Brian J. Reinhardt, MS

Cancer patients experience depression at rates > 5 times that of the general population.^1-11 Despite an increase in palliative care use, depression rates continued to rise.^2-4 Between 5% to 16% of outpatients, 4% to 14% of inpatients, and up to 49% of patients receiving palliative care experience depression.⁵ This issue also impacts families and caregivers.¹ A 2021 meta-analysis found that 23% of active military personnel and 20% of veterans experience depression.¹¹

Antidepressants approved by the US Food and Drug Administration (FDA) target the serotonin, norepinephrine, or dopamine systems and include boxed warnings about an increased risk of suicidal thoughts in adults aged 18 to 24 years.^12,13 These medications are categorized into several classes: monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs), tetracyclic antidepressants (TeCAs), norepinephrine-dopamine reuptake inhibitors (NDRIs), selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), serotonin receptor modulators (SRMs), serotonin-melatonin receptor antagonists (SMRAs), and N—methyl-D-aspartate receptor antagonists (NMDARAs).^14,15 The first FDA-approved antidepressants, iproniazid (an MAOI) and imipramine (a TCA) laid the foundation for the development of newer classes like SSRIs and SNRIs.^15-17

Older antidepressants such as MAOIs and TCAs are used less due to their adverse effects (AEs) and drug interactions. MAOIs, such as iproniazid, selegiline, moclobemide, tranylcypromine, isocarboxazid, and phenelzine, have numerous AEs and drug interactions, making them unsuitable for first- or second-line treatment of depression.^14,18-21 TCAs such as doxepin, amitriptyline, nortriptyline, imipramine, desipramine, clomipramine, trimipramine, protriptyline, maprotiline, and amoxapine have a narrow therapeutic index requiring careful monitoring for signs of toxicity such as QRS widening, tremors, or confusion. Despite the issues, TCAs are generally classified as second-line agents for major depressive disorder (MDD). TCAs have off-label uses for migraine prophylaxis, treatment of obsessive-compulsive disorder (OCD), insomnia, and chronic pain management first-line.^14,22-29

Newer antidepressants, including TeCAs and NDRIs, are typically more effective, but also come with safety concerns. TeCAs like mirtazapine interact with several medications, including MAOIs, serotonin-increasing drugs, alcohol, cannabidiol, and marijuana. Mirtazapine is FDA-approved for the treatment of moderate to severe depression in adults. It is also used off-label to treat insomnia, panic disorder, posttraumatic stress disorder (PTSD), generalized anxiety disorder (GAD), social anxiety disorder (SAD), headaches, and migraines. Compared to other antidepressants, mirtazapine is effective for all stages of depression and addresses a broad range of related symptoms.^14,30-34 NDRIs, such as bupropion, also interact with various medications, including MAOIs, other antidepressants, stimulants, and alcohol. Bupropion is FDA-approved for smoking cessation and to treat depression and SAD. It is also used off-label for depression- related bipolar disorder or sexual dysfunction, attention-deficit/hyperactivity disorder (ADHD), and obesity.^14,35-42

SSRIs, SNRIs, and SRMs should be used with caution. SSRIs such as sertraline, citalopram, escitalopram, fluoxetine, paroxetine, and fluvoxamine are first-line treatments for depression and various psychiatric disorders due to their safety and efficacy. Common AEs of SSRIs include sexual dysfunction, sleep disturbances, weight changes, and gastrointestinal (GI) issues. SSRIs can prolong the QT interval, posing a risk of life-threatening arrhythmia, and may interact with other medications, necessitating treatment adjustments. The FDA approved SSRIs for MDD, GAD, bulimia nervosa, bipolar depression, OCD, panic disorder, premenstrual dysphoric disorder, treatment-resistant depression, PTSD, and SAD. Off-label uses include binge eating disorder, body dysmorphic disorder, fibromyalgia, premature ejaculation, paraphilias, autism, Raynaud phenomenon, and vasomotor symptoms associated with menopause. Among SSRIs, sertraline and escitalopram are noted for their effectiveness and tolerability.^14,43-53

SNRIs, including duloxetine, venlafaxine, desvenlafaxine, milnacipran, and levomilnacipran, may increase bleeding risk, especially when taken with blood thinners. They can also elevate blood pressure, which may worsen if combined with stimulants. SNRIs may interact with other medications that affect serotonin levels, increasing the risk of serotonin syndrome when taken with triptans, pain medications, or other antidepressants.¹⁴ Desvenlafaxine has been approved by the FDA (but not by the European Medicines Agency).^54-56 Duloxetine is FDA-approved for the treatment of depression, neuropathic pain, anxiety disorders, fibromyalgia, and musculoskeletal disorders. It is used off-label to treat chemotherapy-induced peripheral neuropathy and stress urinary incontinence.^57-61 Venlafaxine is FDA-approved for depression, SAD, and panic disorder, and is prescribed off-label to treat ADHD, neuropathy, fibromyalgia, cataplexy, and PTSD, either alone or in combination with other medications.^62,63 Milnacipran is not approved for MDD; levomilnacipran received approval in 2013.⁶⁴

SRMs such as trazodone, nefazodone, vilazodone, and vortioxetine also function as serotonin reuptake inhibitors.^14,15 Trazodone is FDA-approved for MDD. It has been used off-label to treat anxiety, Alzheimer disease, substance misuse, bulimia nervosa, insomnia, fibromyalgia, and PTSD when first-line SSRIs are ineffective. A notable AE of trazodone is orthostatic hypotension, which can lead to dizziness and increase the risk of falls, especially in geriatric patients.^65-70 Nefazodone was discontinued in Europe in 2003 due to rare cases of liver toxicity but remains available in the US.^71-74 Vilazodone and vortioxetine are FDA-approved.

The latest classes of antidepressants include SMRAs and NMDARAs.¹⁴ Agomelatine, an SMRA, was approved in Europe in 2009 but rejected by the FDA in 2011 due to liver toxicity.⁷⁵ NMDARAs like esketamine and a combination of dextromethorphan and bupropion received FDA approval in 2019 and 2022, respectively.^76,77

This retrospective study analyzes noncancer drugs used during systemic chemotherapy based on a dataset of 14 antineoplastic agents. It sought to identify the most dispensed noncancer drug groups, discuss findings, compare patients with and without antidepressant prescriptions, and examine trends in antidepressant use from 2002 to 2023. This analysis expands on prior research.^78-81

Methods

The Walter Reed National Military Medical Center Institutional Review Board approved the study protocol and ensured compliance with the Health Insurance Portability and Accountability Act as an exempt protocol. The Joint Pathology Center (JPC) of the US Department of Defense (DoD) Cancer Registry Program and Military Health System (MHS) data experts from the Comprehensive Ambulatory/Professional Encounter Record (CAPER) and Pharmacy Data Transaction Service (PDTS) provided data for the analysis.

Data Sources

The JPC DoD Cancer Registry Program contains data from 1998 to 2024. CAPER and PDTS are part of the MHS Data Repository/Management Analysis and Reporting Tool database. Each observation in CAPER represents an ambulatory encounter at a military treatment facility (MTF). CAPER records are available from 2003 to 2024. PDTS records are available from 2002 to 2004. Each observation in PDTS represents a prescription filled for an MHS beneficiary, excluding those filled at international civilian pharmacies and inpatient pharmacy prescriptions.

This cross-sectional analysis requested data extraction for specific cancer drugs from the DoD Cancer Registry, focusing on treatment details, diagnosis dates, patient demographics, and physicians’ comments on AEs. After identifying patients, CAPER was used to identify additional health conditions. PDTS was used to compile a list of prescription medications filled during systemic cancer treatment or < 2 years postdiagnosis.

The 2016 Surveillance, Epidemiology, and End Results Program Coding and Staging Manual and International Classification of Diseases for Oncology, 3rd edition, 1st revision, were used to decode disease and cancer types.^82,83 Data sorting and analysis were performed using Microsoft Excel. The percentage for the total was calculated by using the number of patients or data available within the subgroup divided by the total number of patients or data variables. To compare the mean number of dispensed antidepressants to those without antidepressants, a 2-tailed, 2-sample z test was used to calculate the P value and determine statistical significance (P < .05) using socscistatistics.com.

Data were extracted 3 times between 2021 and 2023. The initial 2021 protocol focused on erlotinib and gefitinib. A modified protocol in 2022 added paclitaxel, cisplatin, docetaxel, pemetrexed, and crizotinib; further modification in 2023 included 8 new antineoplastic agents and 2 anticoagulants. Sotorasib has not been prescribed in the MHS, and JPC lacks records for noncancer drugs. The 2023 dataset comprised 2210 patients with cancer treated with 14 antineoplastic agents; 2104 had documented diagnoses and 2113 had recorded prescriptions. Data for erlotinib, gefitinib, and paclitaxel have been published previously.^78,79

Results

Of 2113 patients with recorded prescriptions, 1297 patients (61.4%) received 109 cancer drugs, including 96 antineoplastics, 7 disease-modifying antirheumatic agents, 4 biologic response modifiers, and 2 calcitonin gene-related peptides. Fourteen antineoplastic agents had complete data from JPC, while others were noted for combination therapies or treatment switches from the PDTS (Table 1). Seventy-six cancer drugs were prescribed with antidepressants in 489 patients (eAppendix).

The JPC provided 2242 entries for 2210 patients, ranging in age from 2 months to 88 years (mean, 56 years), documenting treatment from September 1988 to January 2023. Thirty-two patients had duplicate entries due to multiple cancer locations or occurrences. Of the 2242 patients, 1541 (68.7%) were aged > 50 years, 975 patients (43.5%) had cancers that were stage III or IV, and 1267 (56.5%) had cancers that were stage 0, I, II, or not applicable/unknown. There were 51 different types of cancer: breast, lung, testicular, endometrial, and ovarian were most common (n ≥ 100 patients). Forty-two cancer types were documented among 750 patients prescribed antidepressants (Table 2).

The CAPER database recorded 8882 unique diagnoses for 2104 patients, while PDTS noted 1089 unique prescriptions within 273 therapeutic codes for 2113 patients. Nine therapeutic codes (opiate agonists, adrenals, cathartics-laxatives, nonsteroidal anti-inflammatory agents, antihistamines for GI conditions, 5-HT3 receptor antagonists, analgesics and antipyretic miscellanea, antineoplastic agents, and proton-pump inhibitors) and 8 drugs (dexamethasone, prochlorperazine, ondansetron, docusate, acetaminophen, ibuprofen, oxycodone, and polyethylene glycol 3350) were associated with > 1000 patients (≥ 50%). Patients had between 1 and 275 unique health conditions and filled 1 to 108 prescriptions. The mean (SD) number of diagnoses and prescriptions was 50 (28) and 29 (12), respectively. Of the 273 therapeutic codes, 30 groups were analyzed, with others categorized into miscellaneous groups such as lotions, vaccines, and devices. Significant differences in mean number of prescriptions were found for patients taking antidepressants compared to those not (P < .05), except for anticonvulsants and antipsychotics (P = .12 and .09, respectively) (Table 3).

Antidepressants

Of the 2113 patients with recorded prescriptions, 750 (35.5%) were dispensed 17 different antidepressants. Among these 17 antidepressants, 183 (8.7%) patients received duloxetine, 158 (7.5%) received venlafaxine, 118 (5.6%) received trazodone, and 107 (5.1%) received sertraline (Figure 1, Table 4). Of the 750 patients, 509 (67.9%) received 1 antidepressant, 168 (22.4%) received 2, 60 (8.0%) received 3, and 13 (1.7%) received > 3. Combinations varied, but only duloxetine and trazodone were prescribed to > 10 patients.

Antidepressants were prescribed annually at an overall mean (SD) rate of 23% (5%) from 2003 to 2022 (Figure 2). Patients on antidepressants during systemic therapy had a greater number of diagnosed medical conditions and received more prescription medications compared to those not taking antidepressants (P < .001) (Figure 3). The 745 patients taking antidepressants in CAPER data had between 1 and 275 diagnosed medical issues, with a mean (SD) of 55 (31) vs a range of 1 to 209 and a mean (SD) of 46 (26) for the 1359 patients not taking antidepressants. The 750 patients on antidepressants in PDTS data had between 8 and 108 prescriptions dispensed, with a mean (SD) of 32 (12), vs a range of 1 to 65 prescriptions and a mean (SD) of 29 (12) for 1363 patients not taking antidepressants.

Discussion

The JPC DoD Cancer Registry includes information on cancer types, stages, treatment regimens, and physicians’ notes, while noncancer drugs are sourced from the PDTS database. The pharmacy uses a different documentation system, leading to varied classifications.

