Mixed Topics

The Food and Drug Administration (FDA) has approved atezolizumab and hyaluronidase-tqjs (Tecentriq Hybreza, Genentech) as a subcutaneous injection in adults, covering all approved indications of the intravenous (IV) formulation.

Approved indications include non–small cell lung cancer (NSCLC), SCLC, hepatocellular carcinoma, melanoma, and alveolar soft part sarcoma. Specific indications are available with the full prescribing information at Drugs@FDA.

This is the first programmed death–ligand 1 inhibitor to gain approval for subcutaneous administration.

“This approval represents a significant option to improve the patient experience,” Ann Fish-Steagall, RN, Senior Vice President of Patient Services at the LUNGevity Foundation stated in a Genentech press release.

Subcutaneous atezolizumab and hyaluronidase-tqjs was evaluated in the open-label, randomized IMscin001 trial of 371 adult patients with locally advanced or metastatic NSCLC who were not previously exposed to cancer immunotherapy and who had disease progression following treatment with platinum-based chemotherapy. Patients were randomized 2:1 to receive subcutaneous or IV administration until disease progression or unacceptable toxicity.

Atezolizumab exposure, the primary outcome measure of the study, met the lower limit of geometric mean ratio above the prespecified threshold of 0.8 (cycle 1C trough, 1.05; area under the curve for days 0-21, 0.87).

No notable differences were observed in overall response rate, progression-free survival, or overall survival between the two formulations, according to the FDA approval notice.

The confirmed overall response rate was 9% in the subcutaneous arm and 8% intravenous arm.

Adverse events of any grade occurring in at least 10% of patients were fatigue, musculoskeletal pain, cough, dyspnea, and decreased appetite.

The recommended dose for subcutaneous injection is one 15 mL injection, which contains 1875 mg of atezolizumab and 30,000 units of hyaluronidase.

Injections should be administered in the thigh over approximately 7 minutes every 3 weeks. By contrast, IV administration generally takes 30-60 minutes.

A version of this article first appeared on Medscape.com.

The Food and Drug Administration (FDA) has approved atezolizumab and hyaluronidase-tqjs (Tecentriq Hybreza, Genentech) as a subcutaneous injection in adults, covering all approved indications of the intravenous (IV) formulation.

Approved indications include non–small cell lung cancer (NSCLC), SCLC, hepatocellular carcinoma, melanoma, and alveolar soft part sarcoma. Specific indications are available with the full prescribing information at Drugs@FDA.

This is the first programmed death–ligand 1 inhibitor to gain approval for subcutaneous administration.

“This approval represents a significant option to improve the patient experience,” Ann Fish-Steagall, RN, Senior Vice President of Patient Services at the LUNGevity Foundation stated in a Genentech press release.

Subcutaneous atezolizumab and hyaluronidase-tqjs was evaluated in the open-label, randomized IMscin001 trial of 371 adult patients with locally advanced or metastatic NSCLC who were not previously exposed to cancer immunotherapy and who had disease progression following treatment with platinum-based chemotherapy. Patients were randomized 2:1 to receive subcutaneous or IV administration until disease progression or unacceptable toxicity.

Atezolizumab exposure, the primary outcome measure of the study, met the lower limit of geometric mean ratio above the prespecified threshold of 0.8 (cycle 1C trough, 1.05; area under the curve for days 0-21, 0.87).

No notable differences were observed in overall response rate, progression-free survival, or overall survival between the two formulations, according to the FDA approval notice.

The confirmed overall response rate was 9% in the subcutaneous arm and 8% intravenous arm.

Adverse events of any grade occurring in at least 10% of patients were fatigue, musculoskeletal pain, cough, dyspnea, and decreased appetite.

The recommended dose for subcutaneous injection is one 15 mL injection, which contains 1875 mg of atezolizumab and 30,000 units of hyaluronidase.

Injections should be administered in the thigh over approximately 7 minutes every 3 weeks. By contrast, IV administration generally takes 30-60 minutes.

A version of this article first appeared on Medscape.com.

The Food and Drug Administration (FDA) has approved atezolizumab and hyaluronidase-tqjs (Tecentriq Hybreza, Genentech) as a subcutaneous injection in adults, covering all approved indications of the intravenous (IV) formulation.

Approved indications include non–small cell lung cancer (NSCLC), SCLC, hepatocellular carcinoma, melanoma, and alveolar soft part sarcoma. Specific indications are available with the full prescribing information at Drugs@FDA.

This is the first programmed death–ligand 1 inhibitor to gain approval for subcutaneous administration.

“This approval represents a significant option to improve the patient experience,” Ann Fish-Steagall, RN, Senior Vice President of Patient Services at the LUNGevity Foundation stated in a Genentech press release.

Subcutaneous atezolizumab and hyaluronidase-tqjs was evaluated in the open-label, randomized IMscin001 trial of 371 adult patients with locally advanced or metastatic NSCLC who were not previously exposed to cancer immunotherapy and who had disease progression following treatment with platinum-based chemotherapy. Patients were randomized 2:1 to receive subcutaneous or IV administration until disease progression or unacceptable toxicity.

Atezolizumab exposure, the primary outcome measure of the study, met the lower limit of geometric mean ratio above the prespecified threshold of 0.8 (cycle 1C trough, 1.05; area under the curve for days 0-21, 0.87).

No notable differences were observed in overall response rate, progression-free survival, or overall survival between the two formulations, according to the FDA approval notice.

The confirmed overall response rate was 9% in the subcutaneous arm and 8% intravenous arm.

Adverse events of any grade occurring in at least 10% of patients were fatigue, musculoskeletal pain, cough, dyspnea, and decreased appetite.

The recommended dose for subcutaneous injection is one 15 mL injection, which contains 1875 mg of atezolizumab and 30,000 units of hyaluronidase.

Injections should be administered in the thigh over approximately 7 minutes every 3 weeks. By contrast, IV administration generally takes 30-60 minutes.

A version of this article first appeared on Medscape.com.

Research offers promising insights into the ideal frontline therapies for mantle cell lymphoma (MCL), but there are continued unmet needs in the relapsed/refractory setting, blood cancer specialists told colleagues. 

In the frontline setting, findings suggest that regimens should differ significantly on the basis of whether patients are older or younger, whereas more data are needed to understand whether treatment can overcome poor prognoses in patients with TP53 mutations, lymphoma specialist Nina Wagner-Johnston, MD, of Johns Hopkins University School of Medicine, Baltimore, said in a presentation at the annual meeting of the Society of Hematologic Oncology (SOHO) 2024 in Houston, Texas.

On the relapsed/refractory front, patients need better options after treatment with Bruton tyrosine kinase inhibitors or chimeric antigen receptor (CAR) T-cell therapy, Krish Patel, MD, a lymphoma specialist with Swedish Cancer Institute in Seattle, said in an adjoining presentation. Fortunately, he said, some treatments are showing early promise.

Here’s a closer look at the presentations by Dr. Wagner-Johnston and Dr. Patel.
 

Frontline MCL: Age Helps Determine Best Approach

“For older and less fit patients, the standard approach has typically been bendamustine (Bendeka, Treanda) and rituximab (Rituxan), and the median progression-free survival is about 4 years, with overall survival not reached at a median 5 years of follow-up,” Dr. Wagner-Johnston said. 

Low doses of the chemotherapy drug cytarabine have been added to the bendamustine-rituximab regimen, with encouraging results, she said. “Certainly there’s more toxicity associated even with lower doses, but those data look fairly promising.”

For younger and fit patients, “the standard of care approach has been to administer intensive chemoimmunotherapy that contains high-dose cytarabine, and then that’s typically followed with an autologous stem cell transplant,” she said. A 2016 study reported median progression-free survival of 8.5 years and median overall survival of 12.7 years.

Now, second-generation Bruton tyrosine kinase inhibitors “look very promising” in the frontline setting, Dr. Wagner-Johnston said.

The road has been rocky, however. The SHINE trial of more than 500 patients aged over 65 found that adding ibrutinib to bendamustine-rituximab improved progression-free survival. “However, progression-free survival did not [connect] to an overall survival benefit, and that’s likely due to the toxicity seen with ibrutinib,” she said. 

“It’s not surprising to many of you that ibrutinib has been removed from the FDA label for mantle cell lymphoma,” she said. However, “second-generation [Bruton tyrosine kinase inhibitors] are known to be associated with less toxicity and potentially increased potency.”

What about Bruton tyrosine kinase inhibitors in younger and fitter patients? The TRIANGLE trial demonstrated their benefit, Dr. Wagner-Johnston said, linking ibrutinib to improvement in progression-free survival. 

However, “it’s really too early to evaluate the statistical significance for overall survival.” And while the study looks at therapy without stem cell transplant, she believes it’s too early to know whether that’s a good option. 

Dr. Wagner-Johnston tackled another topic: Can Bruton tyrosine kinase inhibitors overcome the poor prognosis seen with MCL with TP53 mutation? For now, the limitations of research makes it “hard to know,” she said, although early results of the BOVen trial are promising. 
 

Relapsed/Refractory MCL: Better Options Are Still Needed

In his presentation, Dr. Patel spoke about therapy in patients with MCL and relapsed/refractory disease. “We know that outcomes for patients who progress on covalent [Bruton tyrosine kinase inhibitors] is really dismal,” he said. “This has been shown by multiple groups now across the globe.”

Noncovalent Bruton tyrosine kinase inhibitors are now an option, he noted. “We do understand that they work for some patients, and it can be quite useful, but even noncovalent [Bruton tyrosine kinase inhibitors] themselves are susceptible to resistance mutations. We’ve seen that in the [chronic lymphocytic leukemia] world.”

Dr. Patel asked the audience, “Why not just give everybody CAR T-cells, post-[Bruton tyrosine kinase inhibitors]? You get a CAR T-cell! You get a CAR T-cell! Everybody gets one.”

However, he noted, “Unfortunately, mantle cell lymphoma patients experience the worst high-grade toxicity when receiving CD19[-targeted] CAR T-cells.” 

Are there better options? At the moment, “really, really early data” suggest benefits from molecular glues and degraders, novel inhibitors, antibody-drug conjugates, novel CAR T-cells, and bispecific antibodies, Dr. Patel said.

“All of these tools are in clinical trials, and hopefully some of them will help,” he said.

Disclosures were not provided. Dr. Wagner-Johnston recently disclosed advisory committee/board of directors’ relationships with ADC Therapeutics, Regeneron, Calibr, and Verastem. Dr. Patel recently disclosed ties with a long list of pharmaceutical companies, including AbbVie, AstraZeneca, BeiGene, Bristol Myers Squibb, Genentech, Janssen, Merck, and others.
 

A version of this article first appeared on Medscape.com.

Research offers promising insights into the ideal frontline therapies for mantle cell lymphoma (MCL), but there are continued unmet needs in the relapsed/refractory setting, blood cancer specialists told colleagues. 

In the frontline setting, findings suggest that regimens should differ significantly on the basis of whether patients are older or younger, whereas more data are needed to understand whether treatment can overcome poor prognoses in patients with TP53 mutations, lymphoma specialist Nina Wagner-Johnston, MD, of Johns Hopkins University School of Medicine, Baltimore, said in a presentation at the annual meeting of the Society of Hematologic Oncology (SOHO) 2024 in Houston, Texas.

On the relapsed/refractory front, patients need better options after treatment with Bruton tyrosine kinase inhibitors or chimeric antigen receptor (CAR) T-cell therapy, Krish Patel, MD, a lymphoma specialist with Swedish Cancer Institute in Seattle, said in an adjoining presentation. Fortunately, he said, some treatments are showing early promise.

Here’s a closer look at the presentations by Dr. Wagner-Johnston and Dr. Patel.
 

Frontline MCL: Age Helps Determine Best Approach

“For older and less fit patients, the standard approach has typically been bendamustine (Bendeka, Treanda) and rituximab (Rituxan), and the median progression-free survival is about 4 years, with overall survival not reached at a median 5 years of follow-up,” Dr. Wagner-Johnston said. 

Low doses of the chemotherapy drug cytarabine have been added to the bendamustine-rituximab regimen, with encouraging results, she said. “Certainly there’s more toxicity associated even with lower doses, but those data look fairly promising.”

For younger and fit patients, “the standard of care approach has been to administer intensive chemoimmunotherapy that contains high-dose cytarabine, and then that’s typically followed with an autologous stem cell transplant,” she said. A 2016 study reported median progression-free survival of 8.5 years and median overall survival of 12.7 years.

Now, second-generation Bruton tyrosine kinase inhibitors “look very promising” in the frontline setting, Dr. Wagner-Johnston said.

The road has been rocky, however. The SHINE trial of more than 500 patients aged over 65 found that adding ibrutinib to bendamustine-rituximab improved progression-free survival. “However, progression-free survival did not [connect] to an overall survival benefit, and that’s likely due to the toxicity seen with ibrutinib,” she said. 

“It’s not surprising to many of you that ibrutinib has been removed from the FDA label for mantle cell lymphoma,” she said. However, “second-generation [Bruton tyrosine kinase inhibitors] are known to be associated with less toxicity and potentially increased potency.”

What about Bruton tyrosine kinase inhibitors in younger and fitter patients? The TRIANGLE trial demonstrated their benefit, Dr. Wagner-Johnston said, linking ibrutinib to improvement in progression-free survival. 

However, “it’s really too early to evaluate the statistical significance for overall survival.” And while the study looks at therapy without stem cell transplant, she believes it’s too early to know whether that’s a good option. 

Dr. Wagner-Johnston tackled another topic: Can Bruton tyrosine kinase inhibitors overcome the poor prognosis seen with MCL with TP53 mutation? For now, the limitations of research makes it “hard to know,” she said, although early results of the BOVen trial are promising. 
 

Relapsed/Refractory MCL: Better Options Are Still Needed

In his presentation, Dr. Patel spoke about therapy in patients with MCL and relapsed/refractory disease. “We know that outcomes for patients who progress on covalent [Bruton tyrosine kinase inhibitors] is really dismal,” he said. “This has been shown by multiple groups now across the globe.”

Noncovalent Bruton tyrosine kinase inhibitors are now an option, he noted. “We do understand that they work for some patients, and it can be quite useful, but even noncovalent [Bruton tyrosine kinase inhibitors] themselves are susceptible to resistance mutations. We’ve seen that in the [chronic lymphocytic leukemia] world.”

Dr. Patel asked the audience, “Why not just give everybody CAR T-cells, post-[Bruton tyrosine kinase inhibitors]? You get a CAR T-cell! You get a CAR T-cell! Everybody gets one.”

However, he noted, “Unfortunately, mantle cell lymphoma patients experience the worst high-grade toxicity when receiving CD19[-targeted] CAR T-cells.” 

Are there better options? At the moment, “really, really early data” suggest benefits from molecular glues and degraders, novel inhibitors, antibody-drug conjugates, novel CAR T-cells, and bispecific antibodies, Dr. Patel said.

“All of these tools are in clinical trials, and hopefully some of them will help,” he said.

Disclosures were not provided. Dr. Wagner-Johnston recently disclosed advisory committee/board of directors’ relationships with ADC Therapeutics, Regeneron, Calibr, and Verastem. Dr. Patel recently disclosed ties with a long list of pharmaceutical companies, including AbbVie, AstraZeneca, BeiGene, Bristol Myers Squibb, Genentech, Janssen, Merck, and others.
 

A version of this article first appeared on Medscape.com.

Research offers promising insights into the ideal frontline therapies for mantle cell lymphoma (MCL), but there are continued unmet needs in the relapsed/refractory setting, blood cancer specialists told colleagues. 

In the frontline setting, findings suggest that regimens should differ significantly on the basis of whether patients are older or younger, whereas more data are needed to understand whether treatment can overcome poor prognoses in patients with TP53 mutations, lymphoma specialist Nina Wagner-Johnston, MD, of Johns Hopkins University School of Medicine, Baltimore, said in a presentation at the annual meeting of the Society of Hematologic Oncology (SOHO) 2024 in Houston, Texas.

On the relapsed/refractory front, patients need better options after treatment with Bruton tyrosine kinase inhibitors or chimeric antigen receptor (CAR) T-cell therapy, Krish Patel, MD, a lymphoma specialist with Swedish Cancer Institute in Seattle, said in an adjoining presentation. Fortunately, he said, some treatments are showing early promise.

Here’s a closer look at the presentations by Dr. Wagner-Johnston and Dr. Patel.
 

Frontline MCL: Age Helps Determine Best Approach

“For older and less fit patients, the standard approach has typically been bendamustine (Bendeka, Treanda) and rituximab (Rituxan), and the median progression-free survival is about 4 years, with overall survival not reached at a median 5 years of follow-up,” Dr. Wagner-Johnston said. 

Low doses of the chemotherapy drug cytarabine have been added to the bendamustine-rituximab regimen, with encouraging results, she said. “Certainly there’s more toxicity associated even with lower doses, but those data look fairly promising.”

For younger and fit patients, “the standard of care approach has been to administer intensive chemoimmunotherapy that contains high-dose cytarabine, and then that’s typically followed with an autologous stem cell transplant,” she said. A 2016 study reported median progression-free survival of 8.5 years and median overall survival of 12.7 years.

Now, second-generation Bruton tyrosine kinase inhibitors “look very promising” in the frontline setting, Dr. Wagner-Johnston said.

The road has been rocky, however. The SHINE trial of more than 500 patients aged over 65 found that adding ibrutinib to bendamustine-rituximab improved progression-free survival. “However, progression-free survival did not [connect] to an overall survival benefit, and that’s likely due to the toxicity seen with ibrutinib,” she said. 

“It’s not surprising to many of you that ibrutinib has been removed from the FDA label for mantle cell lymphoma,” she said. However, “second-generation [Bruton tyrosine kinase inhibitors] are known to be associated with less toxicity and potentially increased potency.”

What about Bruton tyrosine kinase inhibitors in younger and fitter patients? The TRIANGLE trial demonstrated their benefit, Dr. Wagner-Johnston said, linking ibrutinib to improvement in progression-free survival. 

However, “it’s really too early to evaluate the statistical significance for overall survival.” And while the study looks at therapy without stem cell transplant, she believes it’s too early to know whether that’s a good option. 

Dr. Wagner-Johnston tackled another topic: Can Bruton tyrosine kinase inhibitors overcome the poor prognosis seen with MCL with TP53 mutation? For now, the limitations of research makes it “hard to know,” she said, although early results of the BOVen trial are promising. 
 

Relapsed/Refractory MCL: Better Options Are Still Needed

In his presentation, Dr. Patel spoke about therapy in patients with MCL and relapsed/refractory disease. “We know that outcomes for patients who progress on covalent [Bruton tyrosine kinase inhibitors] is really dismal,” he said. “This has been shown by multiple groups now across the globe.”

Noncovalent Bruton tyrosine kinase inhibitors are now an option, he noted. “We do understand that they work for some patients, and it can be quite useful, but even noncovalent [Bruton tyrosine kinase inhibitors] themselves are susceptible to resistance mutations. We’ve seen that in the [chronic lymphocytic leukemia] world.”

Dr. Patel asked the audience, “Why not just give everybody CAR T-cells, post-[Bruton tyrosine kinase inhibitors]? You get a CAR T-cell! You get a CAR T-cell! Everybody gets one.”

However, he noted, “Unfortunately, mantle cell lymphoma patients experience the worst high-grade toxicity when receiving CD19[-targeted] CAR T-cells.” 

Are there better options? At the moment, “really, really early data” suggest benefits from molecular glues and degraders, novel inhibitors, antibody-drug conjugates, novel CAR T-cells, and bispecific antibodies, Dr. Patel said.

“All of these tools are in clinical trials, and hopefully some of them will help,” he said.

Disclosures were not provided. Dr. Wagner-Johnston recently disclosed advisory committee/board of directors’ relationships with ADC Therapeutics, Regeneron, Calibr, and Verastem. Dr. Patel recently disclosed ties with a long list of pharmaceutical companies, including AbbVie, AstraZeneca, BeiGene, Bristol Myers Squibb, Genentech, Janssen, Merck, and others.
 

