Cold and hot tumors: from molecular mechanisms to targeted therapy
What Is Small Cell Lung Cancer (SCLC)?
Treatment for small cell lung cancer (SCLC) depends on the stage. Limited-stage SCLC can be treated with surgery, radiotherapy, chemotherapy, or immunotherapy. For extensive-stage SCLC, treatments like chemotherapy and immunotherapy can slow the cancer and relieve symptoms. Surgery is often ruled out for SCLC that has spread.[12]
Chemotherapy Chemotherapy is strong medicine, often injected into a vein, that travels throughout the bloodstream to kill cancer cells wherever they are in the body. In limited-stage SCLC, chemotherapy given along with radiation kills any remaining cancer cells. For extensive-stage SCLC, chemotherapy is often the main treatment, sometimes along with immunotherapy.[12]
When chemotherapy is combined with radiation, the treatment is called concurrent chemoradiation.[13] The two treatments work together to kill and prevent the spreading of cancer cells.
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The chemotherapy combinations that are most often used to treat SCLC are:[13]
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Immunotherapy This treatment works differently. Instead of killing cancer cells, it helps the immune system more effectively fight the cancer. The most common immunotherapy drugs used to treat SCLC are checkpoint inhibitors. By blocking the protein PD-L1 or PD-1, they "turn on" immune cells to attack cancer cells. Immunotherapy can also be combined with chemotherapy, especially to treat extensive-stage SCLC.[14]
Immune checkpoint inhibitors used for SCLC are:[14]
[16]
Targeted Therapies There are not as many targeted therapies available for SCLC as NSCLC, but new research looks promising. Tyrosine kinase inhibitors (TKIs), such as apatinib (Rivoceranib), block an enzyme used in cell growth and division, which can limit tumor growth.[17]
While these targeted therapies are not yet fully approved, newer therapies might be an option through a clinical trial. Speak with your doctor about what clinical trials you might be eligible for, or look at ClinicalTrials.Gov.
Surgery Surgery isn't a common treatment for SCLC. Less than 5 percent of people qualify for this therapy because they have limited-stage cancer with a small tumor that hasn't spread to any lymph nodes.[2]
Depending on the size and location of the cancer, the surgeon may remove one lobe of the lung (lobectomy). Chemotherapy and/or radiation therapy is given after surgery to ensure that all the cancer cells have been eradicated and to reduce the risk of a recurrence.[14]
Complementary and Integrative Therapies Complementary therapies work alongside conventional treatments like chemotherapy and radiation. Treatments like these don't slow the cancer, but they can help people with SCLC feel better:[18]
[19]
[19]
[19]
[18]
[18]
High Dose Radiation Therapy May Fuel Cancer Spread, UChicago Study Finds
A new study from the University of Chicago Medicine Comprehensive Cancer Center reveals that radiation therapy can spur growth in untreated metastatic tumors—even if they're distant from the site being treated.
Scientists have long observed the "abscopal effect," in which radiation to one tumor causes other, untreated tumors to shrink. But the UChicago team saw the opposite, with untreated metastatic tumors growing with high dose radiation. In a play on words, they dubbed this response the "badscopal effect."
They believe this unexpected response happens because high dose radiation increases the production of a protein called amphiregulin by tumor cells that are directly treated with radiation. High amounts of amphiregulin weaken the immune system's ability to fight cancer and make cancer cells better at protecting themselves.
The findings point to promising new therapeutic strategies that could lead to more effective treatments for metastatic cancer.
Radiotherapy: A double-edged sword?Radiotherapy is often used alone or in combination with surgery and chemotherapy to control localized tumors. More recently, radiotherapy has been used to treat cancers that have limited spread, a condition known as oligometastasis.
Scientists believe radiotherapy activates the immune system, producing regression in tumors at distant sites that are not directly treated with radiation, as in the abscopal effect. However, many patients who receive radiation for oligometastasis or as part of an immunotherapy regimen fail to respond to treatment because of the growth of distant metastasis.
"Our lab postulated that high doses of radiation might actually promote tumor growth at unirradiated sites under certain conditions, potentially accounting for some of these failures," said senior author Ralph Weichselbaum, chair and Daniel K. Ludwig Distinguished Service Professor of Radiation and Cellular Oncology at UChicago Medicine.
"Studies from the 1940s suggested radiation might cause tumor spread, but that never made sense to me because radiation is a highly effective anti-cancer agent within the tumor bed," Weichselbaum said. "However, the communication between the irradiated site and distant metastatic sites is fascinating."
Uncovering the 'badscopal' effectTo investigate this tumor-to-tumor interaction, the research team analyzed biopsy samples from a clinical trial in which patients with different types of cancer treated with high dose focused radiotherapy known as Stereotactic Body Radiotherapy (SBRT) and checkpoint blockade.
That clinical trial team, led by Prof. Steven Chmura, the director of Clinical and Translational Research for Radiation Oncology at UChicago, found that tumors at preexisting metastatic sites increased in size following SBRT, suggesting radiation might promote tumor growth.