Database reliance has its drawbacks. For example, megestrol is coded as a cancer drug, although it’s primarily used for endometrial or gynecologic cancers. Many drugs have multiple therapeutic codes assigned to them, including 10 antineoplastic agents: diclofenac, Bacillus Calmette-Guérin (BCG), megestrol acetate, tamoxifen, anastrozole, letrozole, leuprolide, goserelin, degarelix, and fluorouracil. Diclofenac, BCG, and mitomycin have been repurposed for cancer treatment.^84-87 From 2003 to 2023, diclofenac was prescribed to 350 patients for mild-to-moderate pain, with only 2 patients receiving it for cancer in 2018. FDA-approved for bladder cancer in 1990, BCG was prescribed for cancer treatment for 1 patient in 2021 after being used for vaccines between 2003 and 2018. Tamoxifen, used for hormone receptor-positive breast cancer from 2004 to 2017 with 53 patients, switched to estrogen agonist-antagonists from 2017 to 2023 with 123 patients. Only a few of the 168 patients were prescribed tamoxifen using both codes.^88-91 Anastrozole and letrozole were coded as antiestrogens for 7 and 18 patients, respectively, while leuprolide and goserelin were coded as gonadotropins for 59 and 18 patients. Degarelix was coded as antigonadotropins, fluorouracil as skin and mucous membrane agents miscellaneous, and megestrol acetate as progestins for 7, 6, and 3 patients, respectively. Duloxetine was given to 186 patients, primarily for depression from 2005 to 2023, with 7 patients treated for fibromyalgia from 2022 to 2023.

Antidepressants Observed

Tables 1 and 5 provide insight into the FDA approval of 14 antineoplastics and antidepressants and their CYP metabolic pathways.^92-122 In Table 4, the most prescribed antidepressant classes are SNRIs, SRMs, SSRIs, TeCAs, NDRIs, and TCAs. This trend highlights a preference for newer medications with weak CYP inhibition. A total of 349 patients were prescribed SSRIs, 343 SNRIs, 119 SRMs, 109 TCAs, 83 TeCAs, and 79 NDRIs. MAOIs, SMRAs, and NMDARAs were not observed in this dataset. While there are instances of dextromethorphan-bupropion and sertraline-escitalopram being dispensed together, it remains unclear whether these were NMDARA combinations.

Among the 14 specific antineoplastic agents, 10 are metabolized by CYP isoenzymes, primarily CYP3A4. Duloxetine neither inhibits nor is metabolized by CYP3A4, a reason it is often recommended, following venlafaxine.

Both duloxetine and venlafaxine are used off-label for chemotherapy-induced peripheral neuropathy related to paclitaxel and docetaxel. According to the CYP metabolized pathway, duloxetine tends to have more favorable DDIs than venlafaxine. In PDTS data, 371 patients were treated with paclitaxel and 180 with docetaxel, with respective antidepressant prescriptions of 156 and 70. Of the 156 patients dispensed paclitaxel, 62 (40%) were dispensed with duloxetine compared to 43 (28%) with venlafaxine. Of the 70 patients dispensed docetaxel, 23 (33%) received duloxetine vs 24 (34%) with venlafaxine.

Of 85 patients prescribed duloxetine, 75 received it with either paclitaxel or docetaxel (5 received both). Five patients had documented AEs (1 neuropathy related). Of 67 patients prescribed venlafaxine, 66 received it with either paclitaxel or docetaxel. Two patients had documented AEs (1 was neuropathy related, the same patient who received duloxetine). Of the 687 patients treated with paclitaxel and 337 with docetaxel in all databases, 4 experienced neuropathic AEs from both medications.⁷⁹

Antidepressants can increase the risk of bleeding, especially when combined with blood thinners, and may elevate blood pressure, particularly alongside stimulants. Of the 554 patients prescribed 9 different anticoagulants, enoxaparin, apixaban, and rivaroxaban were the most common (each > 100 patients). Among these, 201 patients (36%) received both anticoagulants and antidepressants: duloxetine for 64 patients, venlafaxine for 30, trazodone for 35, and sertraline for 26. There were no data available to assess bleeding rates related to the evaluation of DDIs between these medication classes.

Antidepressants can be prescribed for erectile dysfunction. Of the 148 patients prescribed an antidepressant for erectile dysfunction, duloxetine, trazodone, and mirtazapine were the most common. Antidepressant preferences varied by cancer type. Duloxetine was the only antidepressant used for all types of cancer. Venlafaxine, duloxetine, trazodone, sertraline, and escitalopram were the most prescribed antidepressants for breast cancer, while duloxetine, mirtazapine, citalopram, sertraline, and trazodone were the most prescribed for lung cancer. Sertraline, duloxetine, trazodone, amitriptyline, and escitalopram were most common for testicular cancer. Duloxetine, venlafaxine, trazodone, amitriptyline, and sertraline were the most prescribed for endometrial cancer, while duloxetine, venlafaxine, amitriptyline, citalopram, and sertraline were most prescribed for ovarian cancer.

The broadness of International Statistical Classification of Diseases, Tenth Revision codes made it challenging to identify nondepression diagnoses in the analyzed population. However, if all antidepressants were prescribed to treat depression, service members with cancer exhibited a higher depression rate (35%) than the general population (25%). Of 2104 patients, 191 (9.1%) had mood disorders, and 706 (33.6%) had mental disorders: 346 (49.0%) had 1 diagnosis, and 360 (51.0%) had multiple diagnoses. The percentage of diagnoses varied yearly, with notable drops in 2003, 2007, 2011, 2014, and 2018, and peaks in 2006, 2008, 2013, 2017, and 2022. This fluctuation was influenced by events like the establishment of PDTS in 2002, the 2008 economic recession, a hospital relocation in 2011, the 2014 Ebola outbreak, and the COVID-19 pandemic. Although the number of patients receiving antidepressants increased from 2019 to 2022, the overall percentage of patients receiving them did not significantly change from 2003 to 2022, aligning with previous research.^5,125

Many medications have potential uses beyond what is detailed in the prescribing information. Antidepressants can relieve pain, while pain medications may help with depression. Opioids were once thought to effectively treat depression, but this perspective has changed with a greater understanding of their risks, including misuse.^126-131 Pain is a severe and often unbearable AE of cancer. Of 2113 patients, 92% received opioids; 34% received both opioids and antidepressants; 2% received only antidepressants; and 7% received neither. This study didn’t clarify whether those on opioids alone recognized their depression or if those on both were aware of their dependence. While SSRIs are generally not addictive, they can lead to physical dependence, and any medication can be abused if not managed properly.^132-134

Conclusions

This retrospective study analyzes data from antineoplastic agents used in systemic cancer treatment between 1988 and 2023, with a particular focus on the use of antidepressants. Data on antidepressant prescriptions are incomplete and specific to these agents, which means the findings cannot be generalized to all antidepressants. Hence, the results indicate that patients taking antidepressants had more diagnosed health issues and received more medications compared to patients who were not on these drugs.

This study underscores the need for further research into the effects of antidepressants on cancer treatment, utilizing all data from the DoD Cancer Registry. Future research should explore DDIs between antidepressants and other cancer and noncancer medications, as this study did not assess AE documentation, unlike in studies involving erlotinib, gefitinib, and paclitaxel.^78,79 Further investigation is needed to evaluate the impact of discontinuing antidepressant use during cancer treatment. This comprehensive overview provides insights for clinicians to help them make informed decisions regarding the prescription of antidepressants in the context of cancer treatment.

Cancer patients experience depression at rates > 5 times that of the general population.^1-11 Despite an increase in palliative care use, depression rates continued to rise.^2-4 Between 5% to 16% of outpatients, 4% to 14% of inpatients, and up to 49% of patients receiving palliative care experience depression.⁵ This issue also impacts families and caregivers.¹ A 2021 meta-analysis found that 23% of active military personnel and 20% of veterans experience depression.¹¹

Antidepressants approved by the US Food and Drug Administration (FDA) target the serotonin, norepinephrine, or dopamine systems and include boxed warnings about an increased risk of suicidal thoughts in adults aged 18 to 24 years.^12,13 These medications are categorized into several classes: monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs), tetracyclic antidepressants (TeCAs), norepinephrine-dopamine reuptake inhibitors (NDRIs), selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), serotonin receptor modulators (SRMs), serotonin-melatonin receptor antagonists (SMRAs), and N—methyl-D-aspartate receptor antagonists (NMDARAs).^14,15 The first FDA-approved antidepressants, iproniazid (an MAOI) and imipramine (a TCA) laid the foundation for the development of newer classes like SSRIs and SNRIs.^15-17

Older antidepressants such as MAOIs and TCAs are used less due to their adverse effects (AEs) and drug interactions. MAOIs, such as iproniazid, selegiline, moclobemide, tranylcypromine, isocarboxazid, and phenelzine, have numerous AEs and drug interactions, making them unsuitable for first- or second-line treatment of depression.^14,18-21 TCAs such as doxepin, amitriptyline, nortriptyline, imipramine, desipramine, clomipramine, trimipramine, protriptyline, maprotiline, and amoxapine have a narrow therapeutic index requiring careful monitoring for signs of toxicity such as QRS widening, tremors, or confusion. Despite the issues, TCAs are generally classified as second-line agents for major depressive disorder (MDD). TCAs have off-label uses for migraine prophylaxis, treatment of obsessive-compulsive disorder (OCD), insomnia, and chronic pain management first-line.^14,22-29

Newer antidepressants, including TeCAs and NDRIs, are typically more effective, but also come with safety concerns. TeCAs like mirtazapine interact with several medications, including MAOIs, serotonin-increasing drugs, alcohol, cannabidiol, and marijuana. Mirtazapine is FDA-approved for the treatment of moderate to severe depression in adults. It is also used off-label to treat insomnia, panic disorder, posttraumatic stress disorder (PTSD), generalized anxiety disorder (GAD), social anxiety disorder (SAD), headaches, and migraines. Compared to other antidepressants, mirtazapine is effective for all stages of depression and addresses a broad range of related symptoms.^14,30-34 NDRIs, such as bupropion, also interact with various medications, including MAOIs, other antidepressants, stimulants, and alcohol. Bupropion is FDA-approved for smoking cessation and to treat depression and SAD. It is also used off-label for depression- related bipolar disorder or sexual dysfunction, attention-deficit/hyperactivity disorder (ADHD), and obesity.^14,35-42

SSRIs, SNRIs, and SRMs should be used with caution. SSRIs such as sertraline, citalopram, escitalopram, fluoxetine, paroxetine, and fluvoxamine are first-line treatments for depression and various psychiatric disorders due to their safety and efficacy. Common AEs of SSRIs include sexual dysfunction, sleep disturbances, weight changes, and gastrointestinal (GI) issues. SSRIs can prolong the QT interval, posing a risk of life-threatening arrhythmia, and may interact with other medications, necessitating treatment adjustments. The FDA approved SSRIs for MDD, GAD, bulimia nervosa, bipolar depression, OCD, panic disorder, premenstrual dysphoric disorder, treatment-resistant depression, PTSD, and SAD. Off-label uses include binge eating disorder, body dysmorphic disorder, fibromyalgia, premature ejaculation, paraphilias, autism, Raynaud phenomenon, and vasomotor symptoms associated with menopause. Among SSRIs, sertraline and escitalopram are noted for their effectiveness and tolerability.^14,43-53

SNRIs, including duloxetine, venlafaxine, desvenlafaxine, milnacipran, and levomilnacipran, may increase bleeding risk, especially when taken with blood thinners. They can also elevate blood pressure, which may worsen if combined with stimulants. SNRIs may interact with other medications that affect serotonin levels, increasing the risk of serotonin syndrome when taken with triptans, pain medications, or other antidepressants.¹⁴ Desvenlafaxine has been approved by the FDA (but not by the European Medicines Agency).^54-56 Duloxetine is FDA-approved for the treatment of depression, neuropathic pain, anxiety disorders, fibromyalgia, and musculoskeletal disorders. It is used off-label to treat chemotherapy-induced peripheral neuropathy and stress urinary incontinence.^57-61 Venlafaxine is FDA-approved for depression, SAD, and panic disorder, and is prescribed off-label to treat ADHD, neuropathy, fibromyalgia, cataplexy, and PTSD, either alone or in combination with other medications.^62,63 Milnacipran is not approved for MDD; levomilnacipran received approval in 2013.⁶⁴

SRMs such as trazodone, nefazodone, vilazodone, and vortioxetine also function as serotonin reuptake inhibitors.^14,15 Trazodone is FDA-approved for MDD. It has been used off-label to treat anxiety, Alzheimer disease, substance misuse, bulimia nervosa, insomnia, fibromyalgia, and PTSD when first-line SSRIs are ineffective. A notable AE of trazodone is orthostatic hypotension, which can lead to dizziness and increase the risk of falls, especially in geriatric patients.^65-70 Nefazodone was discontinued in Europe in 2003 due to rare cases of liver toxicity but remains available in the US.^71-74 Vilazodone and vortioxetine are FDA-approved.

