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Tobacco smoking rates have declined over recent decades but tobacco use remains a leading cause of cancer. Smoking causes 1 in 5 cancers overall and nearly one-third of all cancer deaths in the United States.1 The association is particularly stark for lung cancers, more than 80% of which are caused by tobacco.1 

Continued smoking after a cancer diagnosis is a significant challenge for successful treatment, including radiotherapy, reducing complete response rates and quality of life, and increasing the risk of radiation toxicities and complications, locoregional tumor recurrence, second cancers, and death.2-8 A systematic review of data from 71 studies found that smoking during adjuvant breast cancer radiotherapy is associated with skin reactions and worse cardiovascular, lung function, and breast reconstruction outcomes, and a higher risk of secondary carcinomas and death.4  

Tobacco smoke contains more than 4000 chemicals, including arsenic, benzene, cadmium, formaldehyde, hydrogen cyanide, lead, and other known carcinogens.5 Collectively, this complexly toxic chemical mixture renders cancer treatments — including radiotherapy, chemotherapy, and surgery — less effective and more toxic, while altering tumor biology in ways that can make malignancies more aggressive.2,5-8 Smoking constricts blood vessels, reducing oxygen perfusion; upregulates inflammatory and tumor signaling pathways associated with proliferation, angiogenesis, and tissue invasion; increases the risk of tumor cell radioresistance; impairs tissue healing processes; and worsens radiation toxicities such as mucositis, xerostomia, diarrhea, and weight loss.3,5,7 

Compared to patients who quit smoking at the time of a cancer diagnosis, smokers undergoing cancer treatment have poorer overall survival and more adverse events.9 

Surprisingly, given its critical importance for patient outcomes, the molecular pathways and impacts of continued tobacco use and how a patient’s smoking status and history should guide treatment decisions remain poorly understood.8-10 These gaps do not mean the connection between continued smoking and poorer outcomes is in doubt, but they do need to be studied to better understand how to optimize treatments informed by patient smoking status and history.

“Several studies have demonstrated a clear correlation between smoking and the response to radiation or chemoradiation therapy in various cancers,” explained Srikumar Chellappan, MD, of the H. Lee Moffitt Cancer Center in Tampa, Florida, in a 2022 review of how smoking cessation enhances therapeutic responses.9 “While the underlying molecular mechanisms have not been fully elucidated, the poor response to radiotherapy has been prevalent across several cancer types, indicating that it is a genuine correlation.”

The International Association for the Study of Lung Cancer (IASLC) recently called for more systematic collection of data on patients’ tobacco smoking and smoking cessation efforts in clinical trials to help close that evidence gap.8,10 In 80% of cases, tobacco use data is not collected at baseline (enrollment) in clinical cancer trials. In those trials that do gather the data, it frequently goes unanalyzed.8 Smoking frequency is rarely collected.8 Worse yet, consistent definitions are not implemented across studies, and even how best to ask patients about their tobacco use is unclear.8,10 

IASLC recommendations including documentation of tobacco use with standard definitions used in the validated Cancer Patient Tobacco Use Questionnaire (C-TUQ) when patients enroll to participate in a clinical trial, and to document all tobacco use, including e-cigarettes, smoking cessation efforts, and to analyze how tobacco use and cessation correlate with response rates, survival, adverse events, and quality of life.8,10   

"
There's a whole host of things that negatively impact radiation therapy, and increase toxicity from the radiation for those who continue to smoke.

“There are short-term and long-term effects, because radiation induces more inflammation in the smoker, in the tissues that are in the radiation field,” said William Evans, MD, professor emeritus of Oncology at McMaster University in Ontario, Canada, and a coauthor of the IASLC recommendations [interview; March 5, 2024]. “There's a whole host of things that negatively impact radiation therapy, and increase toxicity from the radiation for those who continue to smoke.” 

Those impacts vary between cancer types and irradiated anatomies, Dr Evans noted. 

“Radiation for laryngeal cancer causes more radiation reaction mucositis in the vocal cords and throat in the treatment field and a weaker voice, generally speaking, at the end of treatment,” he explained. “Radiating the pelvis, say for endometrial cancer, ovarian cancer, or prostate cancer, there's the small bowel, large bowel, and bladder in the radiotherapy fields. All of those will have more inflammation which increases acute symptoms like diarrhea or frequency of painful urination, but they also can lead to long-term effects — more scarring, so that you could end up with a more contracted bladder and hence urinary symptoms on an ongoing basis after the healing occurs to the mucosa and the same in the bowels.” 

Smoking Cessation

There are numerous smoking cessation strategies, which can be broken down into 5 general categories11,12:

  • Nicotine replacement pharmacotherapy (NRT) Provides controlled-dose nicotine to curb cravings without exposure to toxic tobacco smoke
  • Behavioral counseling Psychological support and education, including stress management strategies. Practices vary but can include a single session or sustained counseling throughout cancer treatment
  • Social support Education of patients, their family and caregivers, and cancer care clinicians to support patient efforts to quit smoking through encouragement and reminders
  • Quit plans A structured step-by-step plan for quitting smoking, anticipating and planning for challenges
  • High-intensity or combined interventions These approaches combine behavioral, social support, and pharmacotherapeutic strategies

As with the effects on cancer treatment of continued smoking, the benefits of smoking cessation at diagnosis, as well as the best approaches to cessation, urgently need more high-quality, well-designed trials. A 2024 meta-analysis of data from 72 studies, 19 of which were randomized, controlled clinical trials, by researchers in the Netherlands found that methodologic quality is generally poor.12 However, what is known so far strongly supports benefits to patients.12,13 For example, among people with head and neck cancer, for which cigarette smoking is the leading risk factor, quitting at diagnosis is associated with better overall survival.13 

In a meta-analysis of a subset of relatively high-quality studies (18 randomized controlled trials and 3 observational studies), the Dutch authors of the 2024 meta-analysis found significant benefits to patients of smoking cessation interventions based on behavioral interventions or combined-modality (behavioral support plus pharmacotherapy) interventions, but not for pharmacologic interventions alone.12 

High-intensity combination pharmacotherapeutic and behavioral interventions (sustained counseling during treatment and free smoking-cessation medication) is associated with a 67% greater success rate than telephone counseling and medication advice.12,14  

Integrating comprehensive smoking cessation care into clinical oncology can be time consuming and expensive. But given the stakes, and compared to less effective and more toxic cancer treatment, it is money well spent, experts say.  

Radiation oncology teams and oncology nurses can lead the way, motivating, educating, and assisting patients, and providing or advocating for patient referrals to sustained tobacco cessation support.15-18 The Oncology Nursing Society and US National Heart, Lung, and Blood Institute Smoking Education Program offer advice about how oncology nurses can play a significant role in smoking cessation.18,19

Sustained interventions are key: patients very frequently resume smoking by 12 months after cessation interventions.17 Step one is recording smoking status and history and offering smoking cessation support to all patients undergoing radiotherapy. Patients with prostate or breast cancer are less frequently offered smoking-cessation care.16 Smoking history is recorded less frequently for patients with prostate cancer (65% of the time) than for patients with breast (91%), head and neck (96%), or lung (97%) cancers, according to a 2020 study at the Oregon Health & Science University in Portland.16 

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Cancer is a major public health concern that is expected to impact 2 million people in the year 2024, with an estimated number of 611,720 expected deaths.1 A cancer diagnosis does not discriminate based on race, ethnicity, gender, sexual identity, socioeconomic status, or geographic location. However, these factors are social determinants of health that may impact treatment outcomes, treatment adherence, and survival rates. 

The National Cancer Institute defines health disparities as differences between certain demographics affecting access to proper health care services. These differences are determined by the social factors mentioned. Some of the main disparities that patients face include access to screening services; treatment options; lack of insurance; psychosocial support; mental health support; and assistance with basic needs such as housing, food, and transportation.2 While research on health disparities and how to address them at a larger scale is rapidly increasing, healthcare professionals can actively seek ways to address health disparities on an individual level. 

Patient-Centered Model 

Patient-centered care is an approach designed to prioritize patients' individual needs, values, and preferences.3 Hospitals and cancer centers typically implement programs and psychosocial services providing patient-centered care. These programs and services may focus on addressing barriers to care such as financial assistance for cancer treatment, medications, issues with transportation, access to psychosocial support, and other barriers that may be related to health disparities. 

Nurse navigators, hospital social workers, and patient navigators each provide an essential function in delivering comprehensive and holistic support to the patient receiving cancer care. Establishing a cohesive multidisciplinary approach is crucial to patient-centered care to properly address health disparities and service gaps. 

An important factor is that not all cancer centers and providers incorporate an interprofessional team composed of these professionals. However, establishing cohesiveness between disciplines within patient care may directly address health disparities on an individual level without duplication of services.

Understanding and Delineating Each Role 

To establish a collaborative approach there must be a clear definition of the roles in each discipline and its functions. Disparities may range from the importance of health literacy to address treatment adherence, to needing assistance with coordinating appointments, to discussing side effects and ways to manage them, to addressing depression or anxiety that is directly related to the cancer diagnosis, to needing assistance with finances. 

Social workers, nurse navigators, and patient navigators have a mutual purpose, which is to identify barriers and provide guidance, referrals, and resources that address the barriers identified. These 3 disciplines also utilize similar tools to determine areas of need such as distress screeners, needs assessments, and other forms of assessment tools. 

Although the tools utilized are similar, they operate at various levels of support and have different scopes of practice. A nurse navigator may be the healthcare professional that spends the most time with the patient in a 1-on-1 setting. Nurse navigators' main task is facilitating coordination of care; providing educational information regarding diagnosis and treatment, including side effects; and providing referrals to needs outside of the scope. Nurse navigators also may be able to connect with oncologists regarding their patients' concerns and progress. 

"
Although most healthcare professionals won’t have the tools, bandwidth, or roles to address health disparities on a large scale, a cohesive interdisciplinary team can address health disparities at an individual level.

Social workers may have distinct roles depending on the healthcare setting. However, the main role of any social worker is to address psychosocial concerns and mental health issues that may interfere with patients’ adherence to treatments or access to care, as well as providing self-advocacy tools and techniques. 

A patient navigator may have similar functions to a nurse navigator or a social worker, and social workers may also have the title of a patient navigator depending on the setting and organizational structure. However, this role has increasingly shifted to being fulfilled by survivors and community members.4 

How to Establish a Collaborative and Cohesive Approach 

Once the roles of the treatment team have been clearly defined, several strategies must be implemented to foster a collaborative approach. Although treatment centers may not have all 3 disciplines established in a team, these strategies can still be useful in bridging any gaps in services and providing patient-centered care.5 

  • Channels of communication A clear channel of communication must be established within the team. This includes having interdisciplinary team meetings, electronic communication platforms, and standardized communication procedures. Creating channels of communication gives the team an opportunity to ensure they are informed about patients' care plans, updates, and any changes within their treatment and treatment protocol. Having interdisciplinary team meetings also offers insights on trends with patients, barriers, and access to care. 
  • Continuing education and training Although each respective professional must continue their education to maintain their licensing, offering well-rounded training to all members of the team is crucial in advancing oncology care, supportive interventions, and improving skills and techniques. Training can be geared towards trends the team has been noticing within their populations, as well as training in cultural humility, shared decision making, clinical trials, new and emerging treatments for cancer, disparities, etc. 
  • Quality improvement Establishing quality improvement initiatives will help ensure that the quality of care provided is consistent with patient and institutional goals. This can be done via monitoring, feedback from the team, feedback from patients, and data-driven reports. This can also help identify specific needs for services, or duplication of services. 
  • Employee emotional support and wellness initiatives Recognizing the emotional toll of working in oncology is imperative. The field is often demanding, and burn out and/or compassion fatigue is a common experience among employees. Research shows that burnout and compassion fatigue impact the quality of care and support helping professionals provide to their patients. Wellness initiatives such as yoga, meditation, and peer-to-peer support can facilitate coping skills and resilience.

There are many ways to address health disparities within different levels and systems. Although most healthcare professionals won’t have the tools, bandwidth, or roles to address health disparities on a large scale, a cohesive interdisciplinary team can address health disparities at an individual level. Cohesiveness can enhance creativity through different perspectives, shared responsibility and accountability, and promoting problem solving by integrating a range of expertise. 

Further Reading

Kirschbaum S. The social work perspective: a systematic review of best practices for social workers in healthcare teams. St Paul, MN: Sophia, the St. Catherine University repository website; 2017. Accessed March 7, 2024. https://sophia.stkate.edu/cgi/viewcontent.cgi?article=1858&context=msw_papers

American Association for Cancer Research (AACR). Overcoming cancer health disparities through science-based public policy. In: AACR. AACR Cancer Disparities Progress Report 2022. Philadelphia: American Association for Cancer Research; April 14, 2021. Accessed March 7, 2024. https://cancerprogressreport.aacr.org/wp-content/uploads/sites/2/2022/06/AACR_CDPR_2022.pdf

Taberna M, Gil Moncayo F, Jané-Salas E, et al. The multidisciplinary team (MDT) approach and quality of care. Front Oncol. 2020;10:85. doi:10.3389/fonc.2020.00085

Valentijn PP, Schepman SM, Opheij W, Bruijnzeels MA. Understanding integrated care: a comprehensive conceptual framework based on the integrative functions of primary care. Int J Integr Care, 2013;13:e010. doi:10.5334/ijic.886

Wells KJ, Valverde P, Ustjanauskas AE, Calhoun EA, Risendal BC. What are patient navigators doing, for whom, and where? A national survey evaluating the types of services provided by patient navigators. Patient Edu Couns. 2018;101(2):285-294. doi:10.1016/j.pec.2017.08.017

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The treatment paradigm for multiple myeloma has shifted in recent years. Notably, the gap between clinical trials and real-world practice continues to expand.

A drawback of randomized controlled trials (RCTs) is their inability to address every clinical scenario — patient care is often far more nuanced and complex. With the advent of artificial intelligence (AI) technologies, the integration of machine learning models in clinical decision support systems (CDSS) could be a potential solution to this problem.

In a report published in Blood, Barbara D. Lam, MD, of the department of medicine at Beth Israel Deaconess Medical Center in Boston, Massachusetts, and colleagues developed a CDSS that displays simulated survival and adverse event data from a clinical trial and machine learning model.

In a pilot study, Dr Lam and her colleagues evaluated how physicians utilize the available data to make treatment decisions for patients with multiple myeloma.

Testing the System

To test the system, physicians were recruited from the internal medicine and hematology-oncology departments at an academic medical center. They were presented with varying combinations of RCT and machine learning data in increasing “tiers” of information for 12 patients with multiple myeloma.

In tier 1, only RCT data was presented. In tier 2, participants were shown outcomes of a machine learning model, and in tier 3, they were provided with information about how the machine learning model was trained and validated. 

At each tier, clinicians were asked to choose a treatment (“red pill” or “blue pill”), rate their confidence in treatment on a scale from 1-10, and when machine learning data was available, rate their perceived reliability of the model.

Out of 284 physicians who were invited to participate, 32 (11.3%) took part in the study. Among the participants, 50% were internal medicine residents and 50% were hematology-oncology fellows and attendings. Most were White (69.0%), male (72.0%),  and all were less than 40 years of age.

"
Participants preferred the treatment that demonstrated a survival benefit, regardless of whether it was supported by RCT data or [a machine learning] model.

Across various clinical scenarios, a few trends were observed. “Confidence in treatment was highest when RCT and [machine learning] findings were concordant,” the study authors wrote in their report. “Participants preferred the treatment that demonstrated a survival benefit, regardless of whether it was supported by RCT data or [a machine learning] model.” This was the case even before participants learned how the model was trained or validated.

Finally, participants chose the treatment that showed a survival benefit, regardless of whether it was supported by RCT data or a machine learning model.

Results in Context 

Overall, there has been limited investigation into how clinicians reconcile RCT and machine learning data, especially when the results are conflicting. Larger prospective randomized trials are necessary to bring more clarity to this question.

Undoubtedly, the integration of machine learning models into modern CDSS is intriguing and may offer a new path towards precision oncology. Dr Lam and her colleagues have showcased a prime example in this single-center pilot experience involving patients with multiple myeloma.

A broader question is how to best implement CDSS into clinical workflows. The sample size of the existing research is quite small, and some have questioned the clinical efficiency of such systems in their present state. Despite these difficulties, there is still ample opportunity to further develop and improve the utility of these systems.2

Notably, CDSS are currently unable to replace oncologists. The value of these systems lies in their ability to support clinical decision making and train young physicians.2-3

Even if AI technology provides treatment suggestions, the most appropriate treatment needs to consider the patient's physical and mental wellbeing, financial status, complications, and willingness to receive such treatment.2,4

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The US Food & Drug Administration (FDA) has ordered a class-wide black box warning for all 6 approved genetically engineered BCMA- and CD-19 chimeric antigen receptor T-cell (CAR-T) autologous immunotherapies: axicabtagene ciloleucel (Yescarta®; Kite Pharma Inc), brexucabtagene autoleucel (TecartusTM; Kite Pharma Inc), ciltacabtagene autoleucel (CarvyktiTM; Janssen Biotech Inc), idecabtagene vicleucel (Abecma®; Bristol-Myers Squibb), lisocabtagene maraleucel (Breyanzi®; Bristol-Myers Squibb), and tisagenlecleucel (Kymriah®; Novartis Pharmaceuticals Corp). 

In letters to manufacturers dated January 19, 2024, the FDA said it had “become aware of the risk of T-cell malignancies, with serious outcomes, including hospitalization and death, following treatment with BCMA- and CD19-directed genetically modified autologous T-cell immunotherapies” and told the drugmakers to add warnings to the boxed label for patients and prescribing clinicians that potentially fatal secondary T-cell malignancies “may present as soon as weeks following infusion.”1

The move followed a November 2023 safety notice that the FDA was investigating a possible association between these biologics and secondary T-cell blood cancers.2 As of January 2024, the FDA knew of 25 cases among patients receiving 5 of the 6 approved CAR-T agents, but the agency did not specify the distribution of cases between agents.3,4 (Bristol Myers Squibb stated in January 2024 that the company knew of no CAR-positive T-cell cancers among more than 4700 patients administered idecabtagene vicleucel.5)

Support for FDA’s Action

Half of the 25 cases had occurred within a year of CAR T-cell infusion.4 In the 3 cases with available cancer cell gene sequencing data, the malignant cells harbored CAR transgenes, implicating CAR-T therapies as at least 1 factor in the secondary T-cell cancers.4 

Viruses used to introduce transgenes into patient T cells in the lab can sometimes insert those transgenes into unintended regions of the genome. If that occurs next to tumor suppressor genes or oncogenes, they could trigger up- or downregulation. Such insertional mutagenesis and resulting gene dysregulation might lead to carcinogenesis.5

“That’s always been the theoretical concern,” said David Porter, MD, director of Cell Therapy and Transplant and Jodi Fisher Horowitz Professor in Leukemia Care Excellence at Penn Medicine in Philadelphia. “The basic concern is that whenever you insert new genetic material into the genome, it has the potential of being inserted someplace it’s not supposed to be — and that can result in interrupting genes that are necessary for keeping a cell from becoming a cancer cell.”

The FDA’s initial approvals required 15 years of follow-up with patients to assess that risk. The first commercially available CAR-T therapy was tisagenlecleucel, approved in 2017, and detecting rare adverse events can take many years of real-world monitoring.

Despite the relatively few known cases and concern about news media headlines causing patient alarm,6 black box warnings were the right call, according to clinical experts contacted for this article. It is unlikely to immediately change clinical practice, they said.

“The black box warning is a way to alert clinicians and caregivers, and even patients, to this potential risk, but I don’t know that changes the decision-making process for using these therapies,” Dr Porter said.  “Anything that induces second cancers deserves attention, but I still believe strongly that for the vast majority of patients getting CAR T cells, the potential benefits far outweigh the small potential risk of T-cell lymphoma.”

“We were not surprised about the FDA’s decision … given the recent reports,” said Saad Usmani, MD, chief of the Myeloma Service at Memorial Sloan Kettering Cancer Center in New York. The available evidence suggests the risk of developing a second primary malignancy is “very low” and the benefits of CAR-T for patients with advanced hematologic malignancies outweigh that risk, he noted, echoing the FDA’s January 2024 statement

Risk and Incidence of SPM Remain Low

“The second primary malignancies or SPM issue has been recognized for years in multiple myeloma and is influenced by prior transplant and use of immunomodulatory drugs as maintenance,” Dr Usmani said. “The frontline trials comparing transplants to CAR-T therapies will be the most telling [about] where the SPM risk is originating from, and if the presence or absence of clonal hematopoiesis has a role to play in its origin in an older patient population.”

Johnson & Johnson spokesman Brian Kenney said the manufacturer is working with the FDA to update its anti-BCMA ciltacabtagene autoleucel’s prescribing information (personal interview, February 2024). Two ciltacabtagene-associated T-cell lymphoma cases have been identified, Mr Kenney said: a patient with relapsed/refractory multiple myeloma, who was enrolled in the phase 3 CARTITUDE-4 study (ClinicalTrials.gov Identifier: NCT04181827), and a January 22, 2024, case reported to the postmarketing FDA Adverse Event Reporting System (FAERS) database. 

The CARTITUDE-4 case was described in an abstract presented at the 2023 American Society of Hematology (ASH) Annual Meeting.7 The 51-year-old male patient had achieved a stringent complete response and no minimal residual disease (MRD) at 92 days postinfusion, but at 5 months postinfusion, he developed a rapidly growing erythematous nasofacial plaque that was diagnosed as CD2- and CD3-positive T-cell lymphoma.7 

“To date, more than 2000 patients have been treated with [ciltacabtagene autoleucel] worldwide,” Mr Kenney noted. “We remain confident in the favorable benefit-risk profile.”

A separate 2021 report stated that 2 of 10 patients in a phase 1 clinical trial of a piggyBac transposon-modified, CD-19-targeting CAR-T therapy developed CAR T-cell lymphomas.8 Despite detailed analysis, however, the authors found no evidence of insertional mutagenesis.8 

"
Given the ‘one-and-done’ nature of CAR-T infusions coupled with their potential for rapid and durable remissions, several trials have also shown that CAR-T outperforms standard therapies in terms of meaningful improvements in quality of life.

Genetically engineered CAR T cells are created by modifying a patient's own T cells to specifically target cancer antigens. Long-term outcomes following CAR-T therapy have shown robust and durable remissions among patients with B cell lymphomas.9 Common adverse events include cytokine release syndrome (CRS), characterized by symptoms such as high fever, chills, trouble breathing, and muscle pain, which can be life-threatening if not managed quickly and effectively. Other complications mentioned in the facts include CAR-T related encephalopathy, anemia, thrombocytopenia, and increased infection risk.10

Other Potential Causes of SPM

Some postinfusion secondary cancers may not be caused by CAR-T therapy. Patients receiving CAR-T therapies typically have relapsed or refractory hematologic cancers and have been exposed to bendamustine and other chemotherapy regimens associated with secondary cancer risk, as are stem cell transplantation and lenalidomide. Patients with B-cell cancers who do not receive CAR-T therapy sometimes develop T-cell lymphomas.5 And CAR-T therapies prolong patient survival, allowing secondary cancers caused by other factors time to emerge. 

Impact on Clinical Practice

The black box warnings are unlikely to deter clinicians from prescribing CAR-T therapies, largely because these patients frequently have few other options. But it remains important to describe the potential risk to patients.

“At Memorial Sloan Kettering Cancer Center, we have been following the SPM incidence in our patient population for many years, and we discuss the possibility of second malignancies with all of our multiple myeloma patients,” Dr Usmani explained. 

Widespread news coverage of the potential for secondary blood cancers following CAR-T therapy will likely leave many patients and their loved ones with serious concerns about this treatment modality. Authors from the Fred Hutchinson Cancer Center in Seattle recently suggested that patient communication about the black box warnings should focus on the relatively low risk and the overriding benefits of CAR-T therapy in the relapsed/refractory setting, and the fact that other factors might explain the reported secondary cancers.6 

“Given the ‘one-and-done’ nature of CAR-T infusions coupled with their potential for rapid and durable remissions, several trials have also shown that CAR-T outperforms standard therapies in terms of meaningful improvements in quality of life,” they noted.6 

Disclosure: Dr Porter has received consulting fees from Kite Pharma, and Dr Usmani has received funding from Bristol Myers Squibb and Janssen Biotech.

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