To understand how radiation at the primary site affects distant tumors, researchers led by András Piffkó, a post-doctoral fellow in the Weichselbaum lab, conducted gene expression profiling of patient tumors before and after radiation treatment. They discovered that in tumors that had been treated with radiation, the gene encoding for amphiregulin was significantly increased.
Amphiregulin in turn binds to EGFR, a receptor protein on tumor cell membranes, and turns on major intracellular signaling pathways governing cell survival, proliferation, migration and cell death.
The researchers studied this effect in animal models of lung and breast cancer. They found that while radiation reduced the number of new metastatic sites, it increased the growth of existing ones.
Radiotherapy significantly increased amphiregulin in both tumor cells and blood. But when researchers blocked amphiregulin with antibodies—or deleted its gene in tumor cells using CRISPR technology—tumors outside the radiation field shrank.
"Interestingly, the combination of radiation and amphiregulin blockade decreased both tumor size and the number of metastatic sites," Weichselbaum said.
The role of immune suppressionTo explore this further, the researchers analyzed blood samples from a second clinical trial conducted by Chmura in which lung cancer patients received SBRT either after or at the same time as immunotherapy.
They found that failure to decrease amphiregulin following SBRT was associated with worse outcomes. They also found an increase in certain immune cells that suppress the body's defenses was linked to cancer spread and death.
In a previous study published in Cancer Cell, Weichselbaum and his team showed that removing some of these suppressive immune cells reduces both the size and number of metastases. In the new study, they saw more of these suppressive cells in animals with high levels of amphiregulin in their tumors and blood after radiation—but not in those without it.
The findings suggest that amphiregulin may disrupt how immune cells develop, steering them toward an immunosuppressive form that allows tumors to grow.
Working with UChicago biochemistry Assoc. Prof. Ronald Rock, the team discovered that amphiregulin and radiation increased a protein called CD47, a so-called "don't eat me" signal that helps tumor cells evade immune cells such as macrophages and other myeloid cells.
Blocking both amphiregulin and CD47 along with radiotherapy led to strong control of metastatic tumors in animal models. The findings suggest a new approach to radiation therapy—one in which molecules triggered by radiation are identified and targeted, potentially paving the way for more personalized therapies for patients with metastatic cancers.
"These results open a whole new way of thinking about the systemic effects of radiotherapy," Weichselbaum said. "Based on these findings, we are planning to conduct a clinical trial to further explore and validate the results."
Story originally published here with UChicago Medicine.
The study, "Radiation-induced amphiregulin drives tumor metastasis," was supported by the National Cancer Institute, Ludwig Foundation, the Chicago Tumor Institute, generous gifts from Mr. And Mrs. Vincent Foglia and the Foglia Foundation, Mr. And Mrs. David Kozin and Mr. And Mrs. James Weichselbaum.
How One Mother Is Fighting To Save Others After Lung Cancer Took Her Son
The cancer had spread to Rashad's thymus gland, which needed to be removed, and it was during this surgery that they saw how extensively the lung cancer had spread and knew they needed a new plan. A week later, on Rashad's 28th birthday, he had surgery to remove his right lung. After surgery he needed immunotherapy and radiation, but the cancer was too aggressive and continued to spread to his other lung and his heart.
"He never had a moment of peace; he was so uncomfortable. As a mother it is so terrible to have to watch your child suffer and know there is nothing you can do," Veronica said. Despite all this, on October 31, 2021, at just 29 years old, Rashad passed away.
Before Rashad's unforeseen diagnosis, Veronica knew very little about lung cancer. So, when she discovered a LUNG FORCE Walk in her area, she knew she wanted to get involved. "I had never heard of the Lung Association before my son got sick, which is ridiculous because lung cancer is the number one cancer killer," she said. "Once I got to that first LUNG FORCE event and saw the community of people sharing their stories, I thought, 'this is my mission,' to spread the word and hopefully save other people. It is too late for my son, but maybe we can save someone else. That is all I want to do," she exclaimed.
Her passion didn't go unnoticed, and she was asked to attend the 2025 Advocacy Day in Washington D.C. As a representative of Connecticut, she shared her son's story with her members of Congress. In particular, she shared that during Rashad's treatment, the insurance company did not want to pay for his immunotherapy. "We had a great team, and his main doctor in particular fought hard to get him the treatment he needed," Veronica said. The experience encouraged her to continue advocating for CDC, NIH and Medicaid funding so that people with lung cancer can receive the treatment they need.
"We pleaded for them not to cut these programs because without them, people are going to die. I can't imagine someone going through cancer treatment without insurance, but if they cut Medicaid, for a lot of people that is going to be a reality," she exclaimed. She worries that hospitals may close and make it even harder for people in underserved rural communities to get to clinics that are hours away.
Veronica hopes that by sharing her story, she can make people look beyond the monetary costs and understand this problem is one of life or death. "It can be hard for people who have not been in that situation to understand what it feels like, so I tell them to try. Imagine your child or loved one needed lifesaving care, and someone took it away from them. How would you feel, and wouldn't you do anything and everything to try and save them?"
Learn more about how you can advocate for Medicare, Medicaid and other programs that save lives and are at risk of being cut.
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