The latest classes of antidepressants include SMRAs and NMDARAs.¹⁴ Agomelatine, an SMRA, was approved in Europe in 2009 but rejected by the FDA in 2011 due to liver toxicity.⁷⁵ NMDARAs like esketamine and a combination of dextromethorphan and bupropion received FDA approval in 2019 and 2022, respectively.^76,77

This retrospective study analyzes noncancer drugs used during systemic chemotherapy based on a dataset of 14 antineoplastic agents. It sought to identify the most dispensed noncancer drug groups, discuss findings, compare patients with and without antidepressant prescriptions, and examine trends in antidepressant use from 2002 to 2023. This analysis expands on prior research.^78-81

Methods

The Walter Reed National Military Medical Center Institutional Review Board approved the study protocol and ensured compliance with the Health Insurance Portability and Accountability Act as an exempt protocol. The Joint Pathology Center (JPC) of the US Department of Defense (DoD) Cancer Registry Program and Military Health System (MHS) data experts from the Comprehensive Ambulatory/Professional Encounter Record (CAPER) and Pharmacy Data Transaction Service (PDTS) provided data for the analysis.

Data Sources

The JPC DoD Cancer Registry Program contains data from 1998 to 2024. CAPER and PDTS are part of the MHS Data Repository/Management Analysis and Reporting Tool database. Each observation in CAPER represents an ambulatory encounter at a military treatment facility (MTF). CAPER records are available from 2003 to 2024. PDTS records are available from 2002 to 2004. Each observation in PDTS represents a prescription filled for an MHS beneficiary, excluding those filled at international civilian pharmacies and inpatient pharmacy prescriptions.

This cross-sectional analysis requested data extraction for specific cancer drugs from the DoD Cancer Registry, focusing on treatment details, diagnosis dates, patient demographics, and physicians’ comments on AEs. After identifying patients, CAPER was used to identify additional health conditions. PDTS was used to compile a list of prescription medications filled during systemic cancer treatment or < 2 years postdiagnosis.

The 2016 Surveillance, Epidemiology, and End Results Program Coding and Staging Manual and International Classification of Diseases for Oncology, 3rd edition, 1st revision, were used to decode disease and cancer types.^82,83 Data sorting and analysis were performed using Microsoft Excel. The percentage for the total was calculated by using the number of patients or data available within the subgroup divided by the total number of patients or data variables. To compare the mean number of dispensed antidepressants to those without antidepressants, a 2-tailed, 2-sample z test was used to calculate the P value and determine statistical significance (P < .05) using socscistatistics.com.

Data were extracted 3 times between 2021 and 2023. The initial 2021 protocol focused on erlotinib and gefitinib. A modified protocol in 2022 added paclitaxel, cisplatin, docetaxel, pemetrexed, and crizotinib; further modification in 2023 included 8 new antineoplastic agents and 2 anticoagulants. Sotorasib has not been prescribed in the MHS, and JPC lacks records for noncancer drugs. The 2023 dataset comprised 2210 patients with cancer treated with 14 antineoplastic agents; 2104 had documented diagnoses and 2113 had recorded prescriptions. Data for erlotinib, gefitinib, and paclitaxel have been published previously.^78,79

Results

Of 2113 patients with recorded prescriptions, 1297 patients (61.4%) received 109 cancer drugs, including 96 antineoplastics, 7 disease-modifying antirheumatic agents, 4 biologic response modifiers, and 2 calcitonin gene-related peptides. Fourteen antineoplastic agents had complete data from JPC, while others were noted for combination therapies or treatment switches from the PDTS (Table 1). Seventy-six cancer drugs were prescribed with antidepressants in 489 patients (eAppendix).

The JPC provided 2242 entries for 2210 patients, ranging in age from 2 months to 88 years (mean, 56 years), documenting treatment from September 1988 to January 2023. Thirty-two patients had duplicate entries due to multiple cancer locations or occurrences. Of the 2242 patients, 1541 (68.7%) were aged > 50 years, 975 patients (43.5%) had cancers that were stage III or IV, and 1267 (56.5%) had cancers that were stage 0, I, II, or not applicable/unknown. There were 51 different types of cancer: breast, lung, testicular, endometrial, and ovarian were most common (n ≥ 100 patients). Forty-two cancer types were documented among 750 patients prescribed antidepressants (Table 2).

The CAPER database recorded 8882 unique diagnoses for 2104 patients, while PDTS noted 1089 unique prescriptions within 273 therapeutic codes for 2113 patients. Nine therapeutic codes (opiate agonists, adrenals, cathartics-laxatives, nonsteroidal anti-inflammatory agents, antihistamines for GI conditions, 5-HT3 receptor antagonists, analgesics and antipyretic miscellanea, antineoplastic agents, and proton-pump inhibitors) and 8 drugs (dexamethasone, prochlorperazine, ondansetron, docusate, acetaminophen, ibuprofen, oxycodone, and polyethylene glycol 3350) were associated with > 1000 patients (≥ 50%). Patients had between 1 and 275 unique health conditions and filled 1 to 108 prescriptions. The mean (SD) number of diagnoses and prescriptions was 50 (28) and 29 (12), respectively. Of the 273 therapeutic codes, 30 groups were analyzed, with others categorized into miscellaneous groups such as lotions, vaccines, and devices. Significant differences in mean number of prescriptions were found for patients taking antidepressants compared to those not (P < .05), except for anticonvulsants and antipsychotics (P = .12 and .09, respectively) (Table 3).

Antidepressants

Of the 2113 patients with recorded prescriptions, 750 (35.5%) were dispensed 17 different antidepressants. Among these 17 antidepressants, 183 (8.7%) patients received duloxetine, 158 (7.5%) received venlafaxine, 118 (5.6%) received trazodone, and 107 (5.1%) received sertraline (Figure 1, Table 4). Of the 750 patients, 509 (67.9%) received 1 antidepressant, 168 (22.4%) received 2, 60 (8.0%) received 3, and 13 (1.7%) received > 3. Combinations varied, but only duloxetine and trazodone were prescribed to > 10 patients.

Antidepressants were prescribed annually at an overall mean (SD) rate of 23% (5%) from 2003 to 2022 (Figure 2). Patients on antidepressants during systemic therapy had a greater number of diagnosed medical conditions and received more prescription medications compared to those not taking antidepressants (P < .001) (Figure 3). The 745 patients taking antidepressants in CAPER data had between 1 and 275 diagnosed medical issues, with a mean (SD) of 55 (31) vs a range of 1 to 209 and a mean (SD) of 46 (26) for the 1359 patients not taking antidepressants. The 750 patients on antidepressants in PDTS data had between 8 and 108 prescriptions dispensed, with a mean (SD) of 32 (12), vs a range of 1 to 65 prescriptions and a mean (SD) of 29 (12) for 1363 patients not taking antidepressants.

Discussion

The JPC DoD Cancer Registry includes information on cancer types, stages, treatment regimens, and physicians’ notes, while noncancer drugs are sourced from the PDTS database. The pharmacy uses a different documentation system, leading to varied classifications.

Database reliance has its drawbacks. For example, megestrol is coded as a cancer drug, although it’s primarily used for endometrial or gynecologic cancers. Many drugs have multiple therapeutic codes assigned to them, including 10 antineoplastic agents: diclofenac, Bacillus Calmette-Guérin (BCG), megestrol acetate, tamoxifen, anastrozole, letrozole, leuprolide, goserelin, degarelix, and fluorouracil. Diclofenac, BCG, and mitomycin have been repurposed for cancer treatment.^84-87 From 2003 to 2023, diclofenac was prescribed to 350 patients for mild-to-moderate pain, with only 2 patients receiving it for cancer in 2018. FDA-approved for bladder cancer in 1990, BCG was prescribed for cancer treatment for 1 patient in 2021 after being used for vaccines between 2003 and 2018. Tamoxifen, used for hormone receptor-positive breast cancer from 2004 to 2017 with 53 patients, switched to estrogen agonist-antagonists from 2017 to 2023 with 123 patients. Only a few of the 168 patients were prescribed tamoxifen using both codes.^88-91 Anastrozole and letrozole were coded as antiestrogens for 7 and 18 patients, respectively, while leuprolide and goserelin were coded as gonadotropins for 59 and 18 patients. Degarelix was coded as antigonadotropins, fluorouracil as skin and mucous membrane agents miscellaneous, and megestrol acetate as progestins for 7, 6, and 3 patients, respectively. Duloxetine was given to 186 patients, primarily for depression from 2005 to 2023, with 7 patients treated for fibromyalgia from 2022 to 2023.

Antidepressants Observed

Tables 1 and 5 provide insight into the FDA approval of 14 antineoplastics and antidepressants and their CYP metabolic pathways.^92-122 In Table 4, the most prescribed antidepressant classes are SNRIs, SRMs, SSRIs, TeCAs, NDRIs, and TCAs. This trend highlights a preference for newer medications with weak CYP inhibition. A total of 349 patients were prescribed SSRIs, 343 SNRIs, 119 SRMs, 109 TCAs, 83 TeCAs, and 79 NDRIs. MAOIs, SMRAs, and NMDARAs were not observed in this dataset. While there are instances of dextromethorphan-bupropion and sertraline-escitalopram being dispensed together, it remains unclear whether these were NMDARA combinations.

Among the 14 specific antineoplastic agents, 10 are metabolized by CYP isoenzymes, primarily CYP3A4. Duloxetine neither inhibits nor is metabolized by CYP3A4, a reason it is often recommended, following venlafaxine.

Both duloxetine and venlafaxine are used off-label for chemotherapy-induced peripheral neuropathy related to paclitaxel and docetaxel. According to the CYP metabolized pathway, duloxetine tends to have more favorable DDIs than venlafaxine. In PDTS data, 371 patients were treated with paclitaxel and 180 with docetaxel, with respective antidepressant prescriptions of 156 and 70. Of the 156 patients dispensed paclitaxel, 62 (40%) were dispensed with duloxetine compared to 43 (28%) with venlafaxine. Of the 70 patients dispensed docetaxel, 23 (33%) received duloxetine vs 24 (34%) with venlafaxine.

Of 85 patients prescribed duloxetine, 75 received it with either paclitaxel or docetaxel (5 received both). Five patients had documented AEs (1 neuropathy related). Of 67 patients prescribed venlafaxine, 66 received it with either paclitaxel or docetaxel. Two patients had documented AEs (1 was neuropathy related, the same patient who received duloxetine). Of the 687 patients treated with paclitaxel and 337 with docetaxel in all databases, 4 experienced neuropathic AEs from both medications.⁷⁹

Antidepressants can increase the risk of bleeding, especially when combined with blood thinners, and may elevate blood pressure, particularly alongside stimulants. Of the 554 patients prescribed 9 different anticoagulants, enoxaparin, apixaban, and rivaroxaban were the most common (each > 100 patients). Among these, 201 patients (36%) received both anticoagulants and antidepressants: duloxetine for 64 patients, venlafaxine for 30, trazodone for 35, and sertraline for 26. There were no data available to assess bleeding rates related to the evaluation of DDIs between these medication classes.

Antidepressants can be prescribed for erectile dysfunction. Of the 148 patients prescribed an antidepressant for erectile dysfunction, duloxetine, trazodone, and mirtazapine were the most common. Antidepressant preferences varied by cancer type. Duloxetine was the only antidepressant used for all types of cancer. Venlafaxine, duloxetine, trazodone, sertraline, and escitalopram were the most prescribed antidepressants for breast cancer, while duloxetine, mirtazapine, citalopram, sertraline, and trazodone were the most prescribed for lung cancer. Sertraline, duloxetine, trazodone, amitriptyline, and escitalopram were most common for testicular cancer. Duloxetine, venlafaxine, trazodone, amitriptyline, and sertraline were the most prescribed for endometrial cancer, while duloxetine, venlafaxine, amitriptyline, citalopram, and sertraline were most prescribed for ovarian cancer.

The broadness of International Statistical Classification of Diseases, Tenth Revision codes made it challenging to identify nondepression diagnoses in the analyzed population. However, if all antidepressants were prescribed to treat depression, service members with cancer exhibited a higher depression rate (35%) than the general population (25%). Of 2104 patients, 191 (9.1%) had mood disorders, and 706 (33.6%) had mental disorders: 346 (49.0%) had 1 diagnosis, and 360 (51.0%) had multiple diagnoses. The percentage of diagnoses varied yearly, with notable drops in 2003, 2007, 2011, 2014, and 2018, and peaks in 2006, 2008, 2013, 2017, and 2022. This fluctuation was influenced by events like the establishment of PDTS in 2002, the 2008 economic recession, a hospital relocation in 2011, the 2014 Ebola outbreak, and the COVID-19 pandemic. Although the number of patients receiving antidepressants increased from 2019 to 2022, the overall percentage of patients receiving them did not significantly change from 2003 to 2022, aligning with previous research.^5,125

Many medications have potential uses beyond what is detailed in the prescribing information. Antidepressants can relieve pain, while pain medications may help with depression. Opioids were once thought to effectively treat depression, but this perspective has changed with a greater understanding of their risks, including misuse.^126-131 Pain is a severe and often unbearable AE of cancer. Of 2113 patients, 92% received opioids; 34% received both opioids and antidepressants; 2% received only antidepressants; and 7% received neither. This study didn’t clarify whether those on opioids alone recognized their depression or if those on both were aware of their dependence. While SSRIs are generally not addictive, they can lead to physical dependence, and any medication can be abused if not managed properly.^132-134

Conclusions

This retrospective study analyzes data from antineoplastic agents used in systemic cancer treatment between 1988 and 2023, with a particular focus on the use of antidepressants. Data on antidepressant prescriptions are incomplete and specific to these agents, which means the findings cannot be generalized to all antidepressants. Hence, the results indicate that patients taking antidepressants had more diagnosed health issues and received more medications compared to patients who were not on these drugs.

