Unintended Negative Consequences of Managing Chemotherapy Toxicity

N. Lynn Henry, MD, PhD; Patricia A. Ganz, MD


J Natl Cancer Inst. 2022;114(12):1572-1574. 

With the development of effective cancer treatments such as chemotherapy, survival from breast cancer has increased substantially, but this progress did not come without a toll.[1] Clinicians are keenly aware of long-term effects from chemotherapy, such as neuropathy and heart failure, that can negatively impact function and quality of life.[2] However, it is less well appreciated that there can also be long-term consequences from the medications that are used for management of treatment-emergent acute symptoms, such as nausea, anxiety, and insomnia. Prolonged use of both benzodiazepines and nonbenzodiazepine sedative-hypnotics, referred to as Z-drugs, by patients with breast cancer in the postadjuvant treatment period may be an unintended consequence of well-meaning symptom management.

In this issue of the Journal, Cogan et al.[3] report the findings from a comprehensive study using administrative data to examine prescriptions for sedative-hypnotics before, during, and in the year following adjuvant chemotherapy for breast cancer. Using the MarketScan database, they examined prescriptions for benzodiazepines and Z-drugs, including name of drugs and doses, from 2008 to 2017 for more than 20 000 patients. The authors found that rates of use of either drug class in the months following completion of chemotherapy was higher in those who had received prescriptions for a sedative-hypnotic during chemotherapy compared with those who were not exposed, as well as when compared with the general population. In particular, when examining patients who had not used benzodiazepines in the year prior to chemotherapy, of those who received a prescription for a benzodiazepine during chemotherapy, 15.6% had persistent use in the following 9 months compared with only 0.8% who did not receive a benzodiazepine prescription during chemotherapy. Similarly for Z-drugs, 27.3% had persistent use if they received a Z-drug prescription during chemotherapy compared with only 0.6% who did not receive a prescription during chemotherapy. They also identified patient factors associated with increased risk of persistent sedative-hypnotic use.

Multiple approaches for managing chemotherapy toxicity have been shown to be effective, with newer generation medications and additional drug classes being approved by the US Food and Drug Administration in the past decade. For example, there are now multiple classes of antiemetics available including steroids, dopamine-receptor antagonists, 5-HT3-receptor antagonists, NK1-receptor antagonists, antipsychotics, and cannabinoids, in addition to benzodiazepines.[4] For anxiety, effective medications include selective serotonin receptor antagonists, serotonin-norepinephrine receptor antagonists, and benzodiazepines, as well as nondrug treatment options including cognitive behavioral therapy (CBT) and integrative therapies such as yoga and music therapy.[5–7] Similarly, for insomnia, there are numerous classes of supplements and prescription drugs including melatonin, tricyclic antidepressants, Z-drugs, and benzodiazepines as well as nonpharmacologic approaches such as CBT for insomnia (CBT-i) and integrative medicine strategies such as acupuncture or Tai Chi.[6–9] Although CBT-i is the recommended first-line therapy for treatment of insomnia, according to the National Comprehensive Cancer Network Survivorship guidelines,[6] it may be difficult to find a trained therapist in some communities. Integrative medicine practitioners may be more available, and these treatments may be appealing to the patient who has just completed chemotherapy and would like to focus on health and wellness as part of her recovery.

Management of short-term toxicity from chemotherapy is critical for optimizing cancer treatment delivery to avoid unnecessary delays and early termination of therapy. However, it is also vital to consider which approaches are best for preventing or treating side effects. A clinically meaningful insight from the article by Cogan et al.[3] is the knowledge that these classes of medications (benzodiazepines and Z-drugs) have high addictive potential, especially in association with the use of opioids. Clinicians need to take this characteristic into account when selecting medications to prescribe during and following breast cancer treatment, especially for patients at higher risk of dependence. In addition to being more intentional about which drug to prescribe, it is also essential to limit dose, quantity, and duration as clinically appropriate, because those patients who were prescribed a greater number of prescriptions and a higher total dose of sedative-hypnotic medications were more likely to be persistent users of the drugs.