A version of this article first appeared on Medscape.com.

Cases

Consults for percutaneous gastrostomy (PEG) tube placement for a patient ...

• With dysphagia after stroke: A 70-year-old female with a history of hypertension presented to the hospital with altered mental status and left-sided weakness. She was previously active and independently living. MRI of the brain revealed a right basal ganglia infarct. As a result, she developed dysphagia. She was evaluated by speech and language pathology and underwent a modified barium swallow. Given concerns for aspiration, the recommendation was made for gastroenterology (GI) consultation to place PEG tube for nutrition and medication administration.
• With advanced dementia: An 85-year-old male with an extensive medical history including advanced dementia was admitted from his nursing home for decreased oral intake. His baseline mental status is awake and alert, but he is nonverbal and does not follow commands. Upon 72-hour calorie count, the nutrition consultants determined that he cannot independently meet his nutrition goals. His family wants “everything done” and are asking about a “feeding tube.” The primary team has now consulted GI for PEG tube placement.
• Who is being discharged to a long-term care facility: A 45-year-old male was admitted to the ICU after a heroin overdose. CPR was initiated in the field and return of spontaneous circulation was obtained after 25 minutes. The patient has minimal brainstem reflexes. He is ventilator dependent. He has no family, and now is status-post tracheostomy placement by two-physician consent. The patient is ready for discharge to a long-term care facility that will not accept patients with nasogastric tubes. GI is consulted for PEG tube placement.

Discussion

Gastroenterologists are often consulted for PEG tube placement. However, the circumstances surrounding and the implications of PEG tube placement are often complicated for reasons beyond nutritional or technical considerations. This is rooted in the fact that, as one expert wrote, “feeding, unlike any other medical treatment, has a moral and emotional significance derived from culture.”¹ Understanding the evidence, ethical considerations, and team dynamic behind PEG tube placement is critical for every gastroenterologist. Herein we review these topics and offer guidelines for having patient-centered conversations involving these fundamental concepts.

courtesy Paul Nguyen

First, the gastroenterologist should understand the evidence to debunk myths and clarify truths surrounding PEG tube placement. While PEG tubes may help patients with amyotrophic lateral sclerosis stabilize their weight and can even be prophylactically placed in select patients with head and neck cancer,^2,3 they are not always appropriate in patients in early recovery from stroke and have not been shown to improve outcomes in patients with advanced dementia. At least 50% of stroke-related dysphagia resolves within 1-2 weeks, and so the American Heart Association Stroke Council recommends continuing nasogastric tube feeding for 2-3 weeks in patients such as the one presented in case 1 before considering PEG tube placement.⁴

In situations of advanced dementia such as in case,² several studies demonstrate that PEG tubes do not reduce or prevent aspiration pneumonia, prevent consequences of malnutrition, prolong life, reduce pressure ulcers, reduce urinary of gastrointestinal tract infections, lead to functional improvement, mitigate decline, or even improve comfort or quality of life for patients or their caregivers.^5-7 Despite this evidence, as demonstrated in case,³ it is true that many American skilled nursing facilities will not accept a patient without a PEG if enteral feeding is needed. This restriction may vary by state: One study found that skilled nursing facilities in New York City are much less likely to accept patients with nasogastric feeding tubes than randomly selected skilled nursing facilities throughout the country.⁶ Nonetheless, gastroenterologists should look to the literature to understand the outcomes of populations of patients after PEG tube placement and use that data to guide decision-making.

courtesy Ohio State University Wexner Medical Center

Secondly, the five ethical principles that inform all medical decision making – autonomy, beneficence, nonmaleficence, justice, and futility – should also inform the gastroenterologist’s rationale in offering PEG placement.⁸

Autonomy implies that the medical team has determined who is able to make the decision regarding PEG tube placement for the patient. Beneficence connects the patient’s medical diagnosis and technical parameters of PEG tube placement with his or her goals of care. Nonmaleficence ensures the decision-making party understands the benefits and risks of the procedure, including anticipatory guidance on possible PEG tube management, complications, risks, and need for replacement. Justice incorporates the context of the patient’s life, including family dynamics, religious, cultural, and financial factors. Futility connects the patient’s prognosis with practical aspects of having a PEG tube.

The complexity of PEG placement lies in the fact that these ethical principles are often at odds with each other. For example, case 2 highlights the conflicting principles of autonomy and futility for elderly dementia patients: While PEG tube placements do not improve comfort or quality of life in advanced dementia (futility), the family representing the patient has stated they want everything done for his care, including PEG tube placement (autonomy). Navigating these ethical principles can be difficult, but having a framework to organize the different factors offers sound guidance for the gastroenterologist.

courtesy Rusty Schramm

Finally, the gastroenterologist should recognize the roles of the multidisciplinary team members, including the patient and their representatives, regarding PEG tube placement consults. While gastroenterologists can be viewed as the technicians consulted to simply “place the tube,” they must seek to understand the members of the team representing the patient to be stewards of their skill set. Consulting team physicians carry great responsibility in organizing the medical and psychosocial aspects of each patient’s care, and their proper goals to relieve suffering and prevent death may color their judgment regarding who they believe is a candidate for a PEG tube. Nutritionists, speech therapists, and case managers can help provide objective data on the practicality and feasibility of a PEG tube in their patients. The healthcare system may influence the decision to consult heavily, as seen in the rules of the long-term care facility in case.³ While it is the job of the multidisciplinary medical team to explain the evidence and ethical considerations of PEG tube placement in a patient-centered manner, ultimately the decision belongs to the patient and their family or representatives.

The moral burden of not pursuing PEG placement may supersede the medical advice in many situations. There is an emotionally taxing perception that withholding nutrition via PEG is “starving the patient,” despite literature showing many terminally ill patients do not experience thirst or hunger, and those who do have alleviation of these symptoms with small amounts of food or liquid, not with PEG placement.⁵ As every patient is unique, PEG tube consultation guidelines created with input from all stakeholders have been utilized to ensure that patients are medically optimized for PEG tube placement and that evidence and ethics-based considerations are evaluated by the multidisciplinary team. An example of such a guideline is shown in Figure 1.

courtesy Dr. Emily Seltzer

If the gastroenterologist encounters more contentious consultations, there are ways to build consensus to both alleviate patient and family suffering as well as elevate the discussions between teams.

First, identify the type of consult that is repeatedly bringing differing viewpoints and differing ethical principles into play. Second, get representatives from teams together in a neutral environment to understand stakeholders needs. New data suggest, in stroke cases like case 1, there may be dramatic benefit in long-term ability to recover if patients can get early intensive rehabilitation.⁹ This intense daily rehabilitation is not available within the hospital setting at many locations, and facilitation of discharge may be requested earlier than usually advised tube placement. Third, build a common language for requests and responses between teams. For instance, neurologists can identify and document which patients have less likelihood of early spontaneous recovery, and this can allow gastroenterologists to understand that those patients with little potential for early swallowing recovery can safely be targeted for PEG earlier during the hospital course. Other patients described as having a potential for spontaneous improvement should be given time to recover before an intervention is considered.¹⁰ Having a common understanding of goals and a better-informed decision pathway helps each team member feel fulfilled and rewarded, which will ultimately help reduce compassion fatigue and moral burden on providers.

courtesy Robert Wood Johnson University Hospital

In conclusion, PEG tube placement can be a challenging consultation for gastroenterologists because of the clinical, social, and ethical ramifications at stake for the patient. Even when PEG tube placement is technically feasible, the gastroenterologist should feel empowered to address the evidence-based outcomes of PEG tube placement, discuss the ethical principles of the decision-making process, and communicate with a multidisciplinary team using guidelines as set forth by this paper to best serve the patient.

Dr. Seltzer is based in the Department of Internal Medicine, Mount Sinai Morningside-West, New York City. Dr. Pusateri is based in the Division of Gastroenterology, Hepatology and Nutrition, Ohio State University Wexner Medical Center, Columbus. Dr. Nguyen is based in the Division of Gastroenterology and Center for Esophageal Diseases, Baylor Scott & White Health, Dallas, Texas. Dr. Stein is based in the Division of Gastroenterology, Robert Wood Johnson University Hospital, Rutgers University, New Brunswick, New Jersey. All authors contributed equally to this manuscript, and have no disclosures related to this article.

References

1. Mackie S. Gastroenterol Nurs. 2001 May-Jun;24(3):138-42.

2. Miller RG et al. Neurology. 2009 Oct. doi: 10.1212/WNL.0b013e3181bc0141.

3. Colevas AD et al. J Natl Compr Canc Netw. 2018 May. doi: 10.6004/jnccn.2018.0026.

4. Holloway RG et al. Stroke. 2014 Jun. doi: 10.1161/STR.0000000000000015.

5. Finucane TE et al. JAMA. 1999 Oct. doi: 10.1001/jama.282.14.1365.

6. Burgermaster M et al. Nutr Clin Pract. 2016 Jun. doi: 10.1177/0884533616629636.

7. American Geriatrics Society Ethics C, Clinical P, Models of Care C. J Am Geriatr Soc. 2014 Aug. doi: 10.1111/jgs.12924.

8. Beauchamp TL. Principlism in Bioethics. In: Serna P, eds. Bioethical Decision Making and Argumentation. International Library of Ethics, Law, and the New Medicine, vol 70. Springer; Cham. 2016 Sept:1-16. doi: 10.1007/978-3-319-43419-3_1.

9. Powers WJ et al. Stroke. 2019 Oct. doi: 10.1161/STR.0000000000000211.

10. Galovic M et al. JAMA Neurol. 2019 May. doi: 10.1001/jamaneurol.2018.4858.

Cases

Consults for percutaneous gastrostomy (PEG) tube placement for a patient ...

• With dysphagia after stroke: A 70-year-old female with a history of hypertension presented to the hospital with altered mental status and left-sided weakness. She was previously active and independently living. MRI of the brain revealed a right basal ganglia infarct. As a result, she developed dysphagia. She was evaluated by speech and language pathology and underwent a modified barium swallow. Given concerns for aspiration, the recommendation was made for gastroenterology (GI) consultation to place PEG tube for nutrition and medication administration.
• With advanced dementia: An 85-year-old male with an extensive medical history including advanced dementia was admitted from his nursing home for decreased oral intake. His baseline mental status is awake and alert, but he is nonverbal and does not follow commands. Upon 72-hour calorie count, the nutrition consultants determined that he cannot independently meet his nutrition goals. His family wants “everything done” and are asking about a “feeding tube.” The primary team has now consulted GI for PEG tube placement.
• Who is being discharged to a long-term care facility: A 45-year-old male was admitted to the ICU after a heroin overdose. CPR was initiated in the field and return of spontaneous circulation was obtained after 25 minutes. The patient has minimal brainstem reflexes. He is ventilator dependent. He has no family, and now is status-post tracheostomy placement by two-physician consent. The patient is ready for discharge to a long-term care facility that will not accept patients with nasogastric tubes. GI is consulted for PEG tube placement.

Discussion

Gastroenterologists are often consulted for PEG tube placement. However, the circumstances surrounding and the implications of PEG tube placement are often complicated for reasons beyond nutritional or technical considerations. This is rooted in the fact that, as one expert wrote, “feeding, unlike any other medical treatment, has a moral and emotional significance derived from culture.”¹ Understanding the evidence, ethical considerations, and team dynamic behind PEG tube placement is critical for every gastroenterologist. Herein we review these topics and offer guidelines for having patient-centered conversations involving these fundamental concepts.

courtesy Paul Nguyen

First, the gastroenterologist should understand the evidence to debunk myths and clarify truths surrounding PEG tube placement. While PEG tubes may help patients with amyotrophic lateral sclerosis stabilize their weight and can even be prophylactically placed in select patients with head and neck cancer,^2,3 they are not always appropriate in patients in early recovery from stroke and have not been shown to improve outcomes in patients with advanced dementia. At least 50% of stroke-related dysphagia resolves within 1-2 weeks, and so the American Heart Association Stroke Council recommends continuing nasogastric tube feeding for 2-3 weeks in patients such as the one presented in case 1 before considering PEG tube placement.⁴

In situations of advanced dementia such as in case,² several studies demonstrate that PEG tubes do not reduce or prevent aspiration pneumonia, prevent consequences of malnutrition, prolong life, reduce pressure ulcers, reduce urinary of gastrointestinal tract infections, lead to functional improvement, mitigate decline, or even improve comfort or quality of life for patients or their caregivers.^5-7 Despite this evidence, as demonstrated in case,³ it is true that many American skilled nursing facilities will not accept a patient without a PEG if enteral feeding is needed. This restriction may vary by state: One study found that skilled nursing facilities in New York City are much less likely to accept patients with nasogastric feeding tubes than randomly selected skilled nursing facilities throughout the country.⁶ Nonetheless, gastroenterologists should look to the literature to understand the outcomes of populations of patients after PEG tube placement and use that data to guide decision-making.

courtesy Ohio State University Wexner Medical Center

Secondly, the five ethical principles that inform all medical decision making – autonomy, beneficence, nonmaleficence, justice, and futility – should also inform the gastroenterologist’s rationale in offering PEG placement.⁸

Autonomy implies that the medical team has determined who is able to make the decision regarding PEG tube placement for the patient. Beneficence connects the patient’s medical diagnosis and technical parameters of PEG tube placement with his or her goals of care. Nonmaleficence ensures the decision-making party understands the benefits and risks of the procedure, including anticipatory guidance on possible PEG tube management, complications, risks, and need for replacement. Justice incorporates the context of the patient’s life, including family dynamics, religious, cultural, and financial factors. Futility connects the patient’s prognosis with practical aspects of having a PEG tube.

The complexity of PEG placement lies in the fact that these ethical principles are often at odds with each other. For example, case 2 highlights the conflicting principles of autonomy and futility for elderly dementia patients: While PEG tube placements do not improve comfort or quality of life in advanced dementia (futility), the family representing the patient has stated they want everything done for his care, including PEG tube placement (autonomy). Navigating these ethical principles can be difficult, but having a framework to organize the different factors offers sound guidance for the gastroenterologist.

courtesy Rusty Schramm

Finally, the gastroenterologist should recognize the roles of the multidisciplinary team members, including the patient and their representatives, regarding PEG tube placement consults. While gastroenterologists can be viewed as the technicians consulted to simply “place the tube,” they must seek to understand the members of the team representing the patient to be stewards of their skill set. Consulting team physicians carry great responsibility in organizing the medical and psychosocial aspects of each patient’s care, and their proper goals to relieve suffering and prevent death may color their judgment regarding who they believe is a candidate for a PEG tube. Nutritionists, speech therapists, and case managers can help provide objective data on the practicality and feasibility of a PEG tube in their patients. The healthcare system may influence the decision to consult heavily, as seen in the rules of the long-term care facility in case.³ While it is the job of the multidisciplinary medical team to explain the evidence and ethical considerations of PEG tube placement in a patient-centered manner, ultimately the decision belongs to the patient and their family or representatives.

The moral burden of not pursuing PEG placement may supersede the medical advice in many situations. There is an emotionally taxing perception that withholding nutrition via PEG is “starving the patient,” despite literature showing many terminally ill patients do not experience thirst or hunger, and those who do have alleviation of these symptoms with small amounts of food or liquid, not with PEG placement.⁵ As every patient is unique, PEG tube consultation guidelines created with input from all stakeholders have been utilized to ensure that patients are medically optimized for PEG tube placement and that evidence and ethics-based considerations are evaluated by the multidisciplinary team. An example of such a guideline is shown in Figure 1.

courtesy Dr. Emily Seltzer

If the gastroenterologist encounters more contentious consultations, there are ways to build consensus to both alleviate patient and family suffering as well as elevate the discussions between teams.

First, identify the type of consult that is repeatedly bringing differing viewpoints and differing ethical principles into play. Second, get representatives from teams together in a neutral environment to understand stakeholders needs. New data suggest, in stroke cases like case 1, there may be dramatic benefit in long-term ability to recover if patients can get early intensive rehabilitation.⁹ This intense daily rehabilitation is not available within the hospital setting at many locations, and facilitation of discharge may be requested earlier than usually advised tube placement. Third, build a common language for requests and responses between teams. For instance, neurologists can identify and document which patients have less likelihood of early spontaneous recovery, and this can allow gastroenterologists to understand that those patients with little potential for early swallowing recovery can safely be targeted for PEG earlier during the hospital course. Other patients described as having a potential for spontaneous improvement should be given time to recover before an intervention is considered.¹⁰ Having a common understanding of goals and a better-informed decision pathway helps each team member feel fulfilled and rewarded, which will ultimately help reduce compassion fatigue and moral burden on providers.

courtesy Robert Wood Johnson University Hospital

In conclusion, PEG tube placement can be a challenging consultation for gastroenterologists because of the clinical, social, and ethical ramifications at stake for the patient. Even when PEG tube placement is technically feasible, the gastroenterologist should feel empowered to address the evidence-based outcomes of PEG tube placement, discuss the ethical principles of the decision-making process, and communicate with a multidisciplinary team using guidelines as set forth by this paper to best serve the patient.

Dr. Seltzer is based in the Department of Internal Medicine, Mount Sinai Morningside-West, New York City. Dr. Pusateri is based in the Division of Gastroenterology, Hepatology and Nutrition, Ohio State University Wexner Medical Center, Columbus. Dr. Nguyen is based in the Division of Gastroenterology and Center for Esophageal Diseases, Baylor Scott & White Health, Dallas, Texas. Dr. Stein is based in the Division of Gastroenterology, Robert Wood Johnson University Hospital, Rutgers University, New Brunswick, New Jersey. All authors contributed equally to this manuscript, and have no disclosures related to this article.

References

1. Mackie S. Gastroenterol Nurs. 2001 May-Jun;24(3):138-42.

2. Miller RG et al. Neurology. 2009 Oct. doi: 10.1212/WNL.0b013e3181bc0141.

3. Colevas AD et al. J Natl Compr Canc Netw. 2018 May. doi: 10.6004/jnccn.2018.0026.

4. Holloway RG et al. Stroke. 2014 Jun. doi: 10.1161/STR.0000000000000015.

5. Finucane TE et al. JAMA. 1999 Oct. doi: 10.1001/jama.282.14.1365.

6. Burgermaster M et al. Nutr Clin Pract. 2016 Jun. doi: 10.1177/0884533616629636.

7. American Geriatrics Society Ethics C, Clinical P, Models of Care C. J Am Geriatr Soc. 2014 Aug. doi: 10.1111/jgs.12924.

8. Beauchamp TL. Principlism in Bioethics. In: Serna P, eds. Bioethical Decision Making and Argumentation. International Library of Ethics, Law, and the New Medicine, vol 70. Springer; Cham. 2016 Sept:1-16. doi: 10.1007/978-3-319-43419-3_1.

9. Powers WJ et al. Stroke. 2019 Oct. doi: 10.1161/STR.0000000000000211.

10. Galovic M et al. JAMA Neurol. 2019 May. doi: 10.1001/jamaneurol.2018.4858.

Cases

Consults for percutaneous gastrostomy (PEG) tube placement for a patient ...

• With dysphagia after stroke: A 70-year-old female with a history of hypertension presented to the hospital with altered mental status and left-sided weakness. She was previously active and independently living. MRI of the brain revealed a right basal ganglia infarct. As a result, she developed dysphagia. She was evaluated by speech and language pathology and underwent a modified barium swallow. Given concerns for aspiration, the recommendation was made for gastroenterology (GI) consultation to place PEG tube for nutrition and medication administration.
• With advanced dementia: An 85-year-old male with an extensive medical history including advanced dementia was admitted from his nursing home for decreased oral intake. His baseline mental status is awake and alert, but he is nonverbal and does not follow commands. Upon 72-hour calorie count, the nutrition consultants determined that he cannot independently meet his nutrition goals. His family wants “everything done” and are asking about a “feeding tube.” The primary team has now consulted GI for PEG tube placement.
• Who is being discharged to a long-term care facility: A 45-year-old male was admitted to the ICU after a heroin overdose. CPR was initiated in the field and return of spontaneous circulation was obtained after 25 minutes. The patient has minimal brainstem reflexes. He is ventilator dependent. He has no family, and now is status-post tracheostomy placement by two-physician consent. The patient is ready for discharge to a long-term care facility that will not accept patients with nasogastric tubes. GI is consulted for PEG tube placement.