This study underscores the need for further research into the effects of antidepressants on cancer treatment, utilizing all data from the DoD Cancer Registry. Future research should explore DDIs between antidepressants and other cancer and noncancer medications, as this study did not assess AE documentation, unlike in studies involving erlotinib, gefitinib, and paclitaxel.^78,79 Further investigation is needed to evaluate the impact of discontinuing antidepressant use during cancer treatment. This comprehensive overview provides insights for clinicians to help them make informed decisions regarding the prescription of antidepressants in the context of cancer treatment.

Cancer patients experience depression at rates > 5 times that of the general population.^1-11 Despite an increase in palliative care use, depression rates continued to rise.^2-4 Between 5% to 16% of outpatients, 4% to 14% of inpatients, and up to 49% of patients receiving palliative care experience depression.⁵ This issue also impacts families and caregivers.¹ A 2021 meta-analysis found that 23% of active military personnel and 20% of veterans experience depression.¹¹

Antidepressants approved by the US Food and Drug Administration (FDA) target the serotonin, norepinephrine, or dopamine systems and include boxed warnings about an increased risk of suicidal thoughts in adults aged 18 to 24 years.^12,13 These medications are categorized into several classes: monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs), tetracyclic antidepressants (TeCAs), norepinephrine-dopamine reuptake inhibitors (NDRIs), selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), serotonin receptor modulators (SRMs), serotonin-melatonin receptor antagonists (SMRAs), and N—methyl-D-aspartate receptor antagonists (NMDARAs).^14,15 The first FDA-approved antidepressants, iproniazid (an MAOI) and imipramine (a TCA) laid the foundation for the development of newer classes like SSRIs and SNRIs.^15-17

Older antidepressants such as MAOIs and TCAs are used less due to their adverse effects (AEs) and drug interactions. MAOIs, such as iproniazid, selegiline, moclobemide, tranylcypromine, isocarboxazid, and phenelzine, have numerous AEs and drug interactions, making them unsuitable for first- or second-line treatment of depression.^14,18-21 TCAs such as doxepin, amitriptyline, nortriptyline, imipramine, desipramine, clomipramine, trimipramine, protriptyline, maprotiline, and amoxapine have a narrow therapeutic index requiring careful monitoring for signs of toxicity such as QRS widening, tremors, or confusion. Despite the issues, TCAs are generally classified as second-line agents for major depressive disorder (MDD). TCAs have off-label uses for migraine prophylaxis, treatment of obsessive-compulsive disorder (OCD), insomnia, and chronic pain management first-line.^14,22-29

Newer antidepressants, including TeCAs and NDRIs, are typically more effective, but also come with safety concerns. TeCAs like mirtazapine interact with several medications, including MAOIs, serotonin-increasing drugs, alcohol, cannabidiol, and marijuana. Mirtazapine is FDA-approved for the treatment of moderate to severe depression in adults. It is also used off-label to treat insomnia, panic disorder, posttraumatic stress disorder (PTSD), generalized anxiety disorder (GAD), social anxiety disorder (SAD), headaches, and migraines. Compared to other antidepressants, mirtazapine is effective for all stages of depression and addresses a broad range of related symptoms.^14,30-34 NDRIs, such as bupropion, also interact with various medications, including MAOIs, other antidepressants, stimulants, and alcohol. Bupropion is FDA-approved for smoking cessation and to treat depression and SAD. It is also used off-label for depression- related bipolar disorder or sexual dysfunction, attention-deficit/hyperactivity disorder (ADHD), and obesity.^14,35-42

SSRIs, SNRIs, and SRMs should be used with caution. SSRIs such as sertraline, citalopram, escitalopram, fluoxetine, paroxetine, and fluvoxamine are first-line treatments for depression and various psychiatric disorders due to their safety and efficacy. Common AEs of SSRIs include sexual dysfunction, sleep disturbances, weight changes, and gastrointestinal (GI) issues. SSRIs can prolong the QT interval, posing a risk of life-threatening arrhythmia, and may interact with other medications, necessitating treatment adjustments. The FDA approved SSRIs for MDD, GAD, bulimia nervosa, bipolar depression, OCD, panic disorder, premenstrual dysphoric disorder, treatment-resistant depression, PTSD, and SAD. Off-label uses include binge eating disorder, body dysmorphic disorder, fibromyalgia, premature ejaculation, paraphilias, autism, Raynaud phenomenon, and vasomotor symptoms associated with menopause. Among SSRIs, sertraline and escitalopram are noted for their effectiveness and tolerability.^14,43-53

SNRIs, including duloxetine, venlafaxine, desvenlafaxine, milnacipran, and levomilnacipran, may increase bleeding risk, especially when taken with blood thinners. They can also elevate blood pressure, which may worsen if combined with stimulants. SNRIs may interact with other medications that affect serotonin levels, increasing the risk of serotonin syndrome when taken with triptans, pain medications, or other antidepressants.¹⁴ Desvenlafaxine has been approved by the FDA (but not by the European Medicines Agency).^54-56 Duloxetine is FDA-approved for the treatment of depression, neuropathic pain, anxiety disorders, fibromyalgia, and musculoskeletal disorders. It is used off-label to treat chemotherapy-induced peripheral neuropathy and stress urinary incontinence.^57-61 Venlafaxine is FDA-approved for depression, SAD, and panic disorder, and is prescribed off-label to treat ADHD, neuropathy, fibromyalgia, cataplexy, and PTSD, either alone or in combination with other medications.^62,63 Milnacipran is not approved for MDD; levomilnacipran received approval in 2013.⁶⁴

SRMs such as trazodone, nefazodone, vilazodone, and vortioxetine also function as serotonin reuptake inhibitors.^14,15 Trazodone is FDA-approved for MDD. It has been used off-label to treat anxiety, Alzheimer disease, substance misuse, bulimia nervosa, insomnia, fibromyalgia, and PTSD when first-line SSRIs are ineffective. A notable AE of trazodone is orthostatic hypotension, which can lead to dizziness and increase the risk of falls, especially in geriatric patients.^65-70 Nefazodone was discontinued in Europe in 2003 due to rare cases of liver toxicity but remains available in the US.^71-74 Vilazodone and vortioxetine are FDA-approved.

The latest classes of antidepressants include SMRAs and NMDARAs.¹⁴ Agomelatine, an SMRA, was approved in Europe in 2009 but rejected by the FDA in 2011 due to liver toxicity.⁷⁵ NMDARAs like esketamine and a combination of dextromethorphan and bupropion received FDA approval in 2019 and 2022, respectively.^76,77

This retrospective study analyzes noncancer drugs used during systemic chemotherapy based on a dataset of 14 antineoplastic agents. It sought to identify the most dispensed noncancer drug groups, discuss findings, compare patients with and without antidepressant prescriptions, and examine trends in antidepressant use from 2002 to 2023. This analysis expands on prior research.^78-81

Methods

The Walter Reed National Military Medical Center Institutional Review Board approved the study protocol and ensured compliance with the Health Insurance Portability and Accountability Act as an exempt protocol. The Joint Pathology Center (JPC) of the US Department of Defense (DoD) Cancer Registry Program and Military Health System (MHS) data experts from the Comprehensive Ambulatory/Professional Encounter Record (CAPER) and Pharmacy Data Transaction Service (PDTS) provided data for the analysis.

Data Sources

The JPC DoD Cancer Registry Program contains data from 1998 to 2024. CAPER and PDTS are part of the MHS Data Repository/Management Analysis and Reporting Tool database. Each observation in CAPER represents an ambulatory encounter at a military treatment facility (MTF). CAPER records are available from 2003 to 2024. PDTS records are available from 2002 to 2004. Each observation in PDTS represents a prescription filled for an MHS beneficiary, excluding those filled at international civilian pharmacies and inpatient pharmacy prescriptions.

This cross-sectional analysis requested data extraction for specific cancer drugs from the DoD Cancer Registry, focusing on treatment details, diagnosis dates, patient demographics, and physicians’ comments on AEs. After identifying patients, CAPER was used to identify additional health conditions. PDTS was used to compile a list of prescription medications filled during systemic cancer treatment or < 2 years postdiagnosis.

The 2016 Surveillance, Epidemiology, and End Results Program Coding and Staging Manual and International Classification of Diseases for Oncology, 3rd edition, 1st revision, were used to decode disease and cancer types.^82,83 Data sorting and analysis were performed using Microsoft Excel. The percentage for the total was calculated by using the number of patients or data available within the subgroup divided by the total number of patients or data variables. To compare the mean number of dispensed antidepressants to those without antidepressants, a 2-tailed, 2-sample z test was used to calculate the P value and determine statistical significance (P < .05) using socscistatistics.com.

Data were extracted 3 times between 2021 and 2023. The initial 2021 protocol focused on erlotinib and gefitinib. A modified protocol in 2022 added paclitaxel, cisplatin, docetaxel, pemetrexed, and crizotinib; further modification in 2023 included 8 new antineoplastic agents and 2 anticoagulants. Sotorasib has not been prescribed in the MHS, and JPC lacks records for noncancer drugs. The 2023 dataset comprised 2210 patients with cancer treated with 14 antineoplastic agents; 2104 had documented diagnoses and 2113 had recorded prescriptions. Data for erlotinib, gefitinib, and paclitaxel have been published previously.^78,79

Results

Of 2113 patients with recorded prescriptions, 1297 patients (61.4%) received 109 cancer drugs, including 96 antineoplastics, 7 disease-modifying antirheumatic agents, 4 biologic response modifiers, and 2 calcitonin gene-related peptides. Fourteen antineoplastic agents had complete data from JPC, while others were noted for combination therapies or treatment switches from the PDTS (Table 1). Seventy-six cancer drugs were prescribed with antidepressants in 489 patients (eAppendix).

The JPC provided 2242 entries for 2210 patients, ranging in age from 2 months to 88 years (mean, 56 years), documenting treatment from September 1988 to January 2023. Thirty-two patients had duplicate entries due to multiple cancer locations or occurrences. Of the 2242 patients, 1541 (68.7%) were aged > 50 years, 975 patients (43.5%) had cancers that were stage III or IV, and 1267 (56.5%) had cancers that were stage 0, I, II, or not applicable/unknown. There were 51 different types of cancer: breast, lung, testicular, endometrial, and ovarian were most common (n ≥ 100 patients). Forty-two cancer types were documented among 750 patients prescribed antidepressants (Table 2).

The CAPER database recorded 8882 unique diagnoses for 2104 patients, while PDTS noted 1089 unique prescriptions within 273 therapeutic codes for 2113 patients. Nine therapeutic codes (opiate agonists, adrenals, cathartics-laxatives, nonsteroidal anti-inflammatory agents, antihistamines for GI conditions, 5-HT3 receptor antagonists, analgesics and antipyretic miscellanea, antineoplastic agents, and proton-pump inhibitors) and 8 drugs (dexamethasone, prochlorperazine, ondansetron, docusate, acetaminophen, ibuprofen, oxycodone, and polyethylene glycol 3350) were associated with > 1000 patients (≥ 50%). Patients had between 1 and 275 unique health conditions and filled 1 to 108 prescriptions. The mean (SD) number of diagnoses and prescriptions was 50 (28) and 29 (12), respectively. Of the 273 therapeutic codes, 30 groups were analyzed, with others categorized into miscellaneous groups such as lotions, vaccines, and devices. Significant differences in mean number of prescriptions were found for patients taking antidepressants compared to those not (P < .05), except for anticonvulsants and antipsychotics (P = .12 and .09, respectively) (Table 3).

Antidepressants

Of the 2113 patients with recorded prescriptions, 750 (35.5%) were dispensed 17 different antidepressants. Among these 17 antidepressants, 183 (8.7%) patients received duloxetine, 158 (7.5%) received venlafaxine, 118 (5.6%) received trazodone, and 107 (5.1%) received sertraline (Figure 1, Table 4). Of the 750 patients, 509 (67.9%) received 1 antidepressant, 168 (22.4%) received 2, 60 (8.0%) received 3, and 13 (1.7%) received > 3. Combinations varied, but only duloxetine and trazodone were prescribed to > 10 patients.

