Unexpected ES-SCLC treatment side effects
Key Takeaways
Extensive-stage small-cell lung cancer (ES-SCLC) is highly aggressive, with chemotherapy often causing severe myelosuppression, increasing the risk of life-threatening infections and bleeding.
Immunotherapy, though promising, can trigger rare but serious blood-related toxicities like autoimmune anemia and thrombocytopenia.
Reactive use of standard treatments like G-CSF and transfusions offer only temporary relief and fail to prevent lasting bone marrow damage.
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.[]
A 2024 estimate predicts an 84% rise in lung cancer cases and a 93% increase in deaths by 2050.[]
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%.[] Among these, SCLC is the most rapidly aggressive, with untreated cases having a median survival of just 8 to 16 weeks.[] 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.[]
Response to treatment
Researchers in Cancer Medicine report that ES-SCLC often relapses within a year of treatment despite an initial response.[] 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).[]
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.
ICIs-induced hematological toxicities, albeit rare, include life-threatening high-grade anemia (up to 17% of cases), thrombocytopenia (1.2%–2.5%), and neutropenia (0.4%–1.7%).[] Autoimmune hemolytic anemia, idiopathic aplastic anemia, and immune thrombocytopenia are among the most common immune-mediated hematologic abnormalities observed with these therapies.
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.[] The underlying mechanism in ICI-induced autoimmune hemolytic anemia may involve decreased Treg-mediated immune suppression and B-cell activation.[]
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.[]
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.[]
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.[]
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%.[]
Peripheral neuropathy secondary to platinum drugs results in tingling, numbness, and pain, often necessitating dose adjustments and symptomatic management.[]
Cytokine release syndrome (CRS) caused by Tarlatamab can manifest within the first day of treatment.[]
What this means for you
ES-SCLC is notorious for its rapid progression and early metastasis. Despite advancements in therapeutic strategies, treatment-related toxicities remain a major challenge, particularly hematologic toxicities, which often require proactive management to minimize their impact on patient outcomes.