Discussion

Gastroenterologists are often consulted for PEG tube placement. However, the circumstances surrounding and the implications of PEG tube placement are often complicated for reasons beyond nutritional or technical considerations. This is rooted in the fact that, as one expert wrote, “feeding, unlike any other medical treatment, has a moral and emotional significance derived from culture.”¹ Understanding the evidence, ethical considerations, and team dynamic behind PEG tube placement is critical for every gastroenterologist. Herein we review these topics and offer guidelines for having patient-centered conversations involving these fundamental concepts.

courtesy Paul Nguyen

First, the gastroenterologist should understand the evidence to debunk myths and clarify truths surrounding PEG tube placement. While PEG tubes may help patients with amyotrophic lateral sclerosis stabilize their weight and can even be prophylactically placed in select patients with head and neck cancer,^2,3 they are not always appropriate in patients in early recovery from stroke and have not been shown to improve outcomes in patients with advanced dementia. At least 50% of stroke-related dysphagia resolves within 1-2 weeks, and so the American Heart Association Stroke Council recommends continuing nasogastric tube feeding for 2-3 weeks in patients such as the one presented in case 1 before considering PEG tube placement.⁴

In situations of advanced dementia such as in case,² several studies demonstrate that PEG tubes do not reduce or prevent aspiration pneumonia, prevent consequences of malnutrition, prolong life, reduce pressure ulcers, reduce urinary of gastrointestinal tract infections, lead to functional improvement, mitigate decline, or even improve comfort or quality of life for patients or their caregivers.^5-7 Despite this evidence, as demonstrated in case,³ it is true that many American skilled nursing facilities will not accept a patient without a PEG if enteral feeding is needed. This restriction may vary by state: One study found that skilled nursing facilities in New York City are much less likely to accept patients with nasogastric feeding tubes than randomly selected skilled nursing facilities throughout the country.⁶ Nonetheless, gastroenterologists should look to the literature to understand the outcomes of populations of patients after PEG tube placement and use that data to guide decision-making.

courtesy Ohio State University Wexner Medical Center

Secondly, the five ethical principles that inform all medical decision making – autonomy, beneficence, nonmaleficence, justice, and futility – should also inform the gastroenterologist’s rationale in offering PEG placement.⁸

Autonomy implies that the medical team has determined who is able to make the decision regarding PEG tube placement for the patient. Beneficence connects the patient’s medical diagnosis and technical parameters of PEG tube placement with his or her goals of care. Nonmaleficence ensures the decision-making party understands the benefits and risks of the procedure, including anticipatory guidance on possible PEG tube management, complications, risks, and need for replacement. Justice incorporates the context of the patient’s life, including family dynamics, religious, cultural, and financial factors. Futility connects the patient’s prognosis with practical aspects of having a PEG tube.

The complexity of PEG placement lies in the fact that these ethical principles are often at odds with each other. For example, case 2 highlights the conflicting principles of autonomy and futility for elderly dementia patients: While PEG tube placements do not improve comfort or quality of life in advanced dementia (futility), the family representing the patient has stated they want everything done for his care, including PEG tube placement (autonomy). Navigating these ethical principles can be difficult, but having a framework to organize the different factors offers sound guidance for the gastroenterologist.

courtesy Rusty Schramm

Finally, the gastroenterologist should recognize the roles of the multidisciplinary team members, including the patient and their representatives, regarding PEG tube placement consults. While gastroenterologists can be viewed as the technicians consulted to simply “place the tube,” they must seek to understand the members of the team representing the patient to be stewards of their skill set. Consulting team physicians carry great responsibility in organizing the medical and psychosocial aspects of each patient’s care, and their proper goals to relieve suffering and prevent death may color their judgment regarding who they believe is a candidate for a PEG tube. Nutritionists, speech therapists, and case managers can help provide objective data on the practicality and feasibility of a PEG tube in their patients. The healthcare system may influence the decision to consult heavily, as seen in the rules of the long-term care facility in case.³ While it is the job of the multidisciplinary medical team to explain the evidence and ethical considerations of PEG tube placement in a patient-centered manner, ultimately the decision belongs to the patient and their family or representatives.

The moral burden of not pursuing PEG placement may supersede the medical advice in many situations. There is an emotionally taxing perception that withholding nutrition via PEG is “starving the patient,” despite literature showing many terminally ill patients do not experience thirst or hunger, and those who do have alleviation of these symptoms with small amounts of food or liquid, not with PEG placement.⁵ As every patient is unique, PEG tube consultation guidelines created with input from all stakeholders have been utilized to ensure that patients are medically optimized for PEG tube placement and that evidence and ethics-based considerations are evaluated by the multidisciplinary team. An example of such a guideline is shown in Figure 1.

courtesy Dr. Emily Seltzer

If the gastroenterologist encounters more contentious consultations, there are ways to build consensus to both alleviate patient and family suffering as well as elevate the discussions between teams.

First, identify the type of consult that is repeatedly bringing differing viewpoints and differing ethical principles into play. Second, get representatives from teams together in a neutral environment to understand stakeholders needs. New data suggest, in stroke cases like case 1, there may be dramatic benefit in long-term ability to recover if patients can get early intensive rehabilitation.⁹ This intense daily rehabilitation is not available within the hospital setting at many locations, and facilitation of discharge may be requested earlier than usually advised tube placement. Third, build a common language for requests and responses between teams. For instance, neurologists can identify and document which patients have less likelihood of early spontaneous recovery, and this can allow gastroenterologists to understand that those patients with little potential for early swallowing recovery can safely be targeted for PEG earlier during the hospital course. Other patients described as having a potential for spontaneous improvement should be given time to recover before an intervention is considered.¹⁰ Having a common understanding of goals and a better-informed decision pathway helps each team member feel fulfilled and rewarded, which will ultimately help reduce compassion fatigue and moral burden on providers.

courtesy Robert Wood Johnson University Hospital

In conclusion, PEG tube placement can be a challenging consultation for gastroenterologists because of the clinical, social, and ethical ramifications at stake for the patient. Even when PEG tube placement is technically feasible, the gastroenterologist should feel empowered to address the evidence-based outcomes of PEG tube placement, discuss the ethical principles of the decision-making process, and communicate with a multidisciplinary team using guidelines as set forth by this paper to best serve the patient.

Dr. Seltzer is based in the Department of Internal Medicine, Mount Sinai Morningside-West, New York City. Dr. Pusateri is based in the Division of Gastroenterology, Hepatology and Nutrition, Ohio State University Wexner Medical Center, Columbus. Dr. Nguyen is based in the Division of Gastroenterology and Center for Esophageal Diseases, Baylor Scott & White Health, Dallas, Texas. Dr. Stein is based in the Division of Gastroenterology, Robert Wood Johnson University Hospital, Rutgers University, New Brunswick, New Jersey. All authors contributed equally to this manuscript, and have no disclosures related to this article.

References

1. Mackie S. Gastroenterol Nurs. 2001 May-Jun;24(3):138-42.

2. Miller RG et al. Neurology. 2009 Oct. doi: 10.1212/WNL.0b013e3181bc0141.

3. Colevas AD et al. J Natl Compr Canc Netw. 2018 May. doi: 10.6004/jnccn.2018.0026.

4. Holloway RG et al. Stroke. 2014 Jun. doi: 10.1161/STR.0000000000000015.

5. Finucane TE et al. JAMA. 1999 Oct. doi: 10.1001/jama.282.14.1365.

6. Burgermaster M et al. Nutr Clin Pract. 2016 Jun. doi: 10.1177/0884533616629636.

7. American Geriatrics Society Ethics C, Clinical P, Models of Care C. J Am Geriatr Soc. 2014 Aug. doi: 10.1111/jgs.12924.

8. Beauchamp TL. Principlism in Bioethics. In: Serna P, eds. Bioethical Decision Making and Argumentation. International Library of Ethics, Law, and the New Medicine, vol 70. Springer; Cham. 2016 Sept:1-16. doi: 10.1007/978-3-319-43419-3_1.

9. Powers WJ et al. Stroke. 2019 Oct. doi: 10.1161/STR.0000000000000211.

10. Galovic M et al. JAMA Neurol. 2019 May. doi: 10.1001/jamaneurol.2018.4858.

Vitamin D (VD) regulates keratinocyte proliferation and differentiation, modulates inflammatory pathways, and protects against cellular damage in the skin. ¹ In the setting of tissue injury and acute skin inflammation, active vitamin D—1,25(OH) ₂ D—suppresses signaling from pro-inflammatory chemokines and cytokines such as IFN- γ and IL-17. ^2,3 This suppression reduces proliferation of helper T cells (T _H 1, T _H 17) and B cells, decreasing tissue damage from reactive oxygen species release while enhancing secretion of the anti-inflammatory cytokine IL-10 by antigen-presenting cells. ^2-4

Suboptimal VD levels have been associated with numerous health consequences including malignancy, prompting interest in VD supplementation for improving cancer-related outcomes.⁵ Beyond disease prognosis, high-dose VD supplementation has been suggested as a potential therapy for adverse events (AEs) related to cancer treatments. In one study, mice that received oral vitamin D₃ supplementation of 11,500 IU/kg daily had fewer doxorubicin-induced cardiotoxic effects on ejection fraction (P<.0001) and stroke volume (P<.01) than mice that received VD supplementation of 1500 IU/kg daily.⁶

In this review, we examine the impact of chemoradiation on 25(OH)D levels—which more accurately reflects VD stores than 1,25(OH)₂D levels—and the impact of suboptimal VD on cutaneous toxicities related to chemoradiation. To define the suboptimal VD threshold, we used the Endocrine Society’s clinical practice guidelines, which characterize suboptimal 25(OH)D levels as insufficiency (21–29 ng/mL [52.5–72.5 nmol/L]) or deficiency (<20 ng/mL [50 nmol/L])⁷; deficiency can be further categorized as severe deficiency (<12 ng/mL [30 nmol/L]).⁸ This review also evaluates the evidence for vitamin D₃ supplementation to alleviate the cutaneous AEs of chemotherapy and radiation treatments.

Effects of Chemotherapy on Vitamin D Levels

A high prevalence of VD deficiency is seen in various cancers. In a retrospective review of 25(OH)D levels in 2098 adults with solid tumors of any stage (6% had metastatic disease [n=124]), suboptimal levels were found in 69% of patients with breast cancer (n=617), 75% with colorectal cancer (n=84), 72% with gynecologic cancer (n=65), 79% with kidney and bladder cancer (n=145), 83% with pancreatic and upper gastrointestinal tract cancer (n=178), 73% with lung cancer (n=73), 69% with prostate cancer (n=225), 61% with skin cancer (n=399), and 63% with thyroid cancer (n=172).⁵ Suboptimal VD also has been found in hematologic malignancies. In a prospective cohort study, mean serum 25(OH)D levels in 23 patients with recently diagnosed acute myeloid leukemia demonstrated VD deficiency (mean [SD], 18.6 [6.6] nmol/L).⁹ Given that many patients already exhibit a baseline VD deficiency at cancer diagnosis, it is important to understand the relationship between VD and cancer treatment modalities.⁵

In the United States, breast and colorectal cancers were estimated to be the first and fourth most common cancers, with 313,510 and 152,810 predicted new cases in 2024, respectively.¹⁰ This review will focus on breast and colorectal cancer when describing VD variation associated with chemotherapy exposure due to their high prevalence.

Effects of Chemotherapy on Vitamin D Levels in Breast Cancer—Breast cancer studies have shown suboptimal VD levels in 76% of females 75 years or younger with any T1, T2, or T3; N0 or N1; and M0 breast cancer, in which 38.5% (n=197) had insufficient and 37.5% (n=192) had deficient 25(OH)D levels.¹¹ In a study of female patients with primary breast cancer (stage I, II, or III and T1 with high Ki67 expression [≥30%], T2, or T3), VD deficiency was seen in 60% of patients not receiving VD supplementation.^12,13 A systematic review that included 7 studies of different types of breast cancer suggested that circulating 25(OH)D may be associated with improved prognosis.¹⁴ Thus, studies have investigated risk factors associated with poor or worsening VD status in individuals with breast cancer, including exposure to chemotherapy and/or radiation treatment.^12,15-18

A prospective cohort study assessed 25(OH)D levels in 95 patients with any breast cancer (stages I, II, IIIA, IIIB) before and after initiating chemotherapy with docetaxel, doxorubicin, epirubicin, 5-fluorouracil, or cyclophosphamide, compared with a group of 52 females without cancer.¹⁷ In the breast cancer group, approximately 80% (76/95) had suboptimal and 50% (47/95) had deficient VD levels before chemotherapy initiation (mean [SD], 54.1 [22.8] nmol/L). In the comparison group, 60% (31/52) had suboptimal and 30% (15/52) had deficient VD at baseline (mean [SD], 66.1 [23.5] nmol/L), which was higher than the breast cancer group (P=.03). A subgroup analysis excluded participants who started, stopped, or lacked data on dietary supplements containing VD (n=39); in the remaining 56 participants, a significant decrease in 25(OH)D levels was observed shortly after finishing chemotherapy compared with the prechemotherapy baseline value (mean, −7.9 nmol/L; P=.004). Notably, 6 months after chemotherapy completion, 25(OH)D levels increased (mean, +12.8 nmol/L; P<.001). Vitamin D levels remained stable in the comparison group (P=.987).¹⁷

Consistent with these findings, a cross-sectional study assessing VD status in 394 female patients with primary breast cancer (stage I, II, or III and T1 with high Ki67 expression [≥30%], T2, or T3), found that a history of chemotherapy was associated with increased odds of 25(OH)D levels less than 20 ng/mL compared with breast cancer patients with no prior chemotherapy (odds ratio, 1.86; 95% CI, 1.03-3.38).¹² Although the study data included chemotherapy history, no information was provided on specific chemotherapy agents or regimens used in this cohort, limiting the ability to detect the drugs most often implicated.

Both studies indicated a complex interplay between chemotherapy and VD levels in breast cancer patients. Although Kok et al¹⁷ suggested a transient decrease in VD levels during chemotherapy with a subsequent recovery after cessation, Fassio et al¹² highlighted the increased odds of VD deficiency associated with chemotherapy. Ultimately, larger randomized controlled trials are needed to better understand the relationship between chemotherapy and VD status in breast cancer patients.

Effects of Chemotherapy on Vitamin D Levels in Colorectal Cancer—Similar to patterns seen in breast cancer, a systematic review with 6 studies of different types of colorectal cancer suggested that circulating 25(OH)D levels may be associated with prognosis.¹⁴ Studies also have investigated the relationship between colorectal chemotherapy regimens and VD status.^15,16,18,19

A retrospective study assessed 25(OH)D levels in 315 patients with any colorectal cancer (stage I–IV).¹⁵ Patients were included in the analysis if they received less than 400 IU daily of VD supplementation at baseline. For the whole study sample, the mean (SD) VD level was 23.7 (13.71) ng/mL. Patients who had not received chemotherapy within 3 months of the VD level assessment were categorized as the no chemotherapy group, and the others were designated as the chemotherapy group; the latter group was exposed to various chemotherapy regimens, including combinations of irinotecan, oxaliplatin, 5-fluorouracil, leucovorin, bevacizumab, or cetuximab. Multivariate analysis showed that the chemotherapy group was 3.7 times more likely to have very low VD levels (≤15 ng/mL) compared with those in the no chemotherapy group (P<.0001).¹⁵

A separate cross-sectional study examined serum 25(OH)D concentrations in 1201 patients with any newly diagnosed colorectal carcinoma (stage I–III); 91% of cases were adenocarcinoma.¹⁸ In a multivariate analysis, chemotherapy plus surgery was associated with lower VD levels than surgery alone 6 months after diagnosis (mean, −8.74 nmol/L; 95% CI, −11.30 to −6.18 nmol/L), specifically decreasing by a mean of 6.7 nmol/L (95% CI, −9.8 to −3.8 nmol/L) after adjusting for demographic and lifestyle factors.¹⁸ However, a prospective cohort study demonstrated different findings.¹⁹ Comparing 58 patients with newly diagnosed colorectal adenocarcinoma (stages I–IV) who underwent chemotherapy and 36 patients who did not receive chemotherapy, there was no significant change in 25(OH)D levels from the time of diagnosis to 6 months later. Median VD levels decreased by 0.7 ng/mL in those who received chemotherapy, while a minimal (and not significant) increase of 1.6 ng/mL was observed in those without chemotherapy intervention (P=.26). Notably, supplementation was not restricted in this cohort, which may have resulted in higher VD levels in those taking supplements.¹⁹

Since time of year and geographic location can influence VD levels, one prospective cohort study controlled for differential sun exposure due to these factors in their analysis.¹⁶ Assessment of 25(OH)D levels was completed in 81 chemotherapy-naïve cancer patients immediately before beginning chemotherapy as well as 6 and 12 weeks into treatment. More than 8 primary cancer types were represented in this study, with breast (34% [29/81]) and colorectal (14% [12/81]) cancer being the most common, but the cancer stages of the participants were not detailed. Vitamin D levels decreased after commencing chemotherapy, with the largest drop occurring 6 weeks into treatment. From the 6- to 12-week end points, VD increased but remained below the original baseline level (baseline: mean [SD], 49.2 [22.3] nmol/L; 6 weeks: mean [SD], 40.9 [19.0] nmol/L; 12 weeks: mean [SD], 45.9 [19.7] nmol/L; P=.05).¹⁶

Although focused on breast and colorectal cancers, these studies suggest that various chemotherapy regimens may confer a higher risk for VD deficiency compared with VD status at diagnosis and/or prior to chemotherapy treatment. However, most of these studies only discussed stage-based differences, excluding analysis of the variety of cancer subtypes that comprise breast and colorectal malignancies, which may limit our ability to extrapolate from these data. Ultimately, larger randomized controlled trials are needed to better understand the relationship between chemotherapy and VD status across various primary cancer types.

Effects of Radiation Therapy on Vitamin D Levels

Unlike chemotherapy, studies on the association between radiation therapy and VD levels are minimal, with most reports in the literature discussing the use of VD to potentiate the effects of radiation therapy. In one cross-sectional analysis of 1201 patients with newly diagnosed stage I, II, or III colorectal cancer of any type (94% were adenocarcinoma), radiation plus surgery was associated with slightly lower 25(OH)D levels than surgery alone for tumor treatment 6 months after diagnosis (mean, −3.17; 95% CI, −6.07 to −0.28 nmol/L). However, after adjustment for demographic and lifestyle factors, this decrease in VD levels attributable to radiotherapy was not statistically significant compared with the surgery-only cohort (mean, −1.78; 95% CI, −5.07 to 1.52 nmol/L).¹⁸

Similarly, a cross-sectional study assessing VD status in 394 female patients with primary breast cancer (stage I, II, or III and T1 with high Ki67 expression [≥30%], T2, or T3), found that a history of radiotherapy was not associated with a difference in serum 25(OH)D levels compared with those with breast cancer without prior radiotherapy (odds ratio, 0.90; 95% CI, 0.52-1.54).¹² From the limited existing literature specifically addressing variations of VD levels with radiation, radiation therapy does not appear to significantly impact VD levels.