Antidepressants were prescribed annually at an overall mean (SD) rate of 23% (5%) from 2003 to 2022 (Figure 2). Patients on antidepressants during systemic therapy had a greater number of diagnosed medical conditions and received more prescription medications compared to those not taking antidepressants (P < .001) (Figure 3). The 745 patients taking antidepressants in CAPER data had between 1 and 275 diagnosed medical issues, with a mean (SD) of 55 (31) vs a range of 1 to 209 and a mean (SD) of 46 (26) for the 1359 patients not taking antidepressants. The 750 patients on antidepressants in PDTS data had between 8 and 108 prescriptions dispensed, with a mean (SD) of 32 (12), vs a range of 1 to 65 prescriptions and a mean (SD) of 29 (12) for 1363 patients not taking antidepressants.

Discussion

The JPC DoD Cancer Registry includes information on cancer types, stages, treatment regimens, and physicians’ notes, while noncancer drugs are sourced from the PDTS database. The pharmacy uses a different documentation system, leading to varied classifications.

Database reliance has its drawbacks. For example, megestrol is coded as a cancer drug, although it’s primarily used for endometrial or gynecologic cancers. Many drugs have multiple therapeutic codes assigned to them, including 10 antineoplastic agents: diclofenac, Bacillus Calmette-Guérin (BCG), megestrol acetate, tamoxifen, anastrozole, letrozole, leuprolide, goserelin, degarelix, and fluorouracil. Diclofenac, BCG, and mitomycin have been repurposed for cancer treatment.^84-87 From 2003 to 2023, diclofenac was prescribed to 350 patients for mild-to-moderate pain, with only 2 patients receiving it for cancer in 2018. FDA-approved for bladder cancer in 1990, BCG was prescribed for cancer treatment for 1 patient in 2021 after being used for vaccines between 2003 and 2018. Tamoxifen, used for hormone receptor-positive breast cancer from 2004 to 2017 with 53 patients, switched to estrogen agonist-antagonists from 2017 to 2023 with 123 patients. Only a few of the 168 patients were prescribed tamoxifen using both codes.^88-91 Anastrozole and letrozole were coded as antiestrogens for 7 and 18 patients, respectively, while leuprolide and goserelin were coded as gonadotropins for 59 and 18 patients. Degarelix was coded as antigonadotropins, fluorouracil as skin and mucous membrane agents miscellaneous, and megestrol acetate as progestins for 7, 6, and 3 patients, respectively. Duloxetine was given to 186 patients, primarily for depression from 2005 to 2023, with 7 patients treated for fibromyalgia from 2022 to 2023.

Antidepressants Observed

Tables 1 and 5 provide insight into the FDA approval of 14 antineoplastics and antidepressants and their CYP metabolic pathways.^92-122 In Table 4, the most prescribed antidepressant classes are SNRIs, SRMs, SSRIs, TeCAs, NDRIs, and TCAs. This trend highlights a preference for newer medications with weak CYP inhibition. A total of 349 patients were prescribed SSRIs, 343 SNRIs, 119 SRMs, 109 TCAs, 83 TeCAs, and 79 NDRIs. MAOIs, SMRAs, and NMDARAs were not observed in this dataset. While there are instances of dextromethorphan-bupropion and sertraline-escitalopram being dispensed together, it remains unclear whether these were NMDARA combinations.

Among the 14 specific antineoplastic agents, 10 are metabolized by CYP isoenzymes, primarily CYP3A4. Duloxetine neither inhibits nor is metabolized by CYP3A4, a reason it is often recommended, following venlafaxine.

Both duloxetine and venlafaxine are used off-label for chemotherapy-induced peripheral neuropathy related to paclitaxel and docetaxel. According to the CYP metabolized pathway, duloxetine tends to have more favorable DDIs than venlafaxine. In PDTS data, 371 patients were treated with paclitaxel and 180 with docetaxel, with respective antidepressant prescriptions of 156 and 70. Of the 156 patients dispensed paclitaxel, 62 (40%) were dispensed with duloxetine compared to 43 (28%) with venlafaxine. Of the 70 patients dispensed docetaxel, 23 (33%) received duloxetine vs 24 (34%) with venlafaxine.

Of 85 patients prescribed duloxetine, 75 received it with either paclitaxel or docetaxel (5 received both). Five patients had documented AEs (1 neuropathy related). Of 67 patients prescribed venlafaxine, 66 received it with either paclitaxel or docetaxel. Two patients had documented AEs (1 was neuropathy related, the same patient who received duloxetine). Of the 687 patients treated with paclitaxel and 337 with docetaxel in all databases, 4 experienced neuropathic AEs from both medications.⁷⁹

Antidepressants can increase the risk of bleeding, especially when combined with blood thinners, and may elevate blood pressure, particularly alongside stimulants. Of the 554 patients prescribed 9 different anticoagulants, enoxaparin, apixaban, and rivaroxaban were the most common (each > 100 patients). Among these, 201 patients (36%) received both anticoagulants and antidepressants: duloxetine for 64 patients, venlafaxine for 30, trazodone for 35, and sertraline for 26. There were no data available to assess bleeding rates related to the evaluation of DDIs between these medication classes.

Antidepressants can be prescribed for erectile dysfunction. Of the 148 patients prescribed an antidepressant for erectile dysfunction, duloxetine, trazodone, and mirtazapine were the most common. Antidepressant preferences varied by cancer type. Duloxetine was the only antidepressant used for all types of cancer. Venlafaxine, duloxetine, trazodone, sertraline, and escitalopram were the most prescribed antidepressants for breast cancer, while duloxetine, mirtazapine, citalopram, sertraline, and trazodone were the most prescribed for lung cancer. Sertraline, duloxetine, trazodone, amitriptyline, and escitalopram were most common for testicular cancer. Duloxetine, venlafaxine, trazodone, amitriptyline, and sertraline were the most prescribed for endometrial cancer, while duloxetine, venlafaxine, amitriptyline, citalopram, and sertraline were most prescribed for ovarian cancer.

The broadness of International Statistical Classification of Diseases, Tenth Revision codes made it challenging to identify nondepression diagnoses in the analyzed population. However, if all antidepressants were prescribed to treat depression, service members with cancer exhibited a higher depression rate (35%) than the general population (25%). Of 2104 patients, 191 (9.1%) had mood disorders, and 706 (33.6%) had mental disorders: 346 (49.0%) had 1 diagnosis, and 360 (51.0%) had multiple diagnoses. The percentage of diagnoses varied yearly, with notable drops in 2003, 2007, 2011, 2014, and 2018, and peaks in 2006, 2008, 2013, 2017, and 2022. This fluctuation was influenced by events like the establishment of PDTS in 2002, the 2008 economic recession, a hospital relocation in 2011, the 2014 Ebola outbreak, and the COVID-19 pandemic. Although the number of patients receiving antidepressants increased from 2019 to 2022, the overall percentage of patients receiving them did not significantly change from 2003 to 2022, aligning with previous research.^5,125

Many medications have potential uses beyond what is detailed in the prescribing information. Antidepressants can relieve pain, while pain medications may help with depression. Opioids were once thought to effectively treat depression, but this perspective has changed with a greater understanding of their risks, including misuse.^126-131 Pain is a severe and often unbearable AE of cancer. Of 2113 patients, 92% received opioids; 34% received both opioids and antidepressants; 2% received only antidepressants; and 7% received neither. This study didn’t clarify whether those on opioids alone recognized their depression or if those on both were aware of their dependence. While SSRIs are generally not addictive, they can lead to physical dependence, and any medication can be abused if not managed properly.^132-134

Conclusions

This retrospective study analyzes data from antineoplastic agents used in systemic cancer treatment between 1988 and 2023, with a particular focus on the use of antidepressants. Data on antidepressant prescriptions are incomplete and specific to these agents, which means the findings cannot be generalized to all antidepressants. Hence, the results indicate that patients taking antidepressants had more diagnosed health issues and received more medications compared to patients who were not on these drugs.

This study underscores the need for further research into the effects of antidepressants on cancer treatment, utilizing all data from the DoD Cancer Registry. Future research should explore DDIs between antidepressants and other cancer and noncancer medications, as this study did not assess AE documentation, unlike in studies involving erlotinib, gefitinib, and paclitaxel.^78,79 Further investigation is needed to evaluate the impact of discontinuing antidepressant use during cancer treatment. This comprehensive overview provides insights for clinicians to help them make informed decisions regarding the prescription of antidepressants in the context of cancer treatment.

Most cancer treatment regimens include the administration of several chemotherapeutic agents. Drug-drug interactions (DDIs) can increase the risk of fatal adverse events and reduce therapeutic efficacy.^1,2 Erlotinib, gefitinib, afatinib, osimertinib, and icotinib are epidermal growth factor receptor–tyrosine kinase inhibitors (EGFR-TKIs) that have proven efficacy for treating advanced non–small cell lung cancer (NSCLC). Erlotinib strongly inhibits cytochrome P450 (CYP) isoenzymes CYP 1A1, moderately inhibits CYP 3A4 and 2C8, and induces CYP 1A1 and 1A2.² Gefitinib weakly inhibits CYP 2C19 and 2D6.² CYP 3A4 inducers and inhibitors affect metabolism of both erlotinib and gefitinib.^3,4

Erlotinib and gefitinib are first-generation EGFR-TKIs and have been approved for NSCLC treatment by the US Food and Drug Administration (FDA). These agents have been used since the early 2000s and increase the possibility of long-term response and survival.^2,5,6 EGFR-TKIs have a range of potential DDIs, including interactions with CYP-dependent metabolism, uridine diphosphate-glucuronosyltransferase, and transporter proteins.² Few retrospective studies have focused on the therapeutic efficacy of erlotinib, gefitinib,or the combination of these agents.^7-14

DDIs from cancer and noncancer therapies could lead to treatment discontinuation and affect patient outcomes. The goals for this study were to perform a broad-scale retrospective analysis focused on investigating prescribed drugs used with erlotinib and gefitinib and determine patient outcomes as obtained through several Military Health System (MHS) databases. Our investigation focused on (1) the functions of these drugs; (2) identifying adverse effects (AEs) that patients experienced; (3) evaluating differences when these drugs are used alone vs concomitantly, and between the completed vs discontinued treatment groups; (4) identifying all drugs used during erlotinib or gefitinib treatment; and (5) evaluating DDIs with antidepressants.

This retrospective study was performed at the Department of Research Programs at Walter Reed National Military Medical Center (WRNMMC) in Bethesda, Maryland. The WRNMMC Institutional Review Board approved the study protocol and ensured compliance with the Health Insurance Portability and Accountability Act as an exempt protocol. The Joint Pathology Center of the US Department of Defense (DoD) Cancer Registry and MHS data experts from the Comprehensive Ambulatory/Professional Encounter Record (CAPER) and the Pharmacy Data Transaction Service (PDTS) provided data for the analysis.

Methods

The DoD Cancer Registry Program was established in 1986 by the Assistant Secretary of Defense for Health Affairs. The registry currently contains data from 1998 to 2023. CAPER and PDTS are part of the MHS Data Repository/Management Analysis and Reporting Tool database. Each observation in the CAPER record represents an ambulatory encounter at a military treatment facility (MTF). CAPER records are available from 2003 to 2023.

Each observation in the PDTS record represents an outpatient prescription filled for an MHS beneficiary at MTFs through the TRICARE mail-order program or a retail pharmacy in the United States. Missing from this record are prescriptions filled at civilian pharmacies outside the United States and inpatient pharmacy prescriptions. The MHS Data Repository PDTS record is available from 2002 to 2023. The Composite Health Care System—the legacy system—is being replaced by GENESIS at MTFs.

Data Extraction Design

The study design involved a cross-sectional analysis. We requested data extraction for erlotinib and gefitinib from 1998 to 2021. Data from the DoD Cancer Registry were used to identify patients who received cancer treatment. Once patients were identified, the CAPER database was searched for diagnoses to identify other health conditions, while the PDTS database was used to populate a list of prescription medications filled during chemotherapy treatment.

Data collected from the Joint Pathology Center included cancer treatment (alone or concomitant), cancer information (cancer types and stages), demographics (sex, age at diagnosis), and physicians’ comments on AEs. Collected data from the MHS include diagnosis and filled prescription history from initiation to completion of the therapy period (or a buffer of 6 months after the initial period). We used all collected data in this analysis. The only exclusion criterion was a provided physician’s note commenting that the patient did not use erlotinib or gefitinib.

Data Extraction Analysis

The Surveillance, Epidemiology, and End Results Program Coding and Staging Manual 2016 and the International Classification of Diseases for Oncology (ICD-O) were used to decode disease and cancer types.^15,16 Data sorting and analysis were performed using Microsoft Excel. The percentage for the total was calculated by using the total number of patients or data available within the gefitinib and erlotinib groups divided by total number of patients or data variables. The subgroup percentage was calculated by using the number of patients or data available within the subgroup divided by the total number of patients in that subgroup.

