrome (CRS) caused by Tarlatamab can manifest within the first day of treatment.

  American Cancer Society. Immunotherapy for Small Cell Lung Cancer. June 6, 2024.