Vitamin D Levels and the Severity of Chemotherapy- or Radiation Therapy–Induced AEs

A prospective cohort of 241 patients did not find an increase in the incidence or severity of chemotherapy-induced cutaneous toxicities in those with suboptimal 1,25(OH)₂D₃ levels (≤75 nmol/L).²⁰ Eight different primary cancer types were represented, including breast and colorectal cancer; the tumor stages of the participants were not detailed. Forty-one patients had normal 1,25(OH)₂D₃ levels, while the remaining 200 had suboptimal levels. There was no significant association between serum VD levels and the following dermatologic toxicities: desquamation (P=.26), xerosis (P=.15), mucositis (P=.30), or painful rash (P=.87). Surprisingly, nail changes and hand-foot reactions occurred with greater frequency in patients with normal VD levels (P=.01 and P=.03, respectively).²⁰ Hand-foot reaction is part of the toxic erythema of chemotherapy (TEC) spectrum, which is comprised of a range of cytotoxic skin injuries that typically manifest within 2 to 3 weeks of exposure to the offending chemotherapeutic agents, often characterized by erythema, pain, swelling, and blistering, particularly in intertriginous and acral areas.^21-23 Recovery from TEC generally takes at least 2 to 4 weeks and may necessitate cessation of the offending chemotherapeutic agent.^21,24 Notably, this study measured 1,25(OH)₂D₃ levels instead of 25(OH)D levels, which may not reliably indicate body stores of VD.^7,20 These results underscore the complex nature between chemotherapy and VD; however, VD levels alone do not appear to be a sufficient biomarker for predicting chemotherapy-associated cutaneous AEs.

Interestingly, radiation therapy–induced AEs may be associated with VD levels. A prospective cohort study of 98 patients with prostate, bladder, or gynecologic cancers (tumor stages were not detailed) undergoing pelvic radiotherapy found that females and males with 25(OH)D levels below a threshold of 35 and 40 nmol/L, respectively, were more likely to experience higher Radiation Therapy Oncology Group (RTOG) grade acute proctitis compared with those with VD above these thresholds.²⁵ Specifically, VD below these thresholds was associated with increased odds of RTOG grade 2 or higher radiation-induced proctitis (OR, 3.07; 95% CI, 1.27-7.50 [P=.013]). Additionally, a weak correlation was noted between VD below these thresholds and the RTOG grade, with a Spearman correlation value of −0.189 (P=.031).²⁵

One prospective cohort study included 28 patients with any cancer of the oral cavity, oropharynx, hypopharynx, or larynx stages II, III, or IVA; 93% (26/28) were stage III or IVA.²⁶ The 20 (71%) patients with suboptimal 25(OH)D levels (≤75 nmol/L) experienced a higher prevalence of grade II radiation dermatitis compared with the 8 (29%) patients with optimal VD levels (χ²₂=5.973; P=.0505). This pattern persisted with the severity of mucositis; patients from the suboptimal VD group presented with higher rates of grades II and III mucositis compared with the VD optimal group (χ²₂=13.627; P=.0011).²⁶ Recognizing the small cohort evaluated in the study, we highlight the importance of further studies to clarify these associations.

Chemotherapy-Induced Cutaneous Events Treated with High-Dose Vitamin D

Chemotherapeutic agents are known to induce cellular damage, resulting in a range of cutaneous AEs that can invoke discontinuation of otherwise effective chemotherapeutic interventions.^27,28 Recent research has explored the potential of high-dose vitamin D₃ as a therapeutic agent to mitigate cutaneous reactions.^29,30

A randomized, double-blind, placebo-controlled trial investigated the use of a single high dose of oral ­25(OH)D to treat topical nitrogen mustard (NM)–induced rash.²⁹ To characterize baseline inflammatory responses from NM injury without intervention, clinical measures, serum studies, and tissue analyses from skin biopsies were performed on 28 healthy adults after exposure to topical NM—a chemotherapeutic agent classified as a DNA alkylator. Two weeks later, participants were exposed to topical NM a second time and were split into 2 groups: 14 patients received a single 200,000-IU dose of oral 25(OH)D while the other 14 participants were given a placebo. Using the inflammatory markers induced from baseline exposure to NM alone, posttreatment analysis revealed that the punch biopsies from the 25(OH)D group expressed fewer NM-induced inflammatory markers compared with the placebo group at both 72 hours and 6 weeks following NM injury (72 hours: 12 vs 17 inflammatory markers; 6 weeks: 4 vs 11 inflammatory markers). Notably, NM inflammatory markers were enriched for IL-17 signaling pathways in the placebo biopsies but not in the 25(OH)D intervention group. This study also identified mild and severe patterns of inflammatory responses to NM that were independent of the 25(OH)D intervention. Biomarkers specific to skin biopsies from participants with the severe response included CCL20, CCL2, and CXCL8 (adjusted P<.05). At 6 weeks posttreatment, the 25(OH)D group showed a 67% reduction in NM injury markers compared with a 35% reduction in the placebo group. Despite a reduction in tissue inflammatory markers, there were no clinically significant changes observed in skin redness, swelling, or histologic structure when comparing the 25(OH)D- supplemented group to the placebo group at any time during the study, necessitating further research into the mechanistic roles of high doses VD supplementation.²⁹

Although Ernst et al²⁹ did not observe any clinically significant improvements with VD treatment, a case series of 6 patients with either glioblastoma multiforme, acute myeloid leukemia, or aplastic anemia did demonstrate clinical improvement of TEC after receiving high-dose vitamin D₃.³⁰ The mean time to onset of TEC was noted at 8.5 days following administration of the inciting chemotherapeutic agent, which included combinations of anthracycline, antimetabolite, kinase inhibitor, B-cell lymphoma 2 inhibitor, purine analogue, and alkylating agents. A combination of clinical and histologic findings was used to diagnose TEC. Baseline 25(OH)D levels were not established prior to treatment. The treatment regimen for 1 patient included 2 doses of 50,000 IU of VD spaced 1 week apart, totaling 100,000 IU, while the remaining 5 patients received a total of 200,000 IU, also split into 2 doses given 1 week apart. All patients received their first dose of VD within a week of the cutaneous eruption. Following the initial VD dose, there was a notable improvement in pain, pruritus, or swelling by the next day. Reduction in erythema also was observed within 1 to 4 days.³⁰

No AEs associated with VD supplementation were reported, suggesting a potential beneficial role of high-dose VD in accelerating recovery from chemotherapy-induced rashes without evident safety concerns.

Radiation Therapy–Induced Cutaneous Events Treated with High-Dose Vitamin D

Radiation dermatitis is a common and often severe complication of radiation therapy that affects more than 90% of patients undergoing treatment, with half of these individuals experiencing grade 2 toxicity, according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events.^31,32 Radiation damage to basal keratinocytes and hair follicle stem cells disrupts the renewal of the skin’s outer layer, while a surge of free radicals causes irreversible DNA damage.³³ Symptoms of radiation dermatitis can vary from mild pink erythema to tissue ulceration and necrosis, typically within 1 to 4 weeks of radiation exposure.³⁴ The resulting dermatitis can take 2 to 4 weeks to heal, notably impacting patient quality of life and often necessitating modifications or interruptions in cancer therapy.³³

Prior studies have demonstrated the use of high-dose VD to improve the healing of UV-irradiated skin. A randomized controlled trial investigated high-dose vitamin D₃ to treat experimentally induced sunburn in 20 healthy adults. Compared with those who received a placebo, participants receiving the oral dose of 200,000 IU of vitamin D₃ demonstrated suppression of the pro-inflammatory mediators tumor necrosis factor α (P=.04) and inducible nitric oxide synthase (P=.02), while expression of tissue repair enhancer arginase 1 was increased (P<.005).³⁵ The mechanism of this enhanced tissue repair was investigated using a mouse model, in which intraperitoneal 25(OH)D was administered following severe UV-induced skin injury. On immunofluorescence microscopy, mice treated with VD showed enhanced autophagy within the macrophages infiltrating UV-irradiated skin.³⁶ The use of high-dose VD to treat UV-irradiated skin in these studies established a precedent for using VD to heal cutaneous injury caused by ionizing radiation therapy.

Some studies have focused on the role of VD for treating acute radiation dermatitis. A study of 23 patients with ductal carcinoma in situ or localized invasive ductal carcinoma breast cancer compared the effectiveness of topical calcipotriol to that of a standard hydrating ointment.³⁷ Participants were randomized to 1 of 2 treatments before starting adjuvant radiotherapy to evaluate their potential in preventing radiation dermatitis. In 87% (20/23) of these patients, no difference in skin reaction was observed between the 2 treatments, suggesting that topical VD application may not offer any advantage over the standard hydrating ointment for the prevention of radiation dermatitis.³⁷

Benefits of high-dose oral VD for treating radiation dermatitis also have been reported. Nguyen et al³⁸ documented 3 cases in which patients with neuroendocrine carcinoma of the pancreas, tonsillar carcinoma, and breast cancer received 200,000 IU of oral ergocalciferol distributed over 2 doses given 7 days apart for radiation dermatitis. These patients experienced substantial improvements in pain, swelling, and redness within a week of the initial dose. Additionally, a case of radiation recall dermatitis, which occurred a week after vinorelbine chemotherapy, was treated with 2 doses totaling 100,000 IU of oral ergocalciferol. This patient also had improvement in pain and swelling but continued to have tumor-related induration and ulceration.³⁹

Although topical VD did not show significant benefits over standard treatments for radiation dermatitis, high-dose oral VD appears promising in improving patient outcomes of pain and swelling more rapidly than current practices. Further research is needed to confirm these findings and establish standardized treatment protocols.

Final Thoughts

Suboptimal VD levels are prevalent in numerous cancer types. Chemotherapy often is associated with acute, potentially transient worsening of VD status in patients with breast and colorectal cancer. Although 25(OH)D levels have not corresponded with increased frequency of ­chemotherapy-related dermatologic AEs, suboptimal 25(OH)D levels appear to be associated with increased severity of radiation-induced mucositis and dermatitis.^20,25,26 The use of high-dose VD as a therapeutic agent shows promise in mitigating chemotherapy-induced and radiation therapy–induced rashes in multiple cancer types with reduction of inflammatory markers and a durable anti-inflammatory impact. Although the mechanisms of cellular injury vary among chemotherapeutic agents, the anti-inflammatory and tissue repair properties of VD may make it an effective treatment for chemotherapy-induced cutaneous damage regardless of injury mechanism.^2-4,35 However, reports of clinical improvement vary, and further objective studies to classify optimal dosing, administration, and outcome measures are needed. The absence of reported AEs associated with high-dose VD supplementation is encouraging, but selection of a safe and optimal dosing regimen can only occur with dedicated clinical trials.

Vitamin D (VD) regulates keratinocyte proliferation and differentiation, modulates inflammatory pathways, and protects against cellular damage in the skin. ¹ In the setting of tissue injury and acute skin inflammation, active vitamin D—1,25(OH) ₂ D—suppresses signaling from pro-inflammatory chemokines and cytokines such as IFN- γ and IL-17. ^2,3 This suppression reduces proliferation of helper T cells (T _H 1, T _H 17) and B cells, decreasing tissue damage from reactive oxygen species release while enhancing secretion of the anti-inflammatory cytokine IL-10 by antigen-presenting cells. ^2-4

Suboptimal VD levels have been associated with numerous health consequences including malignancy, prompting interest in VD supplementation for improving cancer-related outcomes.⁵ Beyond disease prognosis, high-dose VD supplementation has been suggested as a potential therapy for adverse events (AEs) related to cancer treatments. In one study, mice that received oral vitamin D₃ supplementation of 11,500 IU/kg daily had fewer doxorubicin-induced cardiotoxic effects on ejection fraction (P<.0001) and stroke volume (P<.01) than mice that received VD supplementation of 1500 IU/kg daily.⁶

In this review, we examine the impact of chemoradiation on 25(OH)D levels—which more accurately reflects VD stores than 1,25(OH)₂D levels—and the impact of suboptimal VD on cutaneous toxicities related to chemoradiation. To define the suboptimal VD threshold, we used the Endocrine Society’s clinical practice guidelines, which characterize suboptimal 25(OH)D levels as insufficiency (21–29 ng/mL [52.5–72.5 nmol/L]) or deficiency (<20 ng/mL [50 nmol/L])⁷; deficiency can be further categorized as severe deficiency (<12 ng/mL [30 nmol/L]).⁸ This review also evaluates the evidence for vitamin D₃ supplementation to alleviate the cutaneous AEs of chemotherapy and radiation treatments.

Effects of Chemotherapy on Vitamin D Levels

A high prevalence of VD deficiency is seen in various cancers. In a retrospective review of 25(OH)D levels in 2098 adults with solid tumors of any stage (6% had metastatic disease [n=124]), suboptimal levels were found in 69% of patients with breast cancer (n=617), 75% with colorectal cancer (n=84), 72% with gynecologic cancer (n=65), 79% with kidney and bladder cancer (n=145), 83% with pancreatic and upper gastrointestinal tract cancer (n=178), 73% with lung cancer (n=73), 69% with prostate cancer (n=225), 61% with skin cancer (n=399), and 63% with thyroid cancer (n=172).⁵ Suboptimal VD also has been found in hematologic malignancies. In a prospective cohort study, mean serum 25(OH)D levels in 23 patients with recently diagnosed acute myeloid leukemia demonstrated VD deficiency (mean [SD], 18.6 [6.6] nmol/L).⁹ Given that many patients already exhibit a baseline VD deficiency at cancer diagnosis, it is important to understand the relationship between VD and cancer treatment modalities.⁵

In the United States, breast and colorectal cancers were estimated to be the first and fourth most common cancers, with 313,510 and 152,810 predicted new cases in 2024, respectively.¹⁰ This review will focus on breast and colorectal cancer when describing VD variation associated with chemotherapy exposure due to their high prevalence.

Effects of Chemotherapy on Vitamin D Levels in Breast Cancer—Breast cancer studies have shown suboptimal VD levels in 76% of females 75 years or younger with any T1, T2, or T3; N0 or N1; and M0 breast cancer, in which 38.5% (n=197) had insufficient and 37.5% (n=192) had deficient 25(OH)D levels.¹¹ In a study of female patients with primary breast cancer (stage I, II, or III and T1 with high Ki67 expression [≥30%], T2, or T3), VD deficiency was seen in 60% of patients not receiving VD supplementation.^12,13 A systematic review that included 7 studies of different types of breast cancer suggested that circulating 25(OH)D may be associated with improved prognosis.¹⁴ Thus, studies have investigated risk factors associated with poor or worsening VD status in individuals with breast cancer, including exposure to chemotherapy and/or radiation treatment.^12,15-18

A prospective cohort study assessed 25(OH)D levels in 95 patients with any breast cancer (stages I, II, IIIA, IIIB) before and after initiating chemotherapy with docetaxel, doxorubicin, epirubicin, 5-fluorouracil, or cyclophosphamide, compared with a group of 52 females without cancer.¹⁷ In the breast cancer group, approximately 80% (76/95) had suboptimal and 50% (47/95) had deficient VD levels before chemotherapy initiation (mean [SD], 54.1 [22.8] nmol/L). In the comparison group, 60% (31/52) had suboptimal and 30% (15/52) had deficient VD at baseline (mean [SD], 66.1 [23.5] nmol/L), which was higher than the breast cancer group (P=.03). A subgroup analysis excluded participants who started, stopped, or lacked data on dietary supplements containing VD (n=39); in the remaining 56 participants, a significant decrease in 25(OH)D levels was observed shortly after finishing chemotherapy compared with the prechemotherapy baseline value (mean, −7.9 nmol/L; P=.004). Notably, 6 months after chemotherapy completion, 25(OH)D levels increased (mean, +12.8 nmol/L; P<.001). Vitamin D levels remained stable in the comparison group (P=.987).¹⁷

Consistent with these findings, a cross-sectional study assessing VD status in 394 female patients with primary breast cancer (stage I, II, or III and T1 with high Ki67 expression [≥30%], T2, or T3), found that a history of chemotherapy was associated with increased odds of 25(OH)D levels less than 20 ng/mL compared with breast cancer patients with no prior chemotherapy (odds ratio, 1.86; 95% CI, 1.03-3.38).¹² Although the study data included chemotherapy history, no information was provided on specific chemotherapy agents or regimens used in this cohort, limiting the ability to detect the drugs most often implicated.

Both studies indicated a complex interplay between chemotherapy and VD levels in breast cancer patients. Although Kok et al¹⁷ suggested a transient decrease in VD levels during chemotherapy with a subsequent recovery after cessation, Fassio et al¹² highlighted the increased odds of VD deficiency associated with chemotherapy. Ultimately, larger randomized controlled trials are needed to better understand the relationship between chemotherapy and VD status in breast cancer patients.

Effects of Chemotherapy on Vitamin D Levels in Colorectal Cancer—Similar to patterns seen in breast cancer, a systematic review with 6 studies of different types of colorectal cancer suggested that circulating 25(OH)D levels may be associated with prognosis.¹⁴ Studies also have investigated the relationship between colorectal chemotherapy regimens and VD status.^15,16,18,19

A retrospective study assessed 25(OH)D levels in 315 patients with any colorectal cancer (stage I–IV).¹⁵ Patients were included in the analysis if they received less than 400 IU daily of VD supplementation at baseline. For the whole study sample, the mean (SD) VD level was 23.7 (13.71) ng/mL. Patients who had not received chemotherapy within 3 months of the VD level assessment were categorized as the no chemotherapy group, and the others were designated as the chemotherapy group; the latter group was exposed to various chemotherapy regimens, including combinations of irinotecan, oxaliplatin, 5-fluorouracil, leucovorin, bevacizumab, or cetuximab. Multivariate analysis showed that the chemotherapy group was 3.7 times more likely to have very low VD levels (≤15 ng/mL) compared with those in the no chemotherapy group (P<.0001).¹⁵

A separate cross-sectional study examined serum 25(OH)D concentrations in 1201 patients with any newly diagnosed colorectal carcinoma (stage I–III); 91% of cases were adenocarcinoma.¹⁸ In a multivariate analysis, chemotherapy plus surgery was associated with lower VD levels than surgery alone 6 months after diagnosis (mean, −8.74 nmol/L; 95% CI, −11.30 to −6.18 nmol/L), specifically decreasing by a mean of 6.7 nmol/L (95% CI, −9.8 to −3.8 nmol/L) after adjusting for demographic and lifestyle factors.¹⁸ However, a prospective cohort study demonstrated different findings.¹⁹ Comparing 58 patients with newly diagnosed colorectal adenocarcinoma (stages I–IV) who underwent chemotherapy and 36 patients who did not receive chemotherapy, there was no significant change in 25(OH)D levels from the time of diagnosis to 6 months later. Median VD levels decreased by 0.7 ng/mL in those who received chemotherapy, while a minimal (and not significant) increase of 1.6 ng/mL was observed in those without chemotherapy intervention (P=.26). Notably, supplementation was not restricted in this cohort, which may have resulted in higher VD levels in those taking supplements.¹⁹

Since time of year and geographic location can influence VD levels, one prospective cohort study controlled for differential sun exposure due to these factors in their analysis.¹⁶ Assessment of 25(OH)D levels was completed in 81 chemotherapy-naïve cancer patients immediately before beginning chemotherapy as well as 6 and 12 weeks into treatment. More than 8 primary cancer types were represented in this study, with breast (34% [29/81]) and colorectal (14% [12/81]) cancer being the most common, but the cancer stages of the participants were not detailed. Vitamin D levels decreased after commencing chemotherapy, with the largest drop occurring 6 weeks into treatment. From the 6- to 12-week end points, VD increased but remained below the original baseline level (baseline: mean [SD], 49.2 [22.3] nmol/L; 6 weeks: mean [SD], 40.9 [19.0] nmol/L; 12 weeks: mean [SD], 45.9 [19.7] nmol/L; P=.05).¹⁶

Although focused on breast and colorectal cancers, these studies suggest that various chemotherapy regimens may confer a higher risk for VD deficiency compared with VD status at diagnosis and/or prior to chemotherapy treatment. However, most of these studies only discussed stage-based differences, excluding analysis of the variety of cancer subtypes that comprise breast and colorectal malignancies, which may limit our ability to extrapolate from these data. Ultimately, larger randomized controlled trials are needed to better understand the relationship between chemotherapy and VD status across various primary cancer types.