In alone vs concomitant and completed vs discontinued treatment groups, a 2-tailed, 2-sample z test was used to calculate P to determine statistical significance (P < .05) using a statistics website.¹⁷ Concomitant was defined as erlotinib or gefitinib taken with other medication(s) before, after, or at the same time as cancer therapy. For the retrospective data analysis, physicians’ notes with “.”, “,”, “/”, “;”, (period, comma, forward slash, semicolon) or space between medication names were interpreted as concurrent, while “+”, “-/+” (plus, minus/plus), or and between drug names were interpreted as combined. Completed treatment was defined as erlotinib or gefitinib as the last medication the patient took without recorded AEs; switching or experiencing AEs was defined as discontinued treatment.

Results

Erlotinib

The Joint Pathology Center provided 387 entries for 382 patients aged 21 to 93 years (mean, 65 years) who were treated systemically with erlotinib from January 1, 2001, to December 31, 2020. Five patients had duplicate entries because they had different cancer sites. There were 287 patients (74%) with lung cancer, 61 (16%) with pancreatic cancer, and 39 (10%) with other cancers. For lung cancer, there were 118 patients (30%) for the upper lobe, 78 (20%) for the lower lobe, and 60 (16%) not otherwise specified (NOS). Other lung cancer sites had fewer patients: 21 (5%) middle lobe lung, 6 (2%) overlapping lung lesion(s), and 4 (1%) main bronchus of the lung. For pancreatic cancer, there were 27 patients (7%) for the head of the pancreas, 10 (3%) pancreas NOS, 9 (2%) body of the pancreas, 9 (2%) tail of the pancreas, 4 (1%) overlapping lesions of the pancreas, 1 (< 1%) pancreatic duct, and 1 (< 1%) other specified parts of the pancreas

There were 342 patients (88%) who were aged > 50 years; 186 male patients (48%) and 201 female patients (52%). There were 293 patients (76%) who had a cancer diagnosis of stage III or IV disease and 94 (24%) who had a cancer diagnosis of stage ≤ II (combination of data for stage 0, 1, and 2, not applicable, and unknown). For their systemic treatment, 161 patients (42%) were treated with erlotinib alone and 226 (58%) received erlotinib concomitantly with additional chemotherapy.

Among the 123 patients who discontinued their treatment, 101 switched treatment with no AEs notes, 22 died or experienced fatigue with blurry vision, constipation, nonspecific gastrointestinal effects, grade-4 diarrhea (as defined by the Common Terminology Criteria for Adverse Events), or developed a pleural fluid, pneumonitis, renal failure, skin swelling and facial rash, and unknown AEs of discontinuation. Patients who discontinued treatment because of unknown AEs had physicians’ notes that detailed emergency department visits, peripheral vascular disease, progressive disease, and treatment cessation, but did not specify the exact symptom(s) that led to discontinuation. The causes of death are unknown because they were not detailed in the available notes or databases. The overall results in this retrospective review cannot establish causality between taking erlotinib or gefitinib and death.

Gefitinib

In September 2021, the Joint Pathology Center provided 33 entries for 33 patients who were systemically treated with gefitinib from January 1, 2002, to December 31, 2017. The patient ages ranged from 49 to 89 years with a mean age of 66 years. There were 31 (94%) and 2 (6%) patients with lung and other cancers, respectively. The upper lobe, lower lobe, and lung NOS had the most patients: 14 (42%), 8 (24%), and 6 (18%), respectively.

There were 31 patients (94%) who were aged > 50 years; 15 were male (45%) and 18 were female (55%). There were 26 patients (79%) who had a cancer diagnosis of stage III or IV disease. Nineteen patients (58%) were treated with gefitinib alone, and 14 (42%) were treated with gefitinib concomitantly with additional chemotherapy. Thirty-one patients (94%) were treated for lung cancer (Table 2). Thirty-three patients are a small sample size to determine whether patients were likely to stop gefitinib if used concomitantly with other drugs. Among the patients treated with gefitinib monotherapy, 5% (n = 1) stopped treatment, whereas 29% (n = 4) of patients treated concomitantly discontinued treatment (P = .06). All comparisons for gefitinib yielded insignificant P values. Physicians’ notes indicated that the reasons for gefitinib discontinuation were life-altering pruritis and unknown (progressive disease outcome) (Table 3).

Management Analysis and Reporting Tool Database

MHS data analysts provided data on diagnoses for 348 patients among 415 submitted, with 232 and 112 patients completing and discontinuing erlotinib or gefitinib treatment, respectively. Each patient had 1 to 104 (completed treatment group) and 1 to 157 (discontinued treatment group) unique health conditions documented. The MHS reported 1319 unique-diagnosis conditions for the completed group and 1266 for the discontinued group. Patients with additional health issues stopped chemotherapy use more often than those without; P < .001 for the completed group (232 patients, 1319 diagnoses) vs the discontinued group (112 patients, 1266 diagnoses). The mean (SD) number of diagnoses was 19 (17) for the completed and 30 (22) for the discontinued treatment groups (Figure).

MHS data was provided for patients who filled erlotinib (n = 240) or gefitinib (n = 18). Among the 258 patients, there were 179 and 79 patients in the completed and discontinued treatment groups, respectively. Each patient filled 1 to 75 (for the completed treatment group) and 3 to 103 (for the discontinued treatment group) prescription drugs. There were 805 unique-filled prescriptions for the completed and 670 for the discontinued group. Patients in the discontinued group filled more prescriptions than those who completed treatment; P < .001 for the completed group (179 patients,805 drugs) vs the discontinued group (79 patients, 670 drugs).

The mean (SD) number of filled prescription drugs was 19 (11) for the completed group and 29 (18) for the discontinued treatment group. The 5 most filled prescriptions with erlotinib from 258 patients with PDTS data were ondansetron (151 prescriptions, 10 recorded AEs), dexamethasone (119 prescriptions, 9 recorded AEs), prochlorperazine (105 prescriptions, 15 recorded AEs), oxycodone (99 prescriptions, 1 AE), and docusate (96 prescriptions, 7 recorded AEs).

Discussion

The difference between erlotinib and gefitinib data can be attributed to the FDA approval date and gefitinib’s association with a higher frequency of hepatotoxicity.^18-20 The FDA designated gefitinib as an orphan drug for EGFR mutation–positive NSCLC treatment. Gefitinib first received accelerated approval in 2003 for the treatment of locally advanced or metastatic NSCLC. Gefitinib then was voluntarily withdrawn from the market following confirmatory clinical trials that did not verify clinical benefit.

The current approval is for a different patient population—previously untreated, metastatic EGFR exon 19 or 21 L858R mutation—than the 2003 approval.^4,6 There was no record of gefitinib use after 2017 in our study.

Erlotinib is a reversible EGFR-TKI that is approved by the FDA as first-line (maintenance) or second-line treatment (after progression following at least 1 earlier chemotherapy regimen) for patients with metastatic NSCLC who harbor EGFR exon 19 deletions or exon 21 L858R substitution mutations, as detected by an FDA-approved test.³ Since 2005, the FDA also approved erlotinib for first-line treatment of patients with locally advanced, unresectable, or metastatic pancreatic cancer in combination with gemcitabine.³ Without FDA indication, erlotinib is used for colorectal, head and neck, ovarian carcinoma, pancreatic carcinoma, and breast cancer.²¹

Erlotinib and gefitinib are not considered first-line treatments in EGFR exon 19 or 21–mutated NSCLC because osimertinib was approved in 2018. Targeted therapies for EGFR mutation continue to advance at a fast pace, with amivantamab and mobocertinib now FDA approved for EGFR exon 20 insertion–mutated NSCLC.

Erlotinib Use

Thirty-nine patients (10%) in this study were prescribed erlotinib for off-label indications. Erlotinib was used alone or in combination with bevacizumab, capecitabine, cisplatin, denosumab, docetaxel, gemcitabine, and the MEK-inhibitor selumetinib. Erlotinib combined with cisplatin, denosumab, docetaxel, and gemcitabine had no recorded AEs, with 10 data entries for gemcitabine and 1 for other drugs. Three patients received bevacizumab and erlotinib, and 1 patient (diagnosed with kidney NOS) showed rash or facial swelling/erythema and diffuse body itching then stable disease after 2 cycles.

One patient (diagnosed with cancer located at the pancreas head) was bridged with capecitabine and erlotinib when going on a vacation, then received FOLFIRINOX (a combination chemotherapy regimen containing folinic acid [leucovorin], fluorouracil, irinotecan, and oxaliplatin), which led to significant fatigue, blurry vision, and constipation. One patient was treated for lung NOS with the MEK-inhibitor selumetinib plus erlotinib and developed pneumonitis following treatment.

Because oncologists followed guidelines and protocols in systemic treatment, DDIs of erlotinib concurrently (before or after) and in combination with cancer drugs were unlikely. Further investigation is needed for several 1:1:1 DDIs with noncancer drugs. A retrospective overview is not a randomized clinical study; therefore, analysis is limited. Data from the MHS were obtained solely from notes from physicians who treated the patients; therefore, exact information explaining whether a patient completed treatment or had to withdraw could not be extrapolated (ie, blood/plasma samples were not obtained to confirm).

Discontinued Treatment

The reasons for treatment discontinuation with erlotinib or gefitinib varied among patients, with no consistent AE or cause. Most data were for switching treatments after discontinuing treatment with erlotinib (101 of 123 patients) and gefitinib (2 of 5 patients). This is not surprising given the widely recognized pillars of therapy for NSCLC: chemotherapy, target therapy, and immunotherapy.²² From the MHS records, the reasons patients switched treatment of erlotinib or gefitinib were not listed or listed as due to negative EGFR testing, lack of responsiveness, or enrollment in a different treatment.

Physicians’ notes on AEs were not detailed in most cases. Notes for gastrointestinal effects, life-altering pruritis, intolerance, peripheral vascular disease, pneumonitis, and progressive disease described the change in status or appearance of a new medical condition but did not indicate whether erlotinib or gefitinib caused the changes or worsened a pre-existing condition.

The causes of AEs were not described in the available notes or the databases. This retrospective data analysis only focused on identifying drugs involved with erlotinib and gefitinib treatment; further mapping of DDIs among patients experiencing AEs needs to be performed, then in vitro data testing before researchers can reach a conclusion.

DDIs With Antidepressants

We used the PDTS database to evaluate patients who experienced AEs, excluding patients who switched treatment. Thirteen patients filled a prescription for erlotinib and reported taking 220 cancer and noncancer prescription drugs. One patient (pruritis) was taking gefitinib along with 16 noncancer prescription drugs.

Selective serotonin reuptake inhibitors and other antidepressants have been implicated in CYP 2D6 inhibition and DDIs.^48,49 Losartan is a widely used antihypertensive drug with a favorable DDI profile.⁵⁰Erlotinib and gefitinib are primarily metabolized via CYP 2D6 and 3A4 pathways. DDIs from in vitro human hepatocytes assays revealed that gefitinib had significant metabolic changes in a 1:1 (P < .05) combination with paroxetine or sertraline, and a 1:1:1 combination with losartan and fluoxetine, fluvoxamine, paroxetine, or sertraline. Citalopram and venlafaxine seemed to be unaffected by any combination (P ≥ .05).⁵¹ Erlotinib with fluoxetine or losartan 1:1 yielded insignificant differences in metabolism for all drugs (P ≥ .05). Three drug combinations of 1:1:1 involving fluoxetine and losartan with erlotinib yielded significant degrees of inhibition of fluoxetine and losartan metabolism (P < .05) but not erlotinib.⁵²

Our data showed that 16 antidepressants (amitriptyline, bupropion, citalopram, desvenlafaxine, duloxetine, escitalopram, imipramine, fluoxetine, fluvoxamine, mirtazapine, nortriptyline, paroxetine, phenelzine, sertraline, trazodone, and venlafaxine) were recorded with concomitant erlotinib or gefitinib from initiation to completion of therapy or a buffer of 6 months from the first diagnosis date. Based on the date dispensed and days’ supply, only escitalopram could be used in combination with gefitinib treatment. The one patient who filled a prescription for gefitinib and escitalopram completed treatment without recorded AEs. PDTS database confirmed that patients experienced AEs with 5 antidepressants (amitriptyline, mirtazapine, paroxetine, trazodone, and venlafaxine) with concomitant erlotinib use.

Based on the date dispensed and days’ supply, only trazodone could be used in combination with erlotinib. PDTS database showed that cancer drugs (erlotinib and megestrol) and 39 noncancer drugs (including acetaminophen, azithromycin, dexamethasone, hydrocortisone, and polyethylene glycol) were filled by 1 patient whose physician noted skin rash. Another limitation of using databases to reflect clinical practice is that although megestrol is listed as a cancer drug by code in the PDTS database, it is not used for nonendometrial or gynecologic cancers. However, because of the PDTS database classification, megestrol is classified as a cancer drug in this retrospective review.

This retrospective review found no significant DDIs for erlotinib or gefitinib, with 1 antidepressant taken by 1 patient for each respective treatment. The degree of inhibition and induction for escitalopram and trazodone are categorized as weak, minimal, or none; therefore, while 1:1 DDIs might be little or no effect, 1:1:1 combination DDIs could have a different outcome. This retrospective data collection cannot be linked to the in­ vitro hepatocyte DDIs from erlotinib and gefitinib in previous studies.^51,52

Conclusions

This retrospective study describes erlotinib and gefitinib use in the MHS and their potential for DDIs. Because of military service requirements, people who are qualified to serve must be healthy or have either controlled or nonactive medical diagnoses and be physically fit. Consequently, our patient population had fewer common medical illnesses, such as diabetes and obesity, compared with the general population. Most noncancer drugs mentioned in this study are not known CYP metabolizers; therefore, recorded AEs alone cannot conclusively determine whether there is a DDI among erlotinib or gefitinib and noncancer drugs. Antidepressants generally are safe but have boxed warnings in the US for increased risk of suicidal ideation in young people.^53,54 This retrospective study did not find statistically significant DDIs for erlotinib or gefitinib with antidepressants. Based on this retrospective data analysis, future in vitro testing is needed to assess DDIs for erlotinib or gefitinib and cancer or noncancer drugs identified in this study.

Acknowledgments

The Department of Research Program funds at Walter Reed National Military Medical Center supported this protocol. We sincerely appreciate the contribution of data extraction from the Joint Pathology Center teams (Francisco J. Rentas, John D. McGeeney, Kimberly M. Greenfield, Beatriz A. Hallo, and Johnny P. Beason) and the MHS database personnel (Maj Ryan Costantino, Lee Ann Zarzabal, Brandon Jenkins, and Alex Rittel). We gratefully thank you for the protocol support from the Department of Research programs: CDR Wesley R. Campbell, CDR Ling Ye, Yaling Zhou, Elizabeth Schafer, Robert Roogow, Micah Stretch, Diane Beaner, Adrienne Woodard, David L. Evers, and Paula Amann.

Most cancer treatment regimens include the administration of several chemotherapeutic agents. Drug-drug interactions (DDIs) can increase the risk of fatal adverse events and reduce therapeutic efficacy.^1,2 Erlotinib, gefitinib, afatinib, osimertinib, and icotinib are epidermal growth factor receptor–tyrosine kinase inhibitors (EGFR-TKIs) that have proven efficacy for treating advanced non–small cell lung cancer (NSCLC). Erlotinib strongly inhibits cytochrome P450 (CYP) isoenzymes CYP 1A1, moderately inhibits CYP 3A4 and 2C8, and induces CYP 1A1 and 1A2.² Gefitinib weakly inhibits CYP 2C19 and 2D6.² CYP 3A4 inducers and inhibitors affect metabolism of both erlotinib and gefitinib.^3,4

Erlotinib and gefitinib are first-generation EGFR-TKIs and have been approved for NSCLC treatment by the US Food and Drug Administration (FDA). These agents have been used since the early 2000s and increase the possibility of long-term response and survival.^2,5,6 EGFR-TKIs have a range of potential DDIs, including interactions with CYP-dependent metabolism, uridine diphosphate-glucuronosyltransferase, and transporter proteins.² Few retrospective studies have focused on the therapeutic efficacy of erlotinib, gefitinib,or the combination of these agents.^7-14

DDIs from cancer and noncancer therapies could lead to treatment discontinuation and affect patient outcomes. The goals for this study were to perform a broad-scale retrospective analysis focused on investigating prescribed drugs used with erlotinib and gefitinib and determine patient outcomes as obtained through several Military Health System (MHS) databases. Our investigation focused on (1) the functions of these drugs; (2) identifying adverse effects (AEs) that patients experienced; (3) evaluating differences when these drugs are used alone vs concomitantly, and between the completed vs discontinued treatment groups; (4) identifying all drugs used during erlotinib or gefitinib treatment; and (5) evaluating DDIs with antidepressants.

This retrospective study was performed at the Department of Research Programs at Walter Reed National Military Medical Center (WRNMMC) in Bethesda, Maryland. The WRNMMC Institutional Review Board approved the study protocol and ensured compliance with the Health Insurance Portability and Accountability Act as an exempt protocol. The Joint Pathology Center of the US Department of Defense (DoD) Cancer Registry and MHS data experts from the Comprehensive Ambulatory/Professional Encounter Record (CAPER) and the Pharmacy Data Transaction Service (PDTS) provided data for the analysis.

Methods

The DoD Cancer Registry Program was established in 1986 by the Assistant Secretary of Defense for Health Affairs. The registry currently contains data from 1998 to 2023. CAPER and PDTS are part of the MHS Data Repository/Management Analysis and Reporting Tool database. Each observation in the CAPER record represents an ambulatory encounter at a military treatment facility (MTF). CAPER records are available from 2003 to 2023.

Each observation in the PDTS record represents an outpatient prescription filled for an MHS beneficiary at MTFs through the TRICARE mail-order program or a retail pharmacy in the United States. Missing from this record are prescriptions filled at civilian pharmacies outside the United States and inpatient pharmacy prescriptions. The MHS Data Repository PDTS record is available from 2002 to 2023. The Composite Health Care System—the legacy system—is being replaced by GENESIS at MTFs.

Data Extraction Design

The study design involved a cross-sectional analysis. We requested data extraction for erlotinib and gefitinib from 1998 to 2021. Data from the DoD Cancer Registry were used to identify patients who received cancer treatment. Once patients were identified, the CAPER database was searched for diagnoses to identify other health conditions, while the PDTS database was used to populate a list of prescription medications filled during chemotherapy treatment.

Data collected from the Joint Pathology Center included cancer treatment (alone or concomitant), cancer information (cancer types and stages), demographics (sex, age at diagnosis), and physicians’ comments on AEs. Collected data from the MHS include diagnosis and filled prescription history from initiation to completion of the therapy period (or a buffer of 6 months after the initial period). We used all collected data in this analysis. The only exclusion criterion was a provided physician’s note commenting that the patient did not use erlotinib or gefitinib.

Data Extraction Analysis

The Surveillance, Epidemiology, and End Results Program Coding and Staging Manual 2016 and the International Classification of Diseases for Oncology (ICD-O) were used to decode disease and cancer types.^15,16 Data sorting and analysis were performed using Microsoft Excel. The percentage for the total was calculated by using the total number of patients or data available within the gefitinib and erlotinib groups divided by total number of patients or data variables. The subgroup percentage was calculated by using the number of patients or data available within the subgroup divided by the total number of patients in that subgroup.

In alone vs concomitant and completed vs discontinued treatment groups, a 2-tailed, 2-sample z test was used to calculate P to determine statistical significance (P < .05) using a statistics website.¹⁷ Concomitant was defined as erlotinib or gefitinib taken with other medication(s) before, after, or at the same time as cancer therapy. For the retrospective data analysis, physicians’ notes with “.”, “,”, “/”, “;”, (period, comma, forward slash, semicolon) or space between medication names were interpreted as concurrent, while “+”, “-/+” (plus, minus/plus), or and between drug names were interpreted as combined. Completed treatment was defined as erlotinib or gefitinib as the last medication the patient took without recorded AEs; switching or experiencing AEs was defined as discontinued treatment.

Results

Erlotinib

The Joint Pathology Center provided 387 entries for 382 patients aged 21 to 93 years (mean, 65 years) who were treated systemically with erlotinib from January 1, 2001, to December 31, 2020. Five patients had duplicate entries because they had different cancer sites. There were 287 patients (74%) with lung cancer, 61 (16%) with pancreatic cancer, and 39 (10%) with other cancers. For lung cancer, there were 118 patients (30%) for the upper lobe, 78 (20%) for the lower lobe, and 60 (16%) not otherwise specified (NOS). Other lung cancer sites had fewer patients: 21 (5%) middle lobe lung, 6 (2%) overlapping lung lesion(s), and 4 (1%) main bronchus of the lung. For pancreatic cancer, there were 27 patients (7%) for the head of the pancreas, 10 (3%) pancreas NOS, 9 (2%) body of the pancreas, 9 (2%) tail of the pancreas, 4 (1%) overlapping lesions of the pancreas, 1 (< 1%) pancreatic duct, and 1 (< 1%) other specified parts of the pancreas

There were 342 patients (88%) who were aged > 50 years; 186 male patients (48%) and 201 female patients (52%). There were 293 patients (76%) who had a cancer diagnosis of stage III or IV disease and 94 (24%) who had a cancer diagnosis of stage ≤ II (combination of data for stage 0, 1, and 2, not applicable, and unknown). For their systemic treatment, 161 patients (42%) were treated with erlotinib alone and 226 (58%) received erlotinib concomitantly with additional chemotherapy.

Among the 123 patients who discontinued their treatment, 101 switched treatment with no AEs notes, 22 died or experienced fatigue with blurry vision, constipation, nonspecific gastrointestinal effects, grade-4 diarrhea (as defined by the Common Terminology Criteria for Adverse Events), or developed a pleural fluid, pneumonitis, renal failure, skin swelling and facial rash, and unknown AEs of discontinuation. Patients who discontinued treatment because of unknown AEs had physicians’ notes that detailed emergency department visits, peripheral vascular disease, progressive disease, and treatment cessation, but did not specify the exact symptom(s) that led to discontinuation. The causes of death are unknown because they were not detailed in the available notes or databases. The overall results in this retrospective review cannot establish causality between taking erlotinib or gefitinib and death.

Gefitinib

In September 2021, the Joint Pathology Center provided 33 entries for 33 patients who were systemically treated with gefitinib from January 1, 2002, to December 31, 2017. The patient ages ranged from 49 to 89 years with a mean age of 66 years. There were 31 (94%) and 2 (6%) patients with lung and other cancers, respectively. The upper lobe, lower lobe, and lung NOS had the most patients: 14 (42%), 8 (24%), and 6 (18%), respectively.

There were 31 patients (94%) who were aged > 50 years; 15 were male (45%) and 18 were female (55%). There were 26 patients (79%) who had a cancer diagnosis of stage III or IV disease. Nineteen patients (58%) were treated with gefitinib alone, and 14 (42%) were treated with gefitinib concomitantly with additional chemotherapy. Thirty-one patients (94%) were treated for lung cancer (Table 2). Thirty-three patients are a small sample size to determine whether patients were likely to stop gefitinib if used concomitantly with other drugs. Among the patients treated with gefitinib monotherapy, 5% (n = 1) stopped treatment, whereas 29% (n = 4) of patients treated concomitantly discontinued treatment (P = .06). All comparisons for gefitinib yielded insignificant P values. Physicians’ notes indicated that the reasons for gefitinib discontinuation were life-altering pruritis and unknown (progressive disease outcome) (Table 3).

Management Analysis and Reporting Tool Database

MHS data analysts provided data on diagnoses for 348 patients among 415 submitted, with 232 and 112 patients completing and discontinuing erlotinib or gefitinib treatment, respectively. Each patient had 1 to 104 (completed treatment group) and 1 to 157 (discontinued treatment group) unique health conditions documented. The MHS reported 1319 unique-diagnosis conditions for the completed group and 1266 for the discontinued group. Patients with additional health issues stopped chemotherapy use more often than those without; P < .001 for the completed group (232 patients, 1319 diagnoses) vs the discontinued group (112 patients, 1266 diagnoses). The mean (SD) number of diagnoses was 19 (17) for the completed and 30 (22) for the discontinued treatment groups (Figure).

MHS data was provided for patients who filled erlotinib (n = 240) or gefitinib (n = 18). Among the 258 patients, there were 179 and 79 patients in the completed and discontinued treatment groups, respectively. Each patient filled 1 to 75 (for the completed treatment group) and 3 to 103 (for the discontinued treatment group) prescription drugs. There were 805 unique-filled prescriptions for the completed and 670 for the discontinued group. Patients in the discontinued group filled more prescriptions than those who completed treatment; P < .001 for the completed group (179 patients,805 drugs) vs the discontinued group (79 patients, 670 drugs).

The mean (SD) number of filled prescription drugs was 19 (11) for the completed group and 29 (18) for the discontinued treatment group. The 5 most filled prescriptions with erlotinib from 258 patients with PDTS data were ondansetron (151 prescriptions, 10 recorded AEs), dexamethasone (119 prescriptions, 9 recorded AEs), prochlorperazine (105 prescriptions, 15 recorded AEs), oxycodone (99 prescriptions, 1 AE), and docusate (96 prescriptions, 7 recorded AEs).

Discussion

The difference between erlotinib and gefitinib data can be attributed to the FDA approval date and gefitinib’s association with a higher frequency of hepatotoxicity.^18-20 The FDA designated gefitinib as an orphan drug for EGFR mutation–positive NSCLC treatment. Gefitinib first received accelerated approval in 2003 for the treatment of locally advanced or metastatic NSCLC. Gefitinib then was voluntarily withdrawn from the market following confirmatory clinical trials that did not verify clinical benefit.

The current approval is for a different patient population—previously untreated, metastatic EGFR exon 19 or 21 L858R mutation—than the 2003 approval.^4,6 There was no record of gefitinib use after 2017 in our study.

Erlotinib is a reversible EGFR-TKI that is approved by the FDA as first-line (maintenance) or second-line treatment (after progression following at least 1 earlier chemotherapy regimen) for patients with metastatic NSCLC who harbor EGFR exon 19 deletions or exon 21 L858R substitution mutations, as detected by an FDA-approved test.³ Since 2005, the FDA also approved erlotinib for first-line treatment of patients with locally advanced, unresectable, or metastatic pancreatic cancer in combination with gemcitabine.³ Without FDA indication, erlotinib is used for colorectal, head and neck, ovarian carcinoma, pancreatic carcinoma, and breast cancer.²¹

Erlotinib and gefitinib are not considered first-line treatments in EGFR exon 19 or 21–mutated NSCLC because osimertinib was approved in 2018. Targeted therapies for EGFR mutation continue to advance at a fast pace, with amivantamab and mobocertinib now FDA approved for EGFR exon 20 insertion–mutated NSCLC.

Erlotinib Use

Thirty-nine patients (10%) in this study were prescribed erlotinib for off-label indications. Erlotinib was used alone or in combination with bevacizumab, capecitabine, cisplatin, denosumab, docetaxel, gemcitabine, and the MEK-inhibitor selumetinib. Erlotinib combined with cisplatin, denosumab, docetaxel, and gemcitabine had no recorded AEs, with 10 data entries for gemcitabine and 1 for other drugs. Three patients received bevacizumab and erlotinib, and 1 patient (diagnosed with kidney NOS) showed rash or facial swelling/erythema and diffuse body itching then stable disease after 2 cycles.

One patient (diagnosed with cancer located at the pancreas head) was bridged with capecitabine and erlotinib when going on a vacation, then received FOLFIRINOX (a combination chemotherapy regimen containing folinic acid [leucovorin], fluorouracil, irinotecan, and oxaliplatin), which led to significant fatigue, blurry vision, and constipation. One patient was treated for lung NOS with the MEK-inhibitor selumetinib plus erlotinib and developed pneumonitis following treatment.

Because oncologists followed guidelines and protocols in systemic treatment, DDIs of erlotinib concurrently (before or after) and in combination with cancer drugs were unlikely. Further investigation is needed for several 1:1:1 DDIs with noncancer drugs. A retrospective overview is not a randomized clinical study; therefore, analysis is limited. Data from the MHS were obtained solely from notes from physicians who treated the patients; therefore, exact information explaining whether a patient completed treatment or had to withdraw could not be extrapolated (ie, blood/plasma samples were not obtained to confirm).

Discontinued Treatment

The reasons for treatment discontinuation with erlotinib or gefitinib varied among patients, with no consistent AE or cause. Most data were for switching treatments after discontinuing treatment with erlotinib (101 of 123 patients) and gefitinib (2 of 5 patients). This is not surprising given the widely recognized pillars of therapy for NSCLC: chemotherapy, target therapy, and immunotherapy.²² From the MHS records, the reasons patients switched treatment of erlotinib or gefitinib were not listed or listed as due to negative EGFR testing, lack of responsiveness, or enrollment in a different treatment.

Physicians’ notes on AEs were not detailed in most cases. Notes for gastrointestinal effects, life-altering pruritis, intolerance, peripheral vascular disease, pneumonitis, and progressive disease described the change in status or appearance of a new medical condition but did not indicate whether erlotinib or gefitinib caused the changes or worsened a pre-existing condition.

The causes of AEs were not described in the available notes or the databases. This retrospective data analysis only focused on identifying drugs involved with erlotinib and gefitinib treatment; further mapping of DDIs among patients experiencing AEs needs to be performed, then in vitro data testing before researchers can reach a conclusion.

DDIs With Antidepressants

We used the PDTS database to evaluate patients who experienced AEs, excluding patients who switched treatment. Thirteen patients filled a prescription for erlotinib and reported taking 220 cancer and noncancer prescription drugs. One patient (pruritis) was taking gefitinib along with 16 noncancer prescription drugs.

Selective serotonin reuptake inhibitors and other antidepressants have been implicated in CYP 2D6 inhibition and DDIs.^48,49 Losartan is a widely used antihypertensive drug with a favorable DDI profile.⁵⁰Erlotinib and gefitinib are primarily metabolized via CYP 2D6 and 3A4 pathways. DDIs from in vitro human hepatocytes assays revealed that gefitinib had significant metabolic changes in a 1:1 (P < .05) combination with paroxetine or sertraline, and a 1:1:1 combination with losartan and fluoxetine, fluvoxamine, paroxetine, or sertraline. Citalopram and venlafaxine seemed to be unaffected by any combination (P ≥ .05).⁵¹ Erlotinib with fluoxetine or losartan 1:1 yielded insignificant differences in metabolism for all drugs (P ≥ .05). Three drug combinations of 1:1:1 involving fluoxetine and losartan with erlotinib yielded significant degrees of inhibition of fluoxetine and losartan metabolism (P < .05) but not erlotinib.⁵²

Our data showed that 16 antidepressants (amitriptyline, bupropion, citalopram, desvenlafaxine, duloxetine, escitalopram, imipramine, fluoxetine, fluvoxamine, mirtazapine, nortriptyline, paroxetine, phenelzine, sertraline, trazodone, and venlafaxine) were recorded with concomitant erlotinib or gefitinib from initiation to completion of therapy or a buffer of 6 months from the first diagnosis date. Based on the date dispensed and days’ supply, only escitalopram could be used in combination with gefitinib treatment. The one patient who filled a prescription for gefitinib and escitalopram completed treatment without recorded AEs. PDTS database confirmed that patients experienced AEs with 5 antidepressants (amitriptyline, mirtazapine, paroxetine, trazodone, and venlafaxine) with concomitant erlotinib use.

Based on the date dispensed and days’ supply, only trazodone could be used in combination with erlotinib. PDTS database showed that cancer drugs (erlotinib and megestrol) and 39 noncancer drugs (including acetaminophen, azithromycin, dexamethasone, hydrocortisone, and polyethylene glycol) were filled by 1 patient whose physician noted skin rash. Another limitation of using databases to reflect clinical practice is that although megestrol is listed as a cancer drug by code in the PDTS database, it is not used for nonendometrial or gynecologic cancers. However, because of the PDTS database classification, megestrol is classified as a cancer drug in this retrospective review.

This retrospective review found no significant DDIs for erlotinib or gefitinib, with 1 antidepressant taken by 1 patient for each respective treatment. The degree of inhibition and induction for escitalopram and trazodone are categorized as weak, minimal, or none; therefore, while 1:1 DDIs might be little or no effect, 1:1:1 combination DDIs could have a different outcome. This retrospective data collection cannot be linked to the in­ vitro hepatocyte DDIs from erlotinib and gefitinib in previous studies.^51,52

Conclusions

This retrospective study describes erlotinib and gefitinib use in the MHS and their potential for DDIs. Because of military service requirements, people who are qualified to serve must be healthy or have either controlled or nonactive medical diagnoses and be physically fit. Consequently, our patient population had fewer common medical illnesses, such as diabetes and obesity, compared with the general population. Most noncancer drugs mentioned in this study are not known CYP metabolizers; therefore, recorded AEs alone cannot conclusively determine whether there is a DDI among erlotinib or gefitinib and noncancer drugs. Antidepressants generally are safe but have boxed warnings in the US for increased risk of suicidal ideation in young people.^53,54 This retrospective study did not find statistically significant DDIs for erlotinib or gefitinib with antidepressants. Based on this retrospective data analysis, future in vitro testing is needed to assess DDIs for erlotinib or gefitinib and cancer or noncancer drugs identified in this study.

Acknowledgments

The Department of Research Program funds at Walter Reed National Military Medical Center supported this protocol. We sincerely appreciate the contribution of data extraction from the Joint Pathology Center teams (Francisco J. Rentas, John D. McGeeney, Kimberly M. Greenfield, Beatriz A. Hallo, and Johnny P. Beason) and the MHS database personnel (Maj Ryan Costantino, Lee Ann Zarzabal, Brandon Jenkins, and Alex Rittel). We gratefully thank you for the protocol support from the Department of Research programs: CDR Wesley R. Campbell, CDR Ling Ye, Yaling Zhou, Elizabeth Schafer, Robert Roogow, Micah Stretch, Diane Beaner, Adrienne Woodard, David L. Evers, and Paula Amann.

Most cancer treatment regimens include the administration of several chemotherapeutic agents. Drug-drug interactions (DDIs) can increase the risk of fatal adverse events and reduce therapeutic efficacy.^1,2 Erlotinib, gefitinib, afatinib, osimertinib, and icotinib are epidermal growth factor receptor–tyrosine kinase inhibitors (EGFR-TKIs) that have proven efficacy for treating advanced non–small cell lung cancer (NSCLC). Erlotinib strongly inhibits cytochrome P450 (CYP) isoenzymes CYP 1A1, moderately inhibits CYP 3A4 and 2C8, and induces CYP 1A1 and 1A2.² Gefitinib weakly inhibits CYP 2C19 and 2D6.² CYP 3A4 inducers and inhibitors affect metabolism of both erlotinib and gefitinib.^3,4

Erlotinib and gefitinib are first-generation EGFR-TKIs and have been approved for NSCLC treatment by the US Food and Drug Administration (FDA). These agents have been used since the early 2000s and increase the possibility of long-term response and survival.^2,5,6 EGFR-TKIs have a range of potential DDIs, including interactions with CYP-dependent metabolism, uridine diphosphate-glucuronosyltransferase, and transporter proteins.² Few retrospective studies have focused on the therapeutic efficacy of erlotinib, gefitinib,or the combination of these agents.^7-14

DDIs from cancer and noncancer therapies could lead to treatment discontinuation and affect patient outcomes. The goals for this study were to perform a broad-scale retrospective analysis focused on investigating prescribed drugs used with erlotinib and gefitinib and determine patient outcomes as obtained through several Military Health System (MHS) databases. Our investigation focused on (1) the functions of these drugs; (2) identifying adverse effects (AEs) that patients experienced; (3) evaluating differences when these drugs are used alone vs concomitantly, and between the completed vs discontinued treatment groups; (4) identifying all drugs used during erlotinib or gefitinib treatment; and (5) evaluating DDIs with antidepressants.

This retrospective study was performed at the Department of Research Programs at Walter Reed National Military Medical Center (WRNMMC) in Bethesda, Maryland. The WRNMMC Institutional Review Board approved the study protocol and ensured compliance with the Health Insurance Portability and Accountability Act as an exempt protocol. The Joint Pathology Center of the US Department of Defense (DoD) Cancer Registry and MHS data experts from the Comprehensive Ambulatory/Professional Encounter Record (CAPER) and the Pharmacy Data Transaction Service (PDTS) provided data for the analysis.

Methods

The DoD Cancer Registry Program was established in 1986 by the Assistant Secretary of Defense for Health Affairs. The registry currently contains data from 1998 to 2023. CAPER and PDTS are part of the MHS Data Repository/Management Analysis and Reporting Tool database. Each observation in the CAPER record represents an ambulatory encounter at a military treatment facility (MTF). CAPER records are available from 2003 to 2023.

Each observation in the PDTS record represents an outpatient prescription filled for an MHS beneficiary at MTFs through the TRICARE mail-order program or a retail pharmacy in the United States. Missing from this record are prescriptions filled at civilian pharmacies outside the United States and inpatient pharmacy prescriptions. The MHS Data Repository PDTS record is available from 2002 to 2023. The Composite Health Care System—the legacy system—is being replaced by GENESIS at MTFs.

Data Extraction Design

The study design involved a cross-sectional analysis. We requested data extraction for erlotinib and gefitinib from 1998 to 2021. Data from the DoD Cancer Registry were used to identify patients who received cancer treatment. Once patients were identified, the CAPER database was searched for diagnoses to identify other health conditions, while the PDTS database was used to populate a list of prescription medications filled during chemotherapy treatment.

Data collected from the Joint Pathology Center included cancer treatment (alone or concomitant), cancer information (cancer types and stages), demographics (sex, age at diagnosis), and physicians’ comments on AEs. Collected data from the MHS include diagnosis and filled prescription history from initiation to completion of the therapy period (or a buffer of 6 months after the initial period). We used all collected data in this analysis. The only exclusion criterion was a provided physician’s note commenting that the patient did not use erