Reference
Fraterman I, Reijers ILM, Dimitriadis P, et al. Association between pretreatment emotional distress and neoadjuvant immune checkpoint blockade response in melanoma. Nat Med. 2023;29(12):3090-3099.
Study Objective
To determine the association between pretreatment levels of emotional distress (ED) and clinical responses after neoadjuvant immune checkpoint blockade (ICB) treatment in patients with stage IIIB–D melanoma
Design
Post-hoc analysis using data from the PRADO trial data
Participants
The participants in this study were part of the PRADO trial, and all had malignant melanoma (IIIB–D melanoma). At this time, PRADO is the largest trial to track data on emotional distress among patients undergoing checkpoint blockade for metastatic melanoma.
Of the 99 adult patients included in the study, 88 (89%) completed a baseline health-related quality-of-life (HRQoL) questionnaire. These patients were included in the current analysis and were defined as either having emotional distress (ED) before therapy (n=28) or having no ED before therapy (n=60). There were no significant differences in age or sex at baseline between those with ED (aged 46–70; 57% men) and those without (aged 52–76; 72% men). There were also no significant differences in tumor stages or molecular characteristics.
Intervention
Investigators used the European Organisation for Research and Treatment of Cancer scale for emotional functioning to identify patients with emotional distress (n=28) vs those without (n=60).
All patients underwent immunotherapy checkpoint blockade using ipilimumab plus nivolumab to target both CTLA-4 and PD-1 checkpoints.
Primary Outcome Measures
Major pathologic responses (MPR), relapse-free survival (RFS) at 2 years, distant metastasis-free survival at 2 years (DMFS)
Key Findings
Pretreatment ED was significantly associated with reduced major pathologic responses (46% vs 65%, adjusted odds ratio 0.20, P=0.038) after adjusting for potential biomarkers of response (such as interferon-gamma [IFNγ] signature and tumor mutational burden [TMB]), reduced 2-year relapse-free survival (74% vs 91%, adjusted hazard ratio 3.81, P=0.034), and reduced 2-year distant metastasis-free survival (78% vs 95%, adjusted hazard ratio 4.33, P=0.040).
Transparency
The PRADO trial is registered as NCT02977052. Sponsors and collaborators are
Practice Implications
While the immunotherapy drugs investigated in this study are outside the scope of practice of most naturopathic physicians, this study nevertheless has importance for all of us as it adds to our knowledge of factors that may influence the checkpoint-targeting drugs, and so, by extension, regulate the immune system’s ability to defend the body against potential threats. Such information, although at first glance esoteric, should still be welcome as it may translate into a broader understanding in naturopathic practice.
Also, as these new immunotherapy drugs are being rapidly adopted and used to treat a wide range of cancers, we will all be seeing patients undergoing checkpoint immunotherapy, and it is becoming vitally important to understand how we might help them. It is evident that many of the lifestyle and nutritional interventions that naturopathic doctors are well-suited and well-trained to rely on during routine practice significantly affect patient responsiveness to these new therapeutic drugs. Without necessarily being a specialist in naturopathic oncology, the average naturopathic physician can still greatly assist cancer patients undergoing checkpoint inhibitor immunotherapy.
First, let us examine the results obtained from this PRADO cohort and consider how we might translate them into our practices and then review briefly what other information we might use to improve treatment outcomes for these patients.
Bertrand Routy recently described both the good news and bad news regarding these drugs: “Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of melanoma and other cancers, in early stages and advanced settings, by inducing durable and sometimes curative clinical responses in subsets of patients. However, most cancer patients do not benefit from ICIs, and strategies to enhance responses remain an unmet clinical need.”1
It is this fact—that although these new drugs are potential miracle cures, most patients simply don’t respond to checkpoint inhibitors—that has inspired an ongoing search for the various factors that influence response.
One might argue that providing the patient with a sense of agency by helping them make these beneficial changes will, in itself, lower their level of emotional distress.