Another important preventive strategy is to actively screen patients for anxiety and depression at the beginning of chemotherapy treatments, for example, with the Generalized Anxiety Disorder-2 item scale[10] and the Patient Health Questionnaire-2 item scale,[11] identifying those with high scores for early referral to a clinical team member who can provide mental health evaluation and counseling, with appropriate medication used as an adjunct. As the authors note, anxiety and depression are common in this population, and although persistent posttreatment use of sedative-hypnotic medication was an identified concern, the vast majority of patients who received these medications during chemotherapy treatment did not persist, suggesting that the indications for their use resolved.

One limitation of the study is that the indication for prescription of the medications was not captured. For example, continued benzodiazepine use beyond the completion of chemotherapy is presumed to be more for anxiety or insomnia rather than for nausea, but the actual reason is unknown in this study. Most patients experience improvement of these symptoms with the completion of chemotherapy and may not require continued pharmacologic therapy for management. However, resolution of symptoms can be difficult to assess when a patient is taking a scheduled medication. For those who have persistent symptoms, there are effective long-term treatment options for anxiety and insomnia that do not cause dependence, such as CBT, mindfulness, and other stress management strategies.[5–7] In addition, it is crucial for patients with clinically relevant mood disorders to have access to psychological services, including oncology-focused psychiatrists, psychologists, and social workers, for management of anxiety, depression, distress, and fear of cancer recurrence. These symptoms often become more prominent once the frequent monitoring in the oncologic clinic subsides, and visits that provide reassurance occur only every 3–4 months.

It would be of interest to know what type of clinicians are prescribing the sedative-hypnotic medications both during and following completion of chemotherapy. No information was provided about whether the prescriptions were written by oncologists vs primary care or other specialists. This information would be helpful to determine who to target for additional education about the increased risks of dependence on benzodiazepines and Z-drugs for patients with breast cancer, as well as alternative symptom management strategies.

The authors also examined opioid use in this population, as it is another commonly used class of medication that can cause dependence. In this cohort, 60% received prescriptions for opioids in the year before chemotherapy, presumably mostly at the time of cancer surgery, and 25%-30% received opioids during chemotherapy.[3] Use of opioids during chemotherapy was found to be associated with increased likelihood of persistent use of both benzodiazepines and Z-drugs. It is unknown, however, whether the recent initiatives to reduce opioid use in the United States may have also impacted persistent use of these other addictive medications.

Strengths of the study include its large size and ability to examine use of benzodiazepines and Z-drugs in the year prior to initiation of chemotherapy. In addition, the authors used administrative data to identify use of adjuvant chemotherapy, thereby excluding patients who received neoadjuvant therapy to ensure a more homogeneous population. They increased generalizability by using the MarketScan database, as opposed to using a Surveillance, Epidemiology, and End Results–Medicare database, which would have limited the cohort to patients aged older than 65 years or using a database that included only patients with commercial insurance. However, race, ethnicity, and marital and socioeconomic status were not available for inclusion in the analysis. An unusual finding was a greater association of persistent posttreatment sedative-hypnotic use among those patients who had shorter courses of chemotherapy (<4 months), which is not easily explained unless it represents individuals who did not complete the intended full course of treatment because of anxiety, toxicity, or nonadherence. One would expect that longer duration of chemotherapy would lead to continued use of these medications and greater potential for addiction.

Symptom management is essential for ensuring optimal quality of life for patients during and following chemotherapy. These findings highlight the importance of careful selection of symptom management approaches to avoid inadvertently inducing long-term complications such as medication dependence, which itself can result in medical, social, and financial problems. Given the wide variety of drugs and nonpharmacologic interventions that have evidence demonstrating efficacy for treating or preventing symptoms, avoidance of medications with the potential for dependence should be possible for the vast majority of patients.