Effects of Radiation Therapy on Vitamin D Levels

Unlike chemotherapy, studies on the association between radiation therapy and VD levels are minimal, with most reports in the literature discussing the use of VD to potentiate the effects of radiation therapy. In one cross-sectional analysis of 1201 patients with newly diagnosed stage I, II, or III colorectal cancer of any type (94% were adenocarcinoma), radiation plus surgery was associated with slightly lower 25(OH)D levels than surgery alone for tumor treatment 6 months after diagnosis (mean, −3.17; 95% CI, −6.07 to −0.28 nmol/L). However, after adjustment for demographic and lifestyle factors, this decrease in VD levels attributable to radiotherapy was not statistically significant compared with the surgery-only cohort (mean, −1.78; 95% CI, −5.07 to 1.52 nmol/L).¹⁸

Similarly, a cross-sectional study assessing VD status in 394 female patients with primary breast cancer (stage I, II, or III and T1 with high Ki67 expression [≥30%], T2, or T3), found that a history of radiotherapy was not associated with a difference in serum 25(OH)D levels compared with those with breast cancer without prior radiotherapy (odds ratio, 0.90; 95% CI, 0.52-1.54).¹² From the limited existing literature specifically addressing variations of VD levels with radiation, radiation therapy does not appear to significantly impact VD levels.

Vitamin D Levels and the Severity of Chemotherapy- or Radiation Therapy–Induced AEs

A prospective cohort of 241 patients did not find an increase in the incidence or severity of chemotherapy-induced cutaneous toxicities in those with suboptimal 1,25(OH)₂D₃ levels (≤75 nmol/L).²⁰ Eight different primary cancer types were represented, including breast and colorectal cancer; the tumor stages of the participants were not detailed. Forty-one patients had normal 1,25(OH)₂D₃ levels, while the remaining 200 had suboptimal levels. There was no significant association between serum VD levels and the following dermatologic toxicities: desquamation (P=.26), xerosis (P=.15), mucositis (P=.30), or painful rash (P=.87). Surprisingly, nail changes and hand-foot reactions occurred with greater frequency in patients with normal VD levels (P=.01 and P=.03, respectively).²⁰ Hand-foot reaction is part of the toxic erythema of chemotherapy (TEC) spectrum, which is comprised of a range of cytotoxic skin injuries that typically manifest within 2 to 3 weeks of exposure to the offending chemotherapeutic agents, often characterized by erythema, pain, swelling, and blistering, particularly in intertriginous and acral areas.^21-23 Recovery from TEC generally takes at least 2 to 4 weeks and may necessitate cessation of the offending chemotherapeutic agent.^21,24 Notably, this study measured 1,25(OH)₂D₃ levels instead of 25(OH)D levels, which may not reliably indicate body stores of VD.^7,20 These results underscore the complex nature between chemotherapy and VD; however, VD levels alone do not appear to be a sufficient biomarker for predicting chemotherapy-associated cutaneous AEs.

Interestingly, radiation therapy–induced AEs may be associated with VD levels. A prospective cohort study of 98 patients with prostate, bladder, or gynecologic cancers (tumor stages were not detailed) undergoing pelvic radiotherapy found that females and males with 25(OH)D levels below a threshold of 35 and 40 nmol/L, respectively, were more likely to experience higher Radiation Therapy Oncology Group (RTOG) grade acute proctitis compared with those with VD above these thresholds.²⁵ Specifically, VD below these thresholds was associated with increased odds of RTOG grade 2 or higher radiation-induced proctitis (OR, 3.07; 95% CI, 1.27-7.50 [P=.013]). Additionally, a weak correlation was noted between VD below these thresholds and the RTOG grade, with a Spearman correlation value of −0.189 (P=.031).²⁵

One prospective cohort study included 28 patients with any cancer of the oral cavity, oropharynx, hypopharynx, or larynx stages II, III, or IVA; 93% (26/28) were stage III or IVA.²⁶ The 20 (71%) patients with suboptimal 25(OH)D levels (≤75 nmol/L) experienced a higher prevalence of grade II radiation dermatitis compared with the 8 (29%) patients with optimal VD levels (χ²₂=5.973; P=.0505). This pattern persisted with the severity of mucositis; patients from the suboptimal VD group presented with higher rates of grades II and III mucositis compared with the VD optimal group (χ²₂=13.627; P=.0011).²⁶ Recognizing the small cohort evaluated in the study, we highlight the importance of further studies to clarify these associations.

Chemotherapy-Induced Cutaneous Events Treated with High-Dose Vitamin D

Chemotherapeutic agents are known to induce cellular damage, resulting in a range of cutaneous AEs that can invoke discontinuation of otherwise effective chemotherapeutic interventions.^27,28 Recent research has explored the potential of high-dose vitamin D₃ as a therapeutic agent to mitigate cutaneous reactions.^29,30

A randomized, double-blind, placebo-controlled trial investigated the use of a single high dose of oral ­25(OH)D to treat topical nitrogen mustard (NM)–induced rash.²⁹ To characterize baseline inflammatory responses from NM injury without intervention, clinical measures, serum studies, and tissue analyses from skin biopsies were performed on 28 healthy adults after exposure to topical NM—a chemotherapeutic agent classified as a DNA alkylator. Two weeks later, participants were exposed to topical NM a second time and were split into 2 groups: 14 patients received a single 200,000-IU dose of oral 25(OH)D while the other 14 participants were given a placebo. Using the inflammatory markers induced from baseline exposure to NM alone, posttreatment analysis revealed that the punch biopsies from the 25(OH)D group expressed fewer NM-induced inflammatory markers compared with the placebo group at both 72 hours and 6 weeks following NM injury (72 hours: 12 vs 17 inflammatory markers; 6 weeks: 4 vs 11 inflammatory markers). Notably, NM inflammatory markers were enriched for IL-17 signaling pathways in the placebo biopsies but not in the 25(OH)D intervention group. This study also identified mild and severe patterns of inflammatory responses to NM that were independent of the 25(OH)D intervention. Biomarkers specific to skin biopsies from participants with the severe response included CCL20, CCL2, and CXCL8 (adjusted P<.05). At 6 weeks posttreatment, the 25(OH)D group showed a 67% reduction in NM injury markers compared with a 35% reduction in the placebo group. Despite a reduction in tissue inflammatory markers, there were no clinically significant changes observed in skin redness, swelling, or histologic structure when comparing the 25(OH)D- supplemented group to the placebo group at any time during the study, necessitating further research into the mechanistic roles of high doses VD supplementation.²⁹

Although Ernst et al²⁹ did not observe any clinically significant improvements with VD treatment, a case series of 6 patients with either glioblastoma multiforme, acute myeloid leukemia, or aplastic anemia did demonstrate clinical improvement of TEC after receiving high-dose vitamin D₃.³⁰ The mean time to onset of TEC was noted at 8.5 days following administration of the inciting chemotherapeutic agent, which included combinations of anthracycline, antimetabolite, kinase inhibitor, B-cell lymphoma 2 inhibitor, purine analogue, and alkylating agents. A combination of clinical and histologic findings was used to diagnose TEC. Baseline 25(OH)D levels were not established prior to treatment. The treatment regimen for 1 patient included 2 doses of 50,000 IU of VD spaced 1 week apart, totaling 100,000 IU, while the remaining 5 patients received a total of 200,000 IU, also split into 2 doses given 1 week apart. All patients received their first dose of VD within a week of the cutaneous eruption. Following the initial VD dose, there was a notable improvement in pain, pruritus, or swelling by the next day. Reduction in erythema also was observed within 1 to 4 days.³⁰

No AEs associated with VD supplementation were reported, suggesting a potential beneficial role of high-dose VD in accelerating recovery from chemotherapy-induced rashes without evident safety concerns.

Radiation Therapy–Induced Cutaneous Events Treated with High-Dose Vitamin D

Radiation dermatitis is a common and often severe complication of radiation therapy that affects more than 90% of patients undergoing treatment, with half of these individuals experiencing grade 2 toxicity, according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events.^31,32 Radiation damage to basal keratinocytes and hair follicle stem cells disrupts the renewal of the skin’s outer layer, while a surge of free radicals causes irreversible DNA damage.³³ Symptoms of radiation dermatitis can vary from mild pink erythema to tissue ulceration and necrosis, typically within 1 to 4 weeks of radiation exposure.³⁴ The resulting dermatitis can take 2 to 4 weeks to heal, notably impacting patient quality of life and often necessitating modifications or interruptions in cancer therapy.³³

Prior studies have demonstrated the use of high-dose VD to improve the healing of UV-irradiated skin. A randomized controlled trial investigated high-dose vitamin D₃ to treat experimentally induced sunburn in 20 healthy adults. Compared with those who received a placebo, participants receiving the oral dose of 200,000 IU of vitamin D₃ demonstrated suppression of the pro-inflammatory mediators tumor necrosis factor α (P=.04) and inducible nitric oxide synthase (P=.02), while expression of tissue repair enhancer arginase 1 was increased (P<.005).³⁵ The mechanism of this enhanced tissue repair was investigated using a mouse model, in which intraperitoneal 25(OH)D was administered following severe UV-induced skin injury. On immunofluorescence microscopy, mice treated with VD showed enhanced autophagy within the macrophages infiltrating UV-irradiated skin.³⁶ The use of high-dose VD to treat UV-irradiated skin in these studies established a precedent for using VD to heal cutaneous injury caused by ionizing radiation therapy.

Some studies have focused on the role of VD for treating acute radiation dermatitis. A study of 23 patients with ductal carcinoma in situ or localized invasive ductal carcinoma breast cancer compared the effectiveness of topical calcipotriol to that of a standard hydrating ointment.³⁷ Participants were randomized to 1 of 2 treatments before starting adjuvant radiotherapy to evaluate their potential in preventing radiation dermatitis. In 87% (20/23) of these patients, no difference in skin reaction was observed between the 2 treatments, suggesting that topical VD application may not offer any advantage over the standard hydrating ointment for the prevention of radiation dermatitis.³⁷

Benefits of high-dose oral VD for treating radiation dermatitis also have been reported. Nguyen et al³⁸ documented 3 cases in which patients with neuroendocrine carcinoma of the pancreas, tonsillar carcinoma, and breast cancer received 200,000 IU of oral ergocalciferol distributed over 2 doses given 7 days apart for radiation dermatitis. These patients experienced substantial improvements in pain, swelling, and redness within a week of the initial dose. Additionally, a case of radiation recall dermatitis, which occurred a week after vinorelbine chemotherapy, was treated with 2 doses totaling 100,000 IU of oral ergocalciferol. This patient also had improvement in pain and swelling but continued to have tumor-related induration and ulceration.³⁹

Although topical VD did not show significant benefits over standard treatments for radiation dermatitis, high-dose oral VD appears promising in improving patient outcomes of pain and swelling more rapidly than current practices. Further research is needed to confirm these findings and establish standardized treatment protocols.

Final Thoughts

Suboptimal VD levels are prevalent in numerous cancer types. Chemotherapy often is associated with acute, potentially transient worsening of VD status in patients with breast and colorectal cancer. Although 25(OH)D levels have not corresponded with increased frequency of ­chemotherapy-related dermatologic AEs, suboptimal 25(OH)D levels appear to be associated with increased severity of radiation-induced mucositis and dermatitis.^20,25,26 The use of high-dose VD as a therapeutic agent shows promise in mitigating chemotherapy-induced and radiation therapy–induced rashes in multiple cancer types with reduction of inflammatory markers and a durable anti-inflammatory impact. Although the mechanisms of cellular injury vary among chemotherapeutic agents, the anti-inflammatory and tissue repair properties of VD may make it an effective treatment for chemotherapy-induced cutaneous damage regardless of injury mechanism.^2-4,35 However, reports of clinical improvement vary, and further objective studies to classify optimal dosing, administration, and outcome measures are needed. The absence of reported AEs associated with high-dose VD supplementation is encouraging, but selection of a safe and optimal dosing regimen can only occur with dedicated clinical trials.

Vitamin D (VD) regulates keratinocyte proliferation and differentiation, modulates inflammatory pathways, and protects against cellular damage in the skin. ¹ In the setting of tissue injury and acute skin inflammation, active vitamin D—1,25(OH) ₂ D—suppresses signaling from pro-inflammatory chemokines and cytokines such as IFN- γ and IL-17. ^2,3 This suppression reduces proliferation of helper T cells (T _H 1, T _H 17) and B cells, decreasing tissue damage from reactive oxygen species release while enhancing secretion of the anti-inflammatory cytokine IL-10 by antigen-presenting cells. ^2-4

Suboptimal VD levels have been associated with numerous health consequences including malignancy, prompting interest in VD supplementation for improving cancer-related outcomes.⁵ Beyond disease prognosis, high-dose VD supplementation has been suggested as a potential therapy for adverse events (AEs) related to cancer treatments. In one study, mice that received oral vitamin D₃ supplementation of 11,500 IU/kg daily had fewer doxorubicin-induced cardiotoxic effects on ejection fraction (P<.0001) and stroke volume (P<.01) than mice that received VD supplementation of 1500 IU/kg daily.⁶

In this review, we examine the impact of chemoradiation on 25(OH)D levels—which more accurately reflects VD stores than 1,25(OH)₂D levels—and the impact of suboptimal VD on cutaneous toxicities related to chemoradiation. To define the suboptimal VD threshold, we used the Endocrine Society’s clinical practice guidelines, which characterize suboptimal 25(OH)D levels as insufficiency (21–29 ng/mL [52.5–72.5 nmol/L]) or deficiency (<20 ng/mL [50 nmol/L])⁷; deficiency can be further categorized as severe deficiency (<12 ng/mL [30 nmol/L]).⁸ This review also evaluates the evidence for vitamin D₃ supplementation to alleviate the cutaneous AEs of chemotherapy and radiation treatments.

Effects of Chemotherapy on Vitamin D Levels

A high prevalence of VD deficiency is seen in various cancers. In a retrospective review of 25(OH)D levels in 2098 adults with solid tumors of any stage (6% had metastatic disease [n=124]), suboptimal levels were found in 69% of patients with breast cancer (n=617), 75% with colorectal cancer (n=84), 72% with gynecologic cancer (n=65), 79% with kidney and bladder cancer (n=145), 83% with pancreatic and upper gastrointestinal tract cancer (n=178), 73% with lung cancer (n=73), 69% with prostate cancer (n=225), 61% with skin cancer (n=399), and 63% with thyroid cancer (n=172).⁵ Suboptimal VD also has been found in hematologic malignancies. In a prospective cohort study, mean serum 25(OH)D levels in 23 patients with recently diagnosed acute myeloid leukemia demonstrated VD deficiency (mean [SD], 18.6 [6.6] nmol/L).⁹ Given that many patients already exhibit a baseline VD deficiency at cancer diagnosis, it is important to understand the relationship between VD and cancer treatment modalities.⁵

In the United States, breast and colorectal cancers were estimated to be the first and fourth most common cancers, with 313,510 and 152,810 predicted new cases in 2024, respectively.¹⁰ This review will focus on breast and colorectal cancer when describing VD variation associated with chemotherapy exposure due to their high prevalence.

Effects of Chemotherapy on Vitamin D Levels in Breast Cancer—Breast cancer studies have shown suboptimal VD levels in 76% of females 75 years or younger with any T1, T2, or T3; N0 or N1; and M0 breast cancer, in which 38.5% (n=197) had insufficient and 37.5% (n=192) had deficient 25(OH)D levels.¹¹ In a study of female patients with primary breast cancer (stage I, II, or III and T1 with high Ki67 expression [≥30%], T2, or T3), VD deficiency was seen in 60% of patients not receiving VD supplementation.^12,13 A systematic review that included 7 studies of different types of breast cancer suggested that circulating 25(OH)D may be associated with improved prognosis.¹⁴ Thus, studies have investigated risk factors associated with poor or worsening VD status in individuals with breast cancer, including exposure to chemotherapy and/or radiation treatment.^12,15-18

A prospective cohort study assessed 25(OH)D levels in 95 patients with any breast cancer (stages I, II, IIIA, IIIB) before and after initiating chemotherapy with docetaxel, doxorubicin, epirubicin, 5-fluorouracil, or cyclophosphamide, compared with a group of 52 females without cancer.¹⁷ In the breast cancer group, approximately 80% (76/95) had suboptimal and 50% (47/95) had deficient VD levels before chemotherapy initiation (mean [SD], 54.1 [22.8] nmol/L). In the comparison group, 60% (31/52) had suboptimal and 30% (15/52) had deficient VD at baseline (mean [SD], 66.1 [23.5] nmol/L), which was higher than the breast cancer group (P=.03). A subgroup analysis excluded participants who started, stopped, or lacked data on dietary supplements containing VD (n=39); in the remaining 56 participants, a significant decrease in 25(OH)D levels was observed shortly after finishing chemotherapy compared with the prechemotherapy baseline value (mean, −7.9 nmol/L; P=.004). Notably, 6 months after chemotherapy completion, 25(OH)D levels increased (mean, +12.8 nmol/L; P<.001). Vitamin D levels remained stable in the comparison group (P=.987).¹⁷

Consistent with these findings, a cross-sectional study assessing VD status in 394 female patients with primary breast cancer (stage I, II, or III and T1 with high Ki67 expression [≥30%], T2, or T3), found that a history of chemotherapy was associated with increased odds of 25(OH)D levels less than 20 ng/mL compared with breast cancer patients with no prior chemotherapy (odds ratio, 1.86; 95% CI, 1.03-3.38).¹² Although the study data included chemotherapy history, no information was provided on specific chemotherapy agents or regimens used in this cohort, limiting the ability to detect the drugs most often implicated.

Both studies indicated a complex interplay between chemotherapy and VD levels in breast cancer patients. Although Kok et al¹⁷ suggested a transient decrease in VD levels during chemotherapy with a subsequent recovery after cessation, Fassio et al¹² highlighted the increased odds of VD deficiency associated with chemotherapy. Ultimately, larger randomized controlled trials are needed to better understand the relationship between chemotherapy and VD status in breast cancer patients.

Effects of Chemotherapy on Vitamin D Levels in Colorectal Cancer—Similar to patterns seen in breast cancer, a systematic review with 6 studies of different types of colorectal cancer suggested that circulating 25(OH)D levels may be associated with prognosis.¹⁴ Studies also have investigated the relationship between colorectal chemotherapy regimens and VD status.^15,16,18,19

A retrospective study assessed 25(OH)D levels in 315 patients with any colorectal cancer (stage I–IV).¹⁵ Patients were included in the analysis if they received less than 400 IU daily of VD supplementation at baseline. For the whole study sample, the mean (SD) VD level was 23.7 (13.71) ng/mL. Patients who had not received chemotherapy within 3 months of the VD level assessment were categorized as the no chemotherapy group, and the others were designated as the chemotherapy group; the latter group was exposed to various chemotherapy regimens, including combinations of irinotecan, oxaliplatin, 5-fluorouracil, leucovorin, bevacizumab, or cetuximab. Multivariate analysis showed that the chemotherapy group was 3.7 times more likely to have very low VD levels (≤15 ng/mL) compared with those in the no chemotherapy group (P<.0001).¹⁵

A separate cross-sectional study examined serum 25(OH)D concentrations in 1201 patients with any newly diagnosed colorectal carcinoma (stage I–III); 91% of cases were adenocarcinoma.¹⁸ In a multivariate analysis, chemotherapy plus surgery was associated with lower VD levels than surgery alone 6 months after diagnosis (mean, −8.74 nmol/L; 95% CI, −11.30 to −6.18 nmol/L), specifically decreasing by a mean of 6.7 nmol/L (95% CI, −9.8 to −3.8 nmol/L) after adjusting for demographic and lifestyle factors.¹⁸ However, a prospective cohort study demonstrated different findings.¹⁹ Comparing 58 patients with newly diagnosed colorectal adenocarcinoma (stages I–IV) who underwent chemotherapy and 36 patients who did not receive chemotherapy, there was no significant change in 25(OH)D levels from the time of diagnosis to 6 months later. Median VD levels decreased by 0.7 ng/mL in those who received chemotherapy, while a minimal (and not significant) increase of 1.6 ng/mL was observed in those without chemotherapy intervention (P=.26). Notably, supplementation was not restricted in this cohort, which may have resulted in higher VD levels in those taking supplements.¹⁹

Since time of year and geographic location can influence VD levels, one prospective cohort study controlled for differential sun exposure due to these factors in their analysis.¹⁶ Assessment of 25(OH)D levels was completed in 81 chemotherapy-naïve cancer patients immediately before beginning chemotherapy as well as 6 and 12 weeks into treatment. More than 8 primary cancer types were represented in this study, with breast (34% [29/81]) and colorectal (14% [12/81]) cancer being the most common, but the cancer stages of the participants were not detailed. Vitamin D levels decreased after commencing chemotherapy, with the largest drop occurring 6 weeks into treatment. From the 6- to 12-week end points, VD increased but remained below the original baseline level (baseline: mean [SD], 49.2 [22.3] nmol/L; 6 weeks: mean [SD], 40.9 [19.0] nmol/L; 12 weeks: mean [SD], 45.9 [19.7] nmol/L; P=.05).¹⁶

Although focused on breast and colorectal cancers, these studies suggest that various chemotherapy regimens may confer a higher risk for VD deficiency compared with VD status at diagnosis and/or prior to chemotherapy treatment. However, most of these studies only discussed stage-based differences, excluding analysis of the variety of cancer subtypes that comprise breast and colorectal malignancies, which may limit our ability to extrapolate from these data. Ultimately, larger randomized controlled trials are needed to better understand the relationship between chemotherapy and VD status across various primary cancer types.

Effects of Radiation Therapy on Vitamin D Levels

Unlike chemotherapy, studies on the association between radiation therapy and VD levels are minimal, with most reports in the literature discussing the use of VD to potentiate the effects of radiation therapy. In one cross-sectional analysis of 1201 patients with newly diagnosed stage I, II, or III colorectal cancer of any type (94% were adenocarcinoma), radiation plus surgery was associated with slightly lower 25(OH)D levels than surgery alone for tumor treatment 6 months after diagnosis (mean, −3.17; 95% CI, −6.07 to −0.28 nmol/L). However, after adjustment for demographic and lifestyle factors, this decrease in VD levels attributable to radiotherapy was not statistically significant compared with the surgery-only cohort (mean, −1.78; 95% CI, −5.07 to 1.52 nmol/L).¹⁸

Similarly, a cross-sectional study assessing VD status in 394 female patients with primary breast cancer (stage I, II, or III and T1 with high Ki67 expression [≥30%], T2, or T3), found that a history of radiotherapy was not associated with a difference in serum 25(OH)D levels compared with those with breast cancer without prior radiotherapy (odds ratio, 0.90; 95% CI, 0.52-1.54).¹² From the limited existing literature specifically addressing variations of VD levels with radiation, radiation therapy does not appear to significantly impact VD levels.

Vitamin D Levels and the Severity of Chemotherapy- or Radiation Therapy–Induced AEs

A prospective cohort of 241 patients did not find an increase in the incidence or severity of chemotherapy-induced cutaneous toxicities in those with suboptimal 1,25(OH)₂D₃ levels (≤75 nmol/L).²⁰ Eight different primary cancer types were represented, including breast and colorectal cancer; the tumor stages of the participants were not detailed. Forty-one patients had normal 1,25(OH)₂D₃ levels, while the remaining 200 had suboptimal levels. There was no significant association between serum VD levels and the following dermatologic toxicities: desquamation (P=.26), xerosis (P=.15), mucositis (P=.30), or painful rash (P=.87). Surprisingly, nail changes and hand-foot reactions occurred with greater frequency in patients with normal VD levels (P=.01 and P=.03, respectively).²⁰ Hand-foot reaction is part of the toxic erythema of chemotherapy (TEC) spectrum, which is comprised of a range of cytotoxic skin injuries that typically manifest within 2 to 3 weeks of exposure to the offending chemotherapeutic agents, often characterized by erythema, pain, swelling, and blistering, particularly in intertriginous and acral areas.^21-23 Recovery from TEC generally takes at least 2 to 4 weeks and may necessitate cessation of the offending chemotherapeutic agent.^21,24 Notably, this study measured 1,25(OH)₂D₃ levels instead of 25(OH)D levels, which may not reliably indicate body stores of VD.^7,20 These results underscore the complex nature between chemotherapy and VD; however, VD levels alone do not appear to be a sufficient biomarker for predicting chemotherapy-associated cutaneous AEs.

Interestingly, radiation therapy–induced AEs may be associated with VD levels. A prospective cohort study of 98 patients with prostate, bladder, or gynecologic cancers (tumor stages were not detailed) undergoing pelvic radiotherapy found that females and males with 25(OH)D levels below a threshold of 35 and 40 nmol/L, respectively, were more likely to experience higher Radiation Therapy Oncology Group (RTOG) grade acute proctitis compared with those with VD above these thresholds.²⁵ Specifically, VD below these thresholds was associated with increased odds of RTOG grade 2 or higher radiation-induced proctitis (OR, 3.07; 95% CI, 1.27-7.50 [P=.013]). Additionally, a weak correlation was noted between VD below these thresholds and the RTOG grade, with a Spearman correlation value of −0.189 (P=.031).²⁵

One prospective cohort study included 28 patients with any cancer of the oral cavity, oropharynx, hypopharynx, or larynx stages II, III, or IVA; 93% (26/28) were stage III or IVA.²⁶ The 20 (71%) patients with suboptimal 25(OH)D levels (≤75 nmol/L) experienced a higher prevalence of grade II radiation dermatitis compared with the 8 (29%) patients with optimal VD levels (χ²₂=5.973; P=.0505). This pattern persisted with the severity of mucositis; patients from the suboptimal VD group presented with higher rates of grades II and III mucositis compared with the VD optimal group (χ²₂=13.627; P=.0011).²⁶ Recognizing the small cohort evaluated in the study, we highlight the importance of further studies to clarify these associations.

Chemotherapy-Induced Cutaneous Events Treated with High-Dose Vitamin D

Chemotherapeutic agents are known to induce cellular damage, resulting in a range of cutaneous AEs that can invoke discontinuation of otherwise effective chemotherapeutic interventions.^27,28 Recent research has explored the potential of high-dose vitamin D₃ as a therapeutic agent to mitigate cutaneous reactions.^29,30

A randomized, double-blind, placebo-controlled trial investigated the use of a single high dose of oral ­25(OH)D to treat topical nitrogen mustard (NM)–induced rash.²⁹ To characterize baseline inflammatory responses from NM injury without intervention, clinical measures, serum studies, and tissue analyses from skin biopsies were performed on 28 healthy adults after exposure to topical NM—a chemotherapeutic agent classified as a DNA alkylator. Two weeks later, participants were exposed to topical NM a second time and were split into 2 groups: 14 patients received a single 200,000-IU dose of oral 25(OH)D while the other 14 participants were given a placebo. Using the inflammatory markers induced from baseline exposure to NM alone, posttreatment analysis revealed that the punch biopsies from the 25(OH)D group expressed fewer NM-induced inflammatory markers compared with the placebo group at both 72 hours and 6 weeks following NM injury (72 hours: 12 vs 17 inflammatory markers; 6 weeks: 4 vs 11 inflammatory markers). Notably, NM inflammatory markers were enriched for IL-17 signaling pathways in the placebo biopsies but not in the 25(OH)D intervention group. This study also identified mild and severe patterns of inflammatory responses to NM that were independent of the 25(OH)D intervention. Biomarkers specific to skin biopsies from participants with the severe response included CCL20, CCL2, and CXCL8 (adjusted P<.05). At 6 weeks posttreatment, the 25(OH)D group showed a 67% reduction in NM injury markers compared with a 35% reduction in the placebo group. Despite a reduction in tissue inflammatory markers, there were no clinically significant changes observed in skin redness, swelling, or histologic structure when comparing the 25(OH)D- supplemented group to the placebo group at any time during the study, necessitating further research into the mechanistic roles of high doses VD supplementation.²⁹

Although Ernst et al²⁹ did not observe any clinically significant improvements with VD treatment, a case series of 6 patients with either glioblastoma multiforme, acute myeloid leukemia, or aplastic anemia did demonstrate clinical improvement of TEC after receiving high-dose vitamin D₃.³⁰ The mean time to onset of TEC was noted at 8.5 days following administration of the inciting chemotherapeutic agent, which included combinations of anthracycline, antimetabolite, kinase inhibitor, B-cell lymphoma 2 inhibitor, purine analogue, and alkylating agents. A combination of clinical and histologic findings was used to diagnose TEC. Baseline 25(OH)D levels were not established prior to treatment. The treatment regimen for 1 patient included 2 doses of 50,000 IU of VD spaced 1 week apart, totaling 100,000 IU, while the remaining 5 patients received a total of 200,000 IU, also split into 2 doses given 1 week apart. All patients received their first dose of VD within a week of the cutaneous eruption. Following the initial VD dose, there was a notable improvement in pain, pruritus, or swelling by the next day. Reduction in erythema also was observed within 1 to 4 days.³⁰

No AEs associated with VD supplementation were reported, suggesting a potential beneficial role of high-dose VD in accelerating recovery from chemotherapy-induced rashes without evident safety concerns.

Radiation Therapy–Induced Cutaneous Events Treated with High-Dose Vitamin D

Radiation dermatitis is a common and often severe complication of radiation therapy that affects more than 90% of patients undergoing treatment, with half of these individuals experiencing grade 2 toxicity, according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events.^31,32 Radiation damage to basal keratinocytes and hair follicle stem cells disrupts the renewal of the skin’s outer layer, while a surge of free radicals causes irreversible DNA damage.³³ Symptoms of radiation dermatitis can vary from mild pink erythema to tissue ulceration and necrosis, typically within 1 to 4 weeks of radiation exposure.³⁴ The resulting dermatitis can take 2 to 4 weeks to heal, notably impacting patient quality of life and often necessitating modifications or interruptions in cancer therapy.³³

Prior studies have demonstrated the use of high-dose VD to improve the healing of UV-irradiated skin. A randomized controlled trial investigated high-dose vitamin D₃ to treat experimentally induced sunburn in 20 healthy adults. Compared with those who received a placebo, participants receiving the oral dose of 200,000 IU of vitamin D₃ demonstrated suppression of the pro-inflammatory mediators tumor necrosis factor α (P=.04) and inducible nitric oxide synthase (P=.02), while expression of tissue repair enhancer arginase 1 was increased (P<.005).³⁵ The mechanism of this enhanced tissue repair was investigated using a mouse model, in which intraperitoneal 25(OH)D was administered following severe UV-induced skin injury. On immunofluorescence microscopy, mice treated with VD showed enhanced autophagy within the macrophages infiltrating UV-irradiated skin.³⁶ The use of high-dose VD to treat UV-irradiated skin in these studies established a precedent for using VD to heal cutaneous injury caused by ionizing radiation therapy.

Some studies have focused on the role of VD for treating acute radiation dermatitis. A study of 23 patients with ductal carcinoma in situ or localized invasive ductal carcinoma breast cancer compared the effectiveness of topical calcipotriol to that of a standard hydrating ointment.³⁷ Participants were randomized to 1 of 2 treatments before starting adjuvant radiotherapy to evaluate their potential in preventing radiation dermatitis. In 87% (20/23) of these patients, no difference in skin reaction was observed between the 2 treatments, suggesting that topical VD application may not offer any advantage over the standard hydrating ointment for the prevention of radiation dermatitis.³⁷

Benefits of high-dose oral VD for treating radiation dermatitis also have been reported. Nguyen et al³⁸ documented 3 cases in which patients with neuroendocrine carcinoma of the pancreas, tonsillar carcinoma, and breast cancer received 200,000 IU of oral ergocalciferol distributed over 2 doses given 7 days apart for radiation dermatitis. These patients experienced substantial improvements in pain, swelling, and redness within a week of the initial dose. Additionally, a case of radiation recall dermatitis, which occurred a week after vinorelbine chemotherapy, was treated with 2 doses totaling 100,000 IU of oral ergocalciferol. This patient also had improvement in pain and swelling but continued to have tumor-related induration and ulceration.³⁹

Although topical VD did not show significant benefits over standard treatments for radiation dermatitis, high-dose oral VD appears promising in improving patient outcomes of pain and swelling more rapidly than current practices. Further research is needed to confirm these findings and establish standardized treatment protocols.

Final Thoughts

Suboptimal VD levels are prevalent in numerous cancer types. Chemotherapy often is associated with acute, potentially transient worsening of VD status in patients with breast and colorectal cancer. Although 25(OH)D levels have not corresponded with increased frequency of ­chemotherapy-related dermatologic AEs, suboptimal 25(OH)D levels appear to be associated with increased severity of radiation-induced mucositis and dermatitis.^20,25,26 The use of high-dose VD as a therapeutic agent shows promise in mitigating chemotherapy-induced and radiation therapy–induced rashes in multiple cancer types with reduction of inflammatory markers and a durable anti-inflammatory impact. Although the mechanisms of cellular injury vary among chemotherapeutic agents, the anti-inflammatory and tissue repair properties of VD may make it an effective treatment for chemotherapy-induced cutaneous damage regardless of injury mechanism.^2-4,35 However, reports of clinical improvement vary, and further objective studies to classify optimal dosing, administration, and outcome measures are needed. The absence of reported AEs associated with high-dose VD supplementation is encouraging, but selection of a safe and optimal dosing regimen can only occur with dedicated clinical trials.

TOPLINE:

Metformin significantly improved symptoms and resulted in hair regrowth in Black women with treatment-refractory central centrifugal cicatricial alopecia (CCCA), in a retrospective case series.

METHODOLOGY:

• Researchers conducted a case series involving 12 Black women in their 30s, 40s, and 50s, with biopsy-confirmed, treatment-refractory CCCA, a chronic inflammatory hair disorder characterized by permanent hair loss, from the Johns Hopkins University alopecia clinic.
• Participants received CCCA treatment for at least 6 months and had stagnant or worsening symptoms before oral extended-release metformin (500 mg daily) was added to treatment. (Treatments included topical clobetasol, compounded minoxidil, and platelet-rich plasma injections.)
• Scalp biopsies were collected from four patients before and after metformin treatment to evaluate gene expression changes.
• Changes in clinical symptoms were assessed, including pruritus, inflammation, pain, scalp resistance, and hair regrowth, following initiation of metformin treatment.

TAKEAWAY:

• Metformin led to significant clinical improvement in eight patients, which included reductions in scalp pain, scalp resistance, pruritus, and inflammation. However, two patients experienced worsening symptoms.
• Six patients showed clinical evidence of hair regrowth after at least 6 months of metformin treatment with one experiencing hair loss again 3 months after discontinuing treatment.
• Transcriptomic analysis revealed 34 upregulated genes, which included upregulated of 23 hair keratin-associated proteins, and pathways related to keratinization, epidermis development, and the hair cycle. In addition, eight genes were downregulated, with pathways that included those associated with extracellular matrix organization, collagen fibril organization, and collagen metabolism.
• Gene set variation analysis showed reduced expression of T helper 17 cell and epithelial-mesenchymal transition pathways and elevated adenosine monophosphate kinase signaling and keratin-associated proteins after treatment with metformin.

IN PRACTICE:

“Metformin’s ability to concomitantly target fibrosis and inflammation provides a plausible mechanism for its therapeutic effects in CCCA and other fibrosing alopecia disorders,” the authors concluded. But, they added, “larger prospective, placebo-controlled randomized clinical trials are needed to rigorously evaluate metformin’s efficacy and optimal dosing for treatment of cicatricial alopecias.”

SOURCE:

The study was led by Aaron Bao, Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, and was published online on September 4 in JAMA Dermatology.

LIMITATIONS:

A small sample size, retrospective design, lack of a placebo control group, and the single-center setting limited the generalizability of the study findings. In addition, the absence of a validated activity or severity scale for CCCA and the single posttreatment sampling limit the assessment and comparison of clinical symptoms and transcriptomic changes.

DISCLOSURES:

The study was supported by the American Academy of Dermatology. One author reported several ties with pharmaceutical companies, a pending patent, and authorship for the UpToDate section on CCCA.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Metformin significantly improved symptoms and resulted in hair regrowth in Black women with treatment-refractory central centrifugal cicatricial alopecia (CCCA), in a retrospective case series.

METHODOLOGY:

• Researchers conducted a case series involving 12 Black women in their 30s, 40s, and 50s, with biopsy-confirmed, treatment-refractory CCCA, a chronic inflammatory hair disorder characterized by permanent hair loss, from the Johns Hopkins University alopecia clinic.
• Participants received CCCA treatment for at least 6 months and had stagnant or worsening symptoms before oral extended-release metformin (500 mg daily) was added to treatment. (Treatments included topical clobetasol, compounded minoxidil, and platelet-rich plasma injections.)
• Scalp biopsies were collected from four patients before and after metformin treatment to evaluate gene expression changes.
• Changes in clinical symptoms were assessed, including pruritus, inflammation, pain, scalp resistance, and hair regrowth, following initiation of metformin treatment.

TAKEAWAY:

• Metformin led to significant clinical improvement in eight patients, which included reductions in scalp pain, scalp resistance, pruritus, and inflammation. However, two patients experienced worsening symptoms.
• Six patients showed clinical evidence of hair regrowth after at least 6 months of metformin treatment with one experiencing hair loss again 3 months after discontinuing treatment.
• Transcriptomic analysis revealed 34 upregulated genes, which included upregulated of 23 hair keratin-associated proteins, and pathways related to keratinization, epidermis development, and the hair cycle. In addition, eight genes were downregulated, with pathways that included those associated with extracellular matrix organization, collagen fibril organization, and collagen metabolism.
• Gene set variation analysis showed reduced expression of T helper 17 cell and epithelial-mesenchymal transition pathways and elevated adenosine monophosphate kinase signaling and keratin-associated proteins after treatment with metformin.

IN PRACTICE:

“Metformin’s ability to concomitantly target fibrosis and inflammation provides a plausible mechanism for its therapeutic effects in CCCA and other fibrosing alopecia disorders,” the authors concluded. But, they added, “larger prospective, placebo-controlled randomized clinical trials are needed to rigorously evaluate metformin’s efficacy and optimal dosing for treatment of cicatricial alopecias.”

SOURCE:

The study was led by Aaron Bao, Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, and was published online on September 4 in JAMA Dermatology.

LIMITATIONS:

A small sample size, retrospective design, lack of a placebo control group, and the single-center setting limited the generalizability of the study findings. In addition, the absence of a validated activity or severity scale for CCCA and the single posttreatment sampling limit the assessment and comparison of clinical symptoms and transcriptomic changes.

DISCLOSURES:

The study was supported by the American Academy of Dermatology. One author reported several ties with pharmaceutical companies, a pending patent, and authorship for the UpToDate section on CCCA.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Metformin significantly improved symptoms and resulted in hair regrowth in Black women with treatment-refractory central centrifugal cicatricial alopecia (CCCA), in a retrospective case series.

METHODOLOGY:

• Researchers conducted a case series involving 12 Black women in their 30s, 40s, and 50s, with biopsy-confirmed, treatment-refractory CCCA, a chronic inflammatory hair disorder characterized by permanent hair loss, from the Johns Hopkins University alopecia clinic.
• Participants received CCCA treatment for at least 6 months and had stagnant or worsening symptoms before oral extended-release metformin (500 mg daily) was added to treatment. (Treatments included topical clobetasol, compounded minoxidil, and platelet-rich plasma injections.)
• Scalp biopsies were collected from four patients before and after metformin treatment to evaluate gene expression changes.
• Changes in clinical symptoms were assessed, including pruritus, inflammation, pain, scalp resistance, and hair regrowth, following initiation of metformin treatment.

TAKEAWAY:

• Metformin led to significant clinical improvement in eight patients, which included reductions in scalp pain, scalp resistance, pruritus, and inflammation. However, two patients experienced worsening symptoms.
• Six patients showed clinical evidence of hair regrowth after at least 6 months of metformin treatment with one experiencing hair loss again 3 months after discontinuing treatment.
• Transcriptomic analysis revealed 34 upregulated genes, which included upregulated of 23 hair keratin-associated proteins, and pathways related to keratinization, epidermis development, and the hair cycle. In addition, eight genes were downregulated, with pathways that included those associated with extracellular matrix organization, collagen fibril organization, and collagen metabolism.
• Gene set variation analysis showed reduced expression of T helper 17 cell and epithelial-mesenchymal transition pathways and elevated adenosine monophosphate kinase signaling and keratin-associated proteins after treatment with metformin.

IN PRACTICE:

“Metformin’s ability to concomitantly target fibrosis and inflammation provides a plausible mechanism for its therapeutic effects in CCCA and other fibrosing alopecia disorders,” the authors concluded. But, they added, “larger prospective, placebo-controlled randomized clinical trials are needed to rigorously evaluate metformin’s efficacy and optimal dosing for treatment of cicatricial alopecias.”

SOURCE:

The study was led by Aaron Bao, Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, and was published online on September 4 in JAMA Dermatology.

LIMITATIONS:

A small sample size, retrospective design, lack of a placebo control group, and the single-center setting limited the generalizability of the study findings. In addition, the absence of a validated activity or severity scale for CCCA and the single posttreatment sampling limit the assessment and comparison of clinical symptoms and transcriptomic changes.

DISCLOSURES:

The study was supported by the American Academy of Dermatology. One author reported several ties with pharmaceutical companies, a pending patent, and authorship for the UpToDate section on CCCA.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

The use of menopausal hormone therapy (MHT) increases breast cancer risk in women with a strong family history of breast cancer. These women have a striking cumulative risk of developing breast cancer (age, 50-80 years) of 22.4%, according to a new modelling study of UK women.

METHODOLOGY:

This was a modeling study integrating two data-sets of UK women: the BOADICEA dataset of age-specific breast cancer risk with family history and the Collaborative Group on Hormonal Factors in Breast Cancer, which covers relative risk for breast cancer with different types and durations of MHT.

Four different breast cancer family history profiles were:

• “Average” family history of breast cancer has unknown affected family members;
• “Modest” family history comprises a single first-degree relative with breast cancer at the age of 60 years.
• “Intermediate” family history comprises a single first-degree relative who developed breast cancer at the age of 40 years.
• “Strong” family history comprises two first-degree relatives who developed breast cancer at the age of 50 years.

TAKEAWAY:

• The lowest risk category: “Average” family history with no MHT use has a cumulative breast cancer risk (age, 50-80 years) of 9.8% and a risk of dying from breast cancer of 1.7%. These risks rise with 5 years’ exposure to MHT (age, 50-55 years) to 11.0% and 1.8%, respectively.
• The highest risk category: “Strong” family history with no MHT use has a cumulative breast cancer risk (age, 50-80 years) of 19.6% and a risk of dying from breast cancer of 3.2%. These risks rise with 5 years’ exposure to MHT (age, 50-55 years) to 22.4% and 3.5%, respectively.

IN PRACTICE:

The authors concluded that, “These integrated data will enable more accurate estimates of absolute and attributable risk associated with MHT exposure for women with a family history of breast cancer, informing shared decision-making.”

SOURCE:

The lead author is Catherine Huntley of the Institute of Cancer Research, London, England. The study appeared in the British Journal of General Practice.

LIMITATIONS:

Limitations included modeling study that did not directly measure individuals with combined risks.

DISCLOSURES:

The study was funded by several sources including Cancer Research UK. The authors reported no conflicts of interest.

A version of this article first appeared on Medscape.com.

TOPLINE:

The use of menopausal hormone therapy (MHT) increases breast cancer risk in women with a strong family history of breast cancer. These women have a striking cumulative risk of developing breast cancer (age, 50-80 years) of 22.4%, according to a new modelling study of UK women.

METHODOLOGY:

This was a modeling study integrating two data-sets of UK women: the BOADICEA dataset of age-specific breast cancer risk with family history and the Collaborative Group on Hormonal Factors in Breast Cancer, which covers relative risk for breast cancer with different types and durations of MHT.

Four different breast cancer family history profiles were:

• “Average” family history of breast cancer has unknown affected family members;
• “Modest” family history comprises a single first-degree relative with breast cancer at the age of 60 years.
• “Intermediate” family history comprises a single first-degree relative who developed breast cancer at the age of 40 years.
• “Strong” family history comprises two first-degree relatives who developed breast cancer at the age of 50 years.

TAKEAWAY:

• The lowest risk category: “Average” family history with no MHT use has a cumulative breast cancer risk (age, 50-80 years) of 9.8% and a risk of dying from breast cancer of 1.7%. These risks rise with 5 years’ exposure to MHT (age, 50-55 years) to 11.0% and 1.8%, respectively.
• The highest risk category: “Strong” family history with no MHT use has a cumulative breast cancer risk (age, 50-80 years) of 19.6% and a risk of dying from breast cancer of 3.2%. These risks rise with 5 years’ exposure to MHT (age, 50-55 years) to 22.4% and 3.5%, respectively.

IN PRACTICE:

The authors concluded that, “These integrated data will enable more accurate estimates of absolute and attributable risk associated with MHT exposure for women with a family history of breast cancer, informing shared decision-making.”

SOURCE:

The lead author is Catherine Huntley of the Institute of Cancer Research, London, England. The study appeared in the British Journal of General Practice.

LIMITATIONS:

Limitations included modeling study that did not directly measure individuals with combined risks.

DISCLOSURES:

The study was funded by several sources including Cancer Research UK. The authors reported no conflicts of interest.

A version of this article first appeared on Medscape.com.

TOPLINE:

The use of menopausal hormone therapy (MHT) increases breast cancer risk in women with a strong family history of breast cancer. These women have a striking cumulative risk of developing breast cancer (age, 50-80 years) of 22.4%, according to a new modelling study of UK women.

METHODOLOGY:

This was a modeling study integrating two data-sets of UK women: the BOADICEA dataset of age-specific breast cancer risk with family history and the Collaborative Group on Hormonal Factors in Breast Cancer, which covers relative risk for breast cancer with different types and durations of MHT.

Four different breast cancer family history profiles were:

• “Average” family history of breast cancer has unknown affected family members;
• “Modest” family history comprises a single first-degree relative with breast cancer at the age of 60 years.
• “Intermediate” family history comprises a single first-degree relative who developed breast cancer at the age of 40 years.
• “Strong” family history comprises two first-degree relatives who developed breast cancer at the age of 50 years.

TAKEAWAY:

• The lowest risk category: “Average” family history with no MHT use has a cumulative breast cancer risk (age, 50-80 years) of 9.8% and a risk of dying from breast cancer of 1.7%. These risks rise with 5 years’ exposure to MHT (age, 50-55 years) to 11.0% and 1.8%, respectively.
• The highest risk category: “Strong” family history with no MHT use has a cumulative breast cancer risk (age, 50-80 years) of 19.6% and a risk of dying from breast cancer of 3.2%. These risks rise with 5 years’ exposure to MHT (age, 50-55 years) to 22.4% and 3.5%, respectively.

IN PRACTICE:

The authors concluded that, “These integrated data will enable more accurate estimates of absolute and attributable risk associated with MHT exposure for women with a family history of breast cancer, informing shared decision-making.”

SOURCE:

The lead author is Catherine Huntley of the Institute of Cancer Research, London, England. The study appeared in the British Journal of General Practice.

LIMITATIONS:

Limitations included modeling study that did not directly measure individuals with combined risks.

DISCLOSURES:

The study was funded by several sources including Cancer Research UK. The authors reported no conflicts of interest.

A version of this article first appeared on Medscape.com.

Clonal hematopoiesis of indeterminate potential (CHIP) and mosaic chromosomal alterations (mCAs) are associated with an increased risk for breast cancer, and CHIP is associated with increased mortality in patients with colon cancer, according to the authors of new research.

These findings, drawn from almost 11,000 patients in the Women’s Health Initiative (WHI) study, add further evidence that CHIP and mCA drive solid tumor risk, alongside known associations with hematologic malignancies, reported lead author Pinkal Desai, MD, associate professor of medicine and clinical director of molecular aging at Englander Institute for Precision Medicine, Weill Cornell Medical College, New York City, and colleagues.
 

How This Study Differs From Others of Breast Cancer Risk Factors

“The independent effect of CHIP and mCA on risk and mortality from solid tumors has not been elucidated due to lack of detailed data on mortality outcomes and risk factors,” the investigators wrote in Cancer, although some previous studies have suggested a link.

In particular, the investigators highlighted a 2022 UK Biobank study, which reported an association between CHIP and lung cancer and a borderline association with breast cancer that did not quite reach statistical significance.

But the UK Biobank study was confined to a UK population, Dr. Desai noted in an interview, and the data were less detailed than those in the present investigation.

“In terms of risk, the part that was lacking in previous studies was a comprehensive assessment of risk factors that increase risk for all these cancers,” Dr. Desai said. “For example, for breast cancer, we had very detailed data on [participants’] Gail risk score, which is known to impact breast cancer risk. We also had mammogram data and colonoscopy data.”

In an accompanying editorial, Koichi Takahashi, MD, PhD , and Nehali Shah, BS, of The University of Texas MD Anderson Cancer Center, Houston, Texas, pointed out the same UK Biobank findings, then noted that CHIP has also been linked with worse overall survival in unselected cancer patients. Still, they wrote, “the impact of CH on cancer risk and mortality remains controversial due to conflicting data and context‐dependent effects,” necessitating studies like this one by Dr. Desai and colleagues.
 

How Was the Relationship Between CHIP, MCA, and Solid Tumor Risk Assessed?

To explore possible associations between CHIP, mCA, and solid tumors, the investigators analyzed whole genome sequencing data from 10,866 women in the WHI, a multi-study program that began in 1992 and involved 161,808 women in both observational and clinical trial cohorts.

In 2002, the first big data release from the WHI suggested that hormone replacement therapy (HRT) increased breast cancer risk, leading to widespread reduction in HRT use.

More recent reports continue to shape our understanding of these risks, suggesting differences across cancer types. For breast cancer, the WHI data suggested that HRT-associated risk was largely driven by formulations involving progesterone and estrogen, whereas estrogen-only formulations, now more common, are generally considered to present an acceptable risk profile for suitable patients.

The new study accounted for this potential HRT-associated risk, including by adjusting for patients who received HRT, type of HRT received, and duration of HRT received. According to Desai, this approach is commonly used when analyzing data from the WHI, nullifying concerns about the potentially deleterious effects of the hormones used in the study.

“Our question was not ‘does HRT cause cancer?’ ” Dr. Desai said in an interview. “But HRT can be linked to breast cancer risk and has a potential to be a confounder, and hence the above methodology.

“So I can say that the confounding/effect modification that HRT would have contributed to in the relationship between exposure (CH and mCA) and outcome (cancer) is well adjusted for as described above. This is standard in WHI analyses,” she continued.

“Every Women’s Health Initiative analysis that comes out — not just for our study — uses a standard method ... where you account for hormonal therapy,” Dr. Desai added, again noting that many other potential risk factors were considered, enabling a “detailed, robust” analysis.

Dr. Takahashi and Ms. Shah agreed. “A notable strength of this study is its adjustment for many confounding factors,” they wrote. “The cohort’s well‐annotated data on other known cancer risk factors allowed for a robust assessment of CH’s independent risk.”
 

How Do Findings Compare With Those of the UK Biobank Study?

CHIP was associated with a 30% increased risk for breast cancer (hazard ratio [HR], 1.30; 95% CI, 1.03-1.64; P = .02), strengthening the borderline association reported by the UK Biobank study.

In contrast with the UK Biobank study, CHIP was not associated with lung cancer risk, although this may have been caused by fewer cases of lung cancer and a lack of male patients, Dr. Desai suggested.

“The discrepancy between the studies lies in the risk of lung cancer, although the point estimate in the current study suggested a positive association,” wrote Dr. Takahashi and Ms. Shah.

As in the UK Biobank study, CHIP was not associated with increased risk of developing colorectal cancer.

Mortality analysis, however, which was not conducted in the UK Biobank study, offered a new insight: Patients with existing colorectal cancer and CHIP had a significantly higher mortality risk than those without CHIP. Before stage adjustment, risk for mortality among those with colorectal cancer and CHIP was fourfold higher than those without CHIP (HR, 3.99; 95% CI, 2.41-6.62; P < .001). After stage adjustment, CHIP was still associated with a twofold higher mortality risk (HR, 2.50; 95% CI, 1.32-4.72; P = .004).

The investigators’ first mCA analyses, which employed a cell fraction cutoff greater than 3%, were unfruitful. But raising the cell fraction threshold to 5% in an exploratory analysis showed that autosomal mCA was associated with a 39% increased risk for breast cancer (HR, 1.39; 95% CI, 1.06-1.83; P = .01). No such associations were found between mCA and colorectal or lung cancer, regardless of cell fraction threshold.

The original 3% cell fraction threshold was selected on the basis of previous studies reporting a link between mCA and hematologic malignancies at this cutoff, Dr. Desai said.

She and her colleagues said a higher 5% cutoff might be needed, as they suspected that the link between mCA and solid tumors may not be causal, requiring a higher mutation rate.
 

Why Do Results Differ Between These Types of Studies?

Dr. Takahashi and Ms. Shah suggested that one possible limitation of the new study, and an obstacle to comparing results with the UK Biobank study and others like it, goes beyond population heterogeneity; incongruent findings could also be explained by differences in whole genome sequencing (WGS) technique.

“Although WGS allows sensitive detection of mCA through broad genomic coverage, it is less effective at detecting CHIP with low variant allele frequency (VAF) due to its relatively shallow depth (30x),” they wrote. “Consequently, the prevalence of mCA (18.8%) was much higher than that of CHIP (8.3%) in this cohort, contrasting with other studies using deeper sequencing.” As a result, the present study may have underestimated CHIP prevalence because of shallow sequencing depth.

“This inconsistency is a common challenge in CH population studies due to the lack of standardized methodologies and the frequent reliance on preexisting data not originally intended for CH detection,” Dr. Takahashi and Ms. Shah said.

Even so, despite the “heavily context-dependent” nature of these reported risks, the body of evidence to date now offers a convincing biological rationale linking CH with cancer development and outcomes, they added.
 

How Do the CHIP- and mCA-associated Risks Differ Between Solid Tumors and Blood Cancers?

“[These solid tumor risks are] not causal in the way CHIP mutations are causal for blood cancers,” Dr. Desai said. “Here we are talking about solid tumor risk, and it’s kind of scattered. It’s not just breast cancer ... there’s also increased colon cancer mortality. So I feel these mutations are doing something different ... they are sort of an added factor.”

Specific mechanisms remain unclear, Dr. Desai said, although she speculated about possible impacts on the inflammatory state or alterations to the tumor microenvironment.

“These are blood cells, right?” Dr. Desai asked. “They’re everywhere, and they’re changing something inherently in these tumors.”
 

Future research and therapeutic development

Siddhartha Jaiswal, MD, PhD, assistant professor in the Department of Pathology at Stanford University in California, whose lab focuses on clonal hematopoiesis, said the causality question is central to future research.

“The key question is, are these mutations acting because they alter the function of blood cells in some way to promote cancer risk, or is it reflective of some sort of shared etiology that’s not causal?” Dr. Jaiswal said in an interview.

Available data support both possibilities.

On one side, “reasonable evidence” supports the noncausal view, Dr. Jaiswal noted, because telomere length is one of the most common genetic risk factors for clonal hematopoiesis and also for solid tumors, suggesting a shared genetic factor. On the other hand, CHIP and mCA could be directly protumorigenic via conferred disturbances of immune cell function.

When asked if both causal and noncausal factors could be at play, Dr. Jaiswal said, “yeah, absolutely.”

The presence of a causal association could be promising from a therapeutic standpoint.

“If it turns out that this association is driven by a direct causal effect of the mutations, perhaps related to immune cell function or dysfunction, then targeting that dysfunction could be a therapeutic path to improve outcomes in people, and there’s a lot of interest in this,” Dr. Jaiswal said. He went on to explain how a trial exploring this approach via interleukin-8 inhibition in lung cancer fell short.

Yet earlier intervention may still hold promise, according to experts.

“[This study] provokes the hypothesis that CH‐targeted interventions could potentially reduce cancer risk in the future,” Dr. Takahashi and Ms. Shah said in their editorial.

The WHI program is funded by the National Heart, Lung, and Blood Institute; National Institutes of Health; and the Department of Health & Human Services. The investigators disclosed relationships with Eli Lilly, AbbVie, Celgene, and others. Dr. Jaiswal reported stock equity in a company that has an interest in clonal hematopoiesis.

A version of this article first appeared on Medscape.com.

Clonal hematopoiesis of indeterminate potential (CHIP) and mosaic chromosomal alterations (mCAs) are associated with an increased risk for breast cancer, and CHIP is associated with increased mortality in patients with colon cancer, according to the authors of new research.

These findings, drawn from almost 11,000 patients in the Women’s Health Initiative (WHI) study, add further evidence that CHIP and mCA drive solid tumor risk, alongside known associations with hematologic malignancies, reported lead author Pinkal Desai, MD, associate professor of medicine and clinical director of molecular aging at Englander Institute for Precision Medicine, Weill Cornell Medical College, New York City, and colleagues.
 

How This Study Differs From Others of Breast Cancer Risk Factors

“The independent effect of CHIP and mCA on risk and mortality from solid tumors has not been elucidated due to lack of detailed data on mortality outcomes and risk factors,” the investigators wrote in Cancer, although some previous studies have suggested a link.

In particular, the investigators highlighted a 2022 UK Biobank study, which reported an association between CHIP and lung cancer and a borderline association with breast cancer that did not quite reach statistical significance.

But the UK Biobank study was confined to a UK population, Dr. Desai noted in an interview, and the data were less detailed than those in the present investigation.

“In terms of risk, the part that was lacking in previous studies was a comprehensive assessment of risk factors that increase risk for all these cancers,” Dr. Desai said. “For example, for breast cancer, we had very detailed data on [participants’] Gail risk score, which is known to impact breast cancer risk. We also had mammogram data and colonoscopy data.”

In an accompanying editorial, Koichi Takahashi, MD, PhD , and Nehali Shah, BS, of The University of Texas MD Anderson Cancer Center, Houston, Texas, pointed out the same UK Biobank findings, then noted that CHIP has also been linked with worse overall survival in unselected cancer patients. Still, they wrote, “the impact of CH on cancer risk and mortality remains controversial due to conflicting data and context‐dependent effects,” necessitating studies like this one by Dr. Desai and colleagues.
 

How Was the Relationship Between CHIP, MCA, and Solid Tumor Risk Assessed?

To explore possible associations between CHIP, mCA, and solid tumors, the investigators analyzed whole genome sequencing data from 10,866 women in the WHI, a multi-study program that began in 1992 and involved 161,808 women in both observational and clinical trial cohorts.

In 2002, the first big data release from the WHI suggested that hormone replacement therapy (HRT) increased breast cancer risk, leading to widespread reduction in HRT use.

More recent reports continue to shape our understanding of these risks, suggesting differences across cancer types. For breast cancer, the WHI data suggested that HRT-associated risk was largely driven by formulations involving progesterone and estrogen, whereas estrogen-only formulations, now more common, are generally considered to present an acceptable risk profile for suitable patients.

The new study accounted for this potential HRT-associated risk, including by adjusting for patients who received HRT, type of HRT received, and duration of HRT received. According to Desai, this approach is commonly used when analyzing data from the WHI, nullifying concerns about the potentially deleterious effects of the hormones used in the study.

“Our question was not ‘does HRT cause cancer?’ ” Dr. Desai said in an interview. “But HRT can be linked to breast cancer risk and has a potential to be a confounder, and hence the above methodology.

“So I can say that the confounding/effect modification that HRT would have contributed to in the relationship between exposure (CH and mCA) and outcome (cancer) is well adjusted for as described above. This is standard in WHI analyses,” she continued.

“Every Women’s Health Initiative analysis that comes out — not just for our study — uses a standard method ... where you account for hormonal therapy,” Dr. Desai added, again noting that many other potential risk factors were considered, enabling a “detailed, robust” analysis.

Dr. Takahashi and Ms. Shah agreed. “A notable strength of this study is its adjustment for many confounding factors,” they wrote. “The cohort’s well‐annotated data on other known cancer risk factors allowed for a robust assessment of CH’s independent risk.”
 

How Do Findings Compare With Those of the UK Biobank Study?

CHIP was associated with a 30% increased risk for breast cancer (hazard ratio [HR], 1.30; 95% CI, 1.03-1.64; P = .02), strengthening the borderline association reported by the UK Biobank study.

In contrast with the UK Biobank study, CHIP was not associated with lung cancer risk, although this may have been caused by fewer cases of lung cancer and a lack of male patients, Dr. Desai suggested.

“The discrepancy between the studies lies in the risk of lung cancer, although the point estimate in the current study suggested a positive association,” wrote Dr. Takahashi and Ms. Shah.

As in the UK Biobank study, CHIP was not associated with increased risk of developing colorectal cancer.

Mortality analysis, however, which was not conducted in the UK Biobank study, offered a new insight: Patients with existing colorectal cancer and CHIP had a significantly higher mortality risk than those without CHIP. Before stage adjustment, risk for mortality among those with colorectal cancer and CHIP was fourfold higher than those without CHIP (HR, 3.99; 95% CI, 2.41-6.62; P < .001). After stage adjustment, CHIP was still associated with a twofold higher mortality risk (HR, 2.50; 95% CI, 1.32-4.72; P = .004).

The investigators’ first mCA analyses, which employed a cell fraction cutoff greater than 3%, were unfruitful. But raising the cell fraction threshold to 5% in an exploratory analysis showed that autosomal mCA was associated with a 39% increased risk for breast cancer (HR, 1.39; 95% CI, 1.06-1.83; P = .01). No such associations were found between mCA and colorectal or lung cancer, regardless of cell fraction threshold.

The original 3% cell fraction threshold was selected on the basis of previous studies reporting a link between mCA and hematologic malignancies at this cutoff, Dr. Desai said.

She and her colleagues said a higher 5% cutoff might be needed, as they suspected that the link between mCA and solid tumors may not be causal, requiring a higher mutation rate.
 

Why Do Results Differ Between These Types of Studies?

Dr. Takahashi and Ms. Shah suggested that one possible limitation of the new study, and an obstacle to comparing results with the UK Biobank study and others like it, goes beyond population heterogeneity; incongruent findings could also be explained by differences in whole genome sequencing (WGS) technique.

“Although WGS allows sensitive detection of mCA through broad genomic coverage, it is less effective at detecting CHIP with low variant allele frequency (VAF) due to its relatively shallow depth (30x),” they wrote. “Consequently, the prevalence of mCA (18.8%) was much higher than that of CHIP (8.3%) in this cohort, contrasting with other studies using deeper sequencing.” As a result, the present study may have underestimated CHIP prevalence because of shallow sequencing depth.

“This inconsistency is a common challenge in CH population studies due to the lack of standardized methodologies and the frequent reliance on preexisting data not originally intended for CH detection,” Dr. Takahashi and Ms. Shah said.

Even so, despite the “heavily context-dependent” nature of these reported risks, the body of evidence to date now offers a convincing biological rationale linking CH with cancer development and outcomes, they added.
 

How Do the CHIP- and mCA-associated Risks Differ Between Solid Tumors and Blood Cancers?

“[These solid tumor risks are] not causal in the way CHIP mutations are causal for blood cancers,” Dr. Desai said. “Here we are talking about solid tumor risk, and it’s kind of scattered. It’s not just breast cancer ... there’s also increased colon cancer mortality. So I feel these mutations are doing something different ... they are sort of an added factor.”

Specific mechanisms remain unclear, Dr. Desai said, although she speculated about possible impacts on the inflammatory state or alterations to the tumor microenvironment.

“These are blood cells, right?” Dr. Desai asked. “They’re everywhere, and they’re changing something inherently in these tumors.”
 

Future research and therapeutic development

Siddhartha Jaiswal, MD, PhD, assistant professor in the Department of Pathology at Stanford University in California, whose lab focuses on clonal hematopoiesis, said the causality question is central to future research.

“The key question is, are these mutations acting because they alter the function of blood cells in some way to promote cancer risk, or is it reflective of some sort of shared etiology that’s not causal?” Dr. Jaiswal said in an interview.

Available data support both possibilities.

On one side, “reasonable evidence” supports the noncausal view, Dr. Jaiswal noted, because telomere length is one of the most common genetic risk factors for clonal hematopoiesis and also for solid tumors, suggesting a shared genetic factor. On the other hand, CHIP and mCA could be directly protumorigenic via conferred disturbances of immune cell function.

When asked if both causal and noncausal factors could be at play, Dr. Jaiswal said, “yeah, absolutely.”

The presence of a causal association could be promising from a therapeutic standpoint.

“If it turns out that this association is driven by a direct causal effect of the mutations, perhaps related to immune cell function or dysfunction, then targeting that dysfunction could be a therapeutic path to improve outcomes in people, and there’s a lot of interest in this,” Dr. Jaiswal said. He went on to explain how a trial exploring this approach via interleukin-8 inhibition in lung cancer fell short.

Yet earlier intervention may still hold promise, according to experts.

“[This study] provokes the hypothesis that CH‐targeted interventions could potentially reduce cancer risk in the future,” Dr. Takahashi and Ms. Shah said in their editorial.

The WHI program is funded by the National Heart, Lung, and Blood Institute; National Institutes of Health; and the Department of Health & Human Services. The investigators disclosed relationships with Eli Lilly, AbbVie, Celgene, and others. Dr. Jaiswal reported stock equity in a company that has an interest in clonal hematopoiesis.

A version of this article first appeared on Medscape.com.

Clonal hematopoiesis of indeterminate potential (CHIP) and mosaic chromosomal alterations (mCAs) are associated with an increased risk for breast cancer, and CHIP is associated with increased mortality in patients with colon cancer, according to the authors of new research.

These findings, drawn from almost 11,000 patients in the Women’s Health Initiative (WHI) study, add further evidence that CHIP and mCA drive solid tumor risk, alongside known associations with hematologic malignancies, reported lead author Pinkal Desai, MD, associate professor of medicine and clinical director of molecular aging at Englander Institute for Precision Medicine, Weill Cornell Medical College, New York City, and colleagues.
 

How This Study Differs From Others of Breast Cancer Risk Factors

“The independent effect of CHIP and mCA on risk and mortality from solid tumors has not been elucidated due to lack of detailed data on mortality outcomes and risk factors,” the investigators wrote in Cancer, although some previous studies have suggested a link.

In particular, the investigators highlighted a 2022 UK Biobank study, which reported an association between CHIP and lung cancer and a borderline association with breast cancer that did not quite reach statistical significance.

But the UK Biobank study was confined to a UK population, Dr. Desai noted in an interview, and the data were less detailed than those in the present investigation.

“In terms of risk, the part that was lacking in previous studies was a comprehensive assessment of risk factors that increase risk for all these cancers,” Dr. Desai said. “For example, for breast cancer, we had very detailed data on [participants’] Gail risk score, which is known to impact breast cancer risk. We also had mammogram data and colonoscopy data.”

In an accompanying editorial, Koichi Takahashi, MD, PhD , and Nehali Shah, BS, of The University of Texas MD Anderson Cancer Center, Houston, Texas, pointed out the same UK Biobank findings, then noted that CHIP has also been linked with worse overall survival in unselected cancer patients. Still, they wrote, “the impact of CH on cancer risk and mortality remains controversial due to conflicting data and context‐dependent effects,” necessitating studies like this one by Dr. Desai and colleagues.
 

How Was the Relationship Between CHIP, MCA, and Solid Tumor Risk Assessed?

To explore possible associations between CHIP, mCA, and solid tumors, the investigators analyzed whole genome sequencing data from 10,866 women in the WHI, a multi-study program that began in 1992 and involved 161,808 women in both observational and clinical trial cohorts.

In 2002, the first big data release from the WHI suggested that hormone replacement therapy (HRT) increased breast cancer risk, leading to widespread reduction in HRT use.

More recent reports continue to shape our understanding of these risks, suggesting differences across cancer types. For breast cancer, the WHI data suggested that HRT-associated risk was largely driven by formulations involving progesterone and estrogen, whereas estrogen-only formulations, now more common, are generally considered to present an acceptable risk profile for suitable patients.

The new study accounted for this potential HRT-associated risk, including by adjusting for patients who received HRT, type of HRT received, and duration of HRT received. According to Desai, this approach is commonly used when analyzing data from the WHI, nullifying concerns about the potentially deleterious effects of the hormones used in the study.

“Our question was not ‘does HRT cause cancer?’ ” Dr. Desai said in an interview. “But HRT can be linked to breast cancer risk and has a potential to be a confounder, and hence the above methodology.

“So I can say that the confounding/effect modification that HRT would have contributed to in the relationship between exposure (CH and mCA) and outcome (cancer) is well adjusted for as described above. This is standard in WHI analyses,” she continued.

“Every Women’s Health Initiative analysis that comes out — not just for our study — uses a standard method ... where you account for hormonal therapy,” Dr. Desai added, again noting that many other potential risk factors were considered, enabling a “detailed, robust” analysis.

Dr. Takahashi and Ms. Shah agreed. “A notable strength of this study is its adjustment for many confounding factors,” they wrote. “The cohort’s well‐annotated data on other known cancer risk factors allowed for a robust assessment of CH’s independent risk.”
 

How Do Findings Compare With Those of the UK Biobank Study?

CHIP was associated with a 30% increased risk for breast cancer (hazard ratio [HR], 1.30; 95% CI, 1.03-1.64; P = .02), strengthening the borderline association reported by the UK Biobank study.

In contrast with the UK Biobank study, CHIP was not associated with lung cancer risk, although this may have been caused by fewer cases of lung cancer and a lack of male patients, Dr. Desai suggested.

“The discrepancy between the studies lies in the risk of lung cancer, although the point estimate in the current study suggested a positive association,” wrote Dr. Takahashi and Ms. Shah.

As in the UK Biobank study, CHIP was not associated with increased risk of developing colorectal cancer.

Mortality analysis, however, which was not conducted in the UK Biobank study, offered a new insight: Patients with existing colorectal cancer and CHIP had a significantly higher mortality risk than those without CHIP. Before stage adjustment, risk for mortality among those with colorectal cancer and CHIP was fourfold higher than those without CHIP (HR, 3.99; 95% CI, 2.41-6.62; P < .001). After stage adjustment, CHIP was still associated with a twofold higher mortality risk (HR, 2.50; 95% CI, 1.32-4.72; P = .004).

The investigators’ first mCA analyses, which employed a cell fraction cutoff greater than 3%, were unfruitful. But raising the cell fraction threshold to 5% in an exploratory analysis showed that autosomal mCA was associated with a 39% increased risk for breast cancer (HR, 1.39; 95% CI, 1.06-1.83; P = .01). No such associations were found between mCA and colorectal or lung cancer, regardless of cell fraction threshold.

The original 3% cell fraction threshold was selected on the basis of previous studies reporting a link between mCA and hematologic malignancies at this cutoff, Dr. Desai said.

She and her colleagues said a higher 5% cutoff might be needed, as they suspected that the link between mCA and solid tumors may not be causal, requiring a higher mutation rate.
 

Why Do Results Differ Between These Types of Studies?

Dr. Takahashi and Ms. Shah suggested that one possible limitation of the new study, and an obstacle to comparing results with the UK Biobank study and others like it, goes beyond population heterogeneity; incongruent findings could also be explained by differences in whole genome sequencing (WGS) technique.

“Although WGS allows sensitive detection of mCA through broad genomic coverage, it is less effective at detecting CHIP with low variant allele frequency (VAF) due to its relatively shallow depth (30x),” they wrote. “Consequently, the prevalence of mCA (18.8%) was much higher than that of CHIP (8.3%) in this cohort, contrasting with other studies using deeper sequencing.” As a result, the present study may have underestimated CHIP prevalence because of shallow sequencing depth.

“This inconsistency is a common challenge in CH population studies due to the lack of standardized methodologies and the frequent reliance on preexisting data not originally intended for CH detection,” Dr. Takahashi and Ms. Shah said.

Even so, despite the “heavily context-dependent” nature of these reported risks, the body of evidence to date now offers a convincing biological rationale linking CH with cancer development and outcomes, they added.
 

How Do the CHIP- and mCA-associated Risks Differ Between Solid Tumors and Blood Cancers?

“[These solid tumor risks are] not causal in the way CHIP mutations are causal for blood cancers,” Dr. Desai said. “Here we are talking about solid tumor risk, and it’s kind of scattered. It’s not just breast cancer ... there’s also increased colon cancer mortality. So I feel these mutations are doing something different ... they are sort of an added factor.”

Specific mechanisms remain unclear, Dr. Desai said, although she speculated about possible impacts on the inflammatory state or alterations to the tumor microenvironment.

“These are blood cells, right?” Dr. Desai asked. “They’re everywhere, and they’re changing something inherently in these tumors.”
 

Future research and therapeutic development

Siddhartha Jaiswal, MD, PhD, assistant professor in the Department of Pathology at Stanford University in California, whose lab focuses on clonal hematopoiesis, said the causality question is central to future research.

“The key question is, are these mutations acting because they alter the function of blood cells in some way to promote cancer risk, or is it reflective of some sort of shared etiology that’s not causal?” Dr. Jaiswal said in an interview.

Available data support both possibilities.

On one side, “reasonable evidence” supports the noncausal view, Dr. Jaiswal noted, because telomere length is one of the most common genetic risk factors for clonal hematopoiesis and also for solid tumors, suggesting a shared genetic factor. On the other hand, CHIP and mCA could be directly protumorigenic via conferred disturbances of immune cell function.

When asked if both causal and noncausal factors could be at play, Dr. Jaiswal said, “yeah, absolutely.”

The presence of a causal association could be promising from a therapeutic standpoint.

“If it turns out that this association is driven by a direct causal effect of the mutations, perhaps related to immune cell function or dysfunction, then targeting that dysfunction could be a therapeutic path to improve outcomes in people, and there’s a lot of interest in this,” Dr. Jaiswal said. He went on to explain how a trial exploring this approach via interleukin-8 inhibition in lung cancer fell short.

Yet earlier intervention may still hold promise, according to experts.

“[This study] provokes the hypothesis that CH‐targeted interventions could potentially reduce cancer risk in the future,” Dr. Takahashi and Ms. Shah said in their editorial.

The WHI program is funded by the National Heart, Lung, and Blood Institute; National Institutes of Health; and the Department of Health & Human Services. The investigators disclosed relationships with Eli Lilly, AbbVie, Celgene, and others. Dr. Jaiswal reported stock equity in a company that has an interest in clonal hematopoiesis.

A version of this article first appeared on Medscape.com.

Pulmonology Data Trends 2024 is a supplement to CHEST Physician highlighting the latest breakthroughs in pulmonology research and treatments through a series of infographics.

Read more: 

Artificial Intelligence in Sleep Apnea
Ritwick Agrawal, MD, MS, FCCP

RSV Updates: Prophylaxis Approval and Hospitalization for Severe RSV
Riddhi Upadhyay, MD

Biologics in Asthma: Changing the Severe Asthma Paradigm
Shyam Subramanian, MD, FCCP

Updates in COPD Guidelines and Treatment
Dharani K. Narendra, MD, FCCP

Targeted Therapies and Surgical Resection for Lung Cancer: Evolving Treatment Options
Saadia A. Faiz, MD, FCCP

Closing the GAP in Idiopathic Pulmonary Fibrosis
Humayun Anjum, MD, FCCP

Severe Community-Acquired Pneumonia: Diagnostic Criteria, Treatment, and COVID-19
Sujith V. Cherian, MD, FCCP

Pulmonary Hypertension: Comorbidities and Novel Therapies
Mary Jo S. Farmer, MD, PhD, FCCP

The Genetic Side of Interstitial Lung Disease
Priya Balakrishnan, MD, MS, FCCP

Noninvasive Ventilation in Neuromuscular Disease
Sreelatha Naik, MD, FCCP, and Kelly Lobrutto, CRNP

Pulmonology Data Trends 2024 is a supplement to CHEST Physician highlighting the latest breakthroughs in pulmonology research and treatments through a series of infographics.

Read more: 

Artificial Intelligence in Sleep Apnea
Ritwick Agrawal, MD, MS, FCCP

RSV Updates: Prophylaxis Approval and Hospitalization for Severe RSV
Riddhi Upadhyay, MD

Biologics in Asthma: Changing the Severe Asthma Paradigm
Shyam Subramanian, MD, FCCP

Updates in COPD Guidelines and Treatment
Dharani K. Narendra, MD, FCCP

Targeted Therapies and Surgical Resection for Lung Cancer: Evolving Treatment Options
Saadia A. Faiz, MD, FCCP

Closing the GAP in Idiopathic Pulmonary Fibrosis
Humayun Anjum, MD, FCCP

Severe Community-Acquired Pneumonia: Diagnostic Criteria, Treatment, and COVID-19
Sujith V. Cherian, MD, FCCP

Pulmonary Hypertension: Comorbidities and Novel Therapies
Mary Jo S. Farmer, MD, PhD, FCCP

The Genetic Side of Interstitial Lung Disease
Priya Balakrishnan, MD, MS, FCCP

Noninvasive Ventilation in Neuromuscular Disease
Sreelatha Naik, MD, FCCP, and Kelly Lobrutto, CRNP

Pulmonology Data Trends 2024 is a supplement to CHEST Physician highlighting the latest breakthroughs in pulmonology research and treatments through a series of infographics.

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Artificial Intelligence in Sleep Apnea
Ritwick Agrawal, MD, MS, FCCP

RSV Updates: Prophylaxis Approval and Hospitalization for Severe RSV
Riddhi Upadhyay, MD

Biologics in Asthma: Changing the Severe Asthma Paradigm
Shyam Subramanian, MD, FCCP

Updates in COPD Guidelines and Treatment
Dharani K. Narendra, MD, FCCP

Targeted Therapies and Surgical Resection for Lung Cancer: Evolving Treatment Options
Saadia A. Faiz, MD, FCCP

Closing the GAP in Idiopathic Pulmonary Fibrosis
Humayun Anjum, MD, FCCP

Severe Community-Acquired Pneumonia: Diagnostic Criteria, Treatment, and COVID-19
Sujith V. Cherian, MD, FCCP

Pulmonary Hypertension: Comorbidities and Novel Therapies
Mary Jo S. Farmer, MD, PhD, FCCP

The Genetic Side of Interstitial Lung Disease
Priya Balakrishnan, MD, MS, FCCP

Noninvasive Ventilation in Neuromuscular Disease
Sreelatha Naik, MD, FCCP, and Kelly Lobrutto, CRNP