The data from Fraterman et al suggest that patients under stress don’t do as well as less stressed patients. Reading the Fraterman results raises a simple question though: whether emotional distress decreases the immune system’s responsiveness to the immune-checkpoint blockade or whether the stress is simply stimulating cancer growth or creating a more aggressive expression of the disease.
An example that should come to mind was described in a past issue of Natural Medicine Journal. It is that emotional distress is associated with a worse prognosis in ovarian cancer.
In 2014, Lise Alschuler reviewed Guillermo et al’s study, which suggested that chronic stress activated the pathways that hastened progression of ovarian cancer. As Alschuler wrote, “Ovarian cancer cells do not produce norepinephrine (NE) but do express adrenergic receptors that bind NE. Experimentally exposing these cells to various NE concentrations that correlate with the physiologic levels found in ovarian tissues and tumors under physiological and stress conditions provide a reliable indication of the external influence of NE on ovarian cancer cell behavior.”2 In other words, stress and the hormones produced in the body favor growth of ovarian cancer.
Fraterman et al attempted to identify the underlying mechanism by which emotional distress impaired the outcomes among their patients but without conclusive results. Knowing that stress causes release of stress hormones like glucocorticoids, adrenaline, and noradrenaline, they measured baseline cortisol levels and even hormone-signaling-pathway gene expressions in blood samples and tumor biopsies of their patients. Only marginal differences in baseline cortisol levels were found between their 2 groups of patients.
This current Fraterman study is not the first or only paper to report outcome differences in those treated with immune checkpoint blockade immunotherapy based on levels of emotional distress. Both Bi et al and Wu et al published studies in 2022 suggesting that similar reductions in therapy effectiveness occurred with non–small cell lung cancer (NSCLC).
Wu et al reported that in a group of 77 NSCLC patients (median age 61, median follow-up 16 months), 44 (67%) of whom were categorized as in psychological distress, this distress was associated with poorer QoL (P<0.001). The distressed group had a significantly lower objective response rate (ORR; 35.9% vs 63.64%; P=0.033) and shorter progression-free survival (PFS; median 12.63 vs 14.60 months; 95% CI: 0.36–1.98; P=0.026). Moreover, psychological distress was the only independent predictor for PFS (HR: 2.71, 95% CI: 1.06～6.90; P=0.037) in multivariate Cox regression analyses. In this case, the patients with psychological distress had higher levels of serum cortisol (P=0.040) and plasma epi (P=0.023). Additionally, the serum cortisol (P=0.043) and plasma epi (P=0.025) concentrations were associated with inferior immune-checkpoint inhibitor (ICI_ response.3
Bi et al reported in February 2022 on a group of 104 NSCLC patients who were separated into 2 groups by levels of psychological stress. The ORR and disease control rate (DCR) of the psychological distress group were 6% and 50%, respectively, and those of the nondistress group were 18.5% and 83.3%. The PFS of advanced NSCLC patients who received comprehensive immunotherapy and had no psychological distress was significantly better than that of the psychological distress group (HR, 0.338; 95% CI, 0.192–0.592; P<0.05).4
There is an old but still good argument that melanoma and also NSCLC are both worsened/aggravated by stress hormones. Reports first appeared in a report by DeGiorgi et al in 2011 that the β-blocking drug propranolol slows melanoma progression and improved treatment outcomes. They described a trial (N=121melanoma patients) in which some patients were treated with β-blockers (n=30) for 1 year. “After a median follow-up time of 2.5 years, tumor progression was observed in 3.3% of the treated subgroup and in 34.1% of the untreated subgroup. The Cox model on progression indicated a 36% (95% confidence interval, 11%-54%) (P = .002) risk reduction for each year of β-blocker use. No deaths were observed in the treated group, whereas in the untreated group 24 patients died.”5
Similar benefits from β-blocker use have been reported in NSCLC patients. A review by Garramona et al published in January 2024 summarized 24 studies on lung cancer.
Their composite “data indicated an increased expression of β-2-adrenergic receptors in lung cancer, which was associated with poor prognosis. However, the use of β-blockers as an add-on to standard treatment promoted enhanced overall survival, recurrence-free survival and reduced metastasis occurrence.” The autonomic nervous system (both sympathetic and parasympathetic) is seen as a regulator of cancer growth and spread.
“In this sense, add-on strategies to standard cancer treatments have been investigating [sic] and one of them has stood out: the incidental use of β-blockers (patients who used β-blockers for the treatment of hypertension and/or cardiovascular diseases or anxiety) before surgeries or during chemotherapy, which has been associated with improved clinical outcomes,” the authors state.6
The benefit of β-blockers in lung cancer is still up for debate though. A January 2024 trial by Duarte et al used β-blockers in NSCLC patients receiving immunotherapy, and while trends toward better outcomes were seen, they did not reach statistical significance:
“Among the 171 patients included, 36 concomitantly received β-blockers and ICIs. No significant increase was found in progression-free survival among patients who took β-blockers (HR 0.74, 95% confidence interval (CI) 0.48-1.12, p = 0.151)… An apparent trend was observed towards better outcomes in the β-blocker group, with a median overall survival of 9.93 months in the group not taking β-blockers versus 14.90 months in the β-blocker group (p = 0.291) and a median progression-free survival of 5.37 in the group not taking β-blockers versus 10.87 months in the β-blocker group (p = 0.151). Nine (25%) patients in the β-blocker group and 16 (12%) in the non- β-blocker group were progressive disease-free at the end of follow-up.”7
While we weigh statistical significance heavily, given a choice, most patients would still prefer to be in the group that is trending toward a better outcome.
A similar situation appears to be true for melanoma. It appears that emotional distress worsens prognosis for melanoma regardless of treatment type unless the impact of the stress hormones is somehow blocked or neutralized. The best evidence points toward using β-blocker drugs.
One possible explanation for this phenomenon of stress’s impact on immunotherapy was published in 2023 by Globig et al. They suggest that stress exhausts the immune system. CD8+ T cells are essential components of the immune response against viral infections and tumors and are capable of eliminating infected and cancerous cells. However, when the antigen cannot be cleared, T cells enter a state known as exhaustion.
Globig suggested that chronic-stress responses create a similar response in CD8 T cells as if they had been exposed to antigens that cannot be cleared. Both situations lead to what is termed “CD8 T cell exhaustion.” Globig and colleagues were able to identify a receptor (ADRB1) whose expression increases in response to exhausted CD8 T cells. The authors state, “… our results establish a connection between the sympathetic stress response, tissue innervation and T cell exhaustion. Here, we uncover a new mechanism by which blocking β-adrenergic signaling in CD8+ T cells rejuvenates anti-tumor functions.”8 Such an elaboration of mechanism might lead to the creation of future targeted drugs more effective than propranolol to block T cell exhaustion.
It may be unclear whether emotional distress lowers effectiveness of immune checkpoint inhibitors or simply worsens the prognosis of certain types of cancer; and it may not be 1 or the other but some combination of both. At this point, we have no reports of specific psychological interventions that neutralize the effect of stress on checkpoint blockade treatment in melanoma. While we might suggest various stress-reduction techniques, we do not have evidence to support effectiveness. As mentioned, there is some support for use of prescription β-blockers. Many of our patients, in their effort to maintain their health, ‘naturally’ may refrain from taking such drugs. For those with melanoma or NSCLC and who exhibit emotional distress, these drugs may provide significant benefit. For those patients who have comorbidities such as cardiovascular disease for which these drugs are clearly indicated but who nevertheless refrain from using them, it might be our responsibility in the overall picture to encourage use.
This raises another question as to how much of this information should we share with such patients who present with high degrees of emotional stress? Do we inform them that stress worsens their prognosis and encourage them to calm down? Do we tell them that taking β-blockers might help? Few of us have the option of prescribing these drugs, and past experience suggests that most oncologists hesitate to write such a prescription. For these distressed patients, knowing their stress is making their prognosis worse may further aggravate the situation. You can’t just tell them to relax.
One possible path to take with these patients—actually any patient undergoing checkpoint-targeting immunotherapy—is to be proactive with things that they can do that will improve their chances of a favorable response to treatment.
Remember, as exciting as treatment outcomes can be, at this point most patients do not respond to checkpoint immunotherapy. We are, however, aware of a growing number of distinct lifestyle choices that appear to have a greater impact on prognosis than patients’ level of emotional distress. One might argue that providing the patient with a sense of agency by helping them make these beneficial changes will, in itself, lower their level of emotional distress.
For most of the past decade, researchers’ attention has been focused on the gut microbiome and how it influences the immune response—in particular, how the gut microbiome somehow regulates response to the checkpoint-inhibiting drugs. As these drugs came into use in 2014, researchers became aware that the drugs were ineffective in both germ-free mice and those recently treated with antibiotics. The gut microbiome was apparently crucial for the drugs to work or, put another way, for the immune system to defend against cancer. Despite multiple human trials that have compared the gut microbiomes of patients who have had good responses to immunotherapy drugs to patients who have not responded, researchers have yet to define the exact differences adequately to translate into practice. Fecal microbiota transplants from patients who have responded to immune checkpoint inhibition treatment into patients who have failed to respond does transfer their “responsiveness” in about 30% of attempted cases.9,10 This practice has not become available to patients outside of research settings. However, it is estimated that an equal or superior frequency of response may be achieved through simple dietary and lifestyle habits that alter the gut microbiome.
There are 2 summary papers on these lifestyle factors that affect immunotherapy treatment. The first, by Karla Lee et al (“The gut microbiome: what the oncologist ought to know”11), is a useful resource for both your patient and, as the title suggests, their oncologists. (Printed out, it makes a good patient handout.) To sum up Lee and colleagues’ suggestions, patients undergoing treatment with immune checkpoint inhibitor drugs should:
- Eat 30 grams of fiber per day.
- Avoid probiotic supplements, especially Acidophilus or Bifidobacterium, which significantly lower effectiveness of these drugs. Note: Clostridium butyricum is the exception to this rule as clinical trials suggest these specific bacteria may increase benefits of treatment.12,13
- Avoid proton pump inhibitors, antibiotics, and steroids. They all may lower response rates.
- Follow a Mediterranean diet. Doing so is associated with higher response rates.
- Fecal microbiota transplants may be helpful for some patients.
A second, more recent review, written by Nina Fuller-Shavel and Jonathan Krell, was published in early 2024 and adds several more points to Lee’s recommendations.14 Specifically:
- Exercise improves prognosis.
- Low vitamin D status should be treated, and doing so improves prognosis.
- Cannabis use worsens prognosis.
We, as well as our patients, tend to segregate cancer chemotherapy into 2 groups: the nasty, traditional, poisonous ones vs the newer, easier-to-tolerate monoclonal antibodies that serve to block checkpoint pathways and that are called immunotherapy. Their underlying mechanisms of action are not as different as usually assumed. All rely on the translocation of microbiota from the intestine into the enteric lymph system to stimulate an immune response that will hopefully attack cancer cells. The basic lifestyle and dietary guidelines being used to improve responsiveness to the checkpoint-targeted drugs by modifying the gut microbiome may well impact a broad category of cancer chemotherapies in a similar beneficial manner.15,16
Research attention is shifting away from hunting to identify the crucial microbes responsible for modulating immune responses toward identifying the microbial metabolites essential for regulation of these responses. It is now believed that more than 1 microbial species may produce the same metabolites, and thus, different possible combinations of gut microbial species may produce similar desirable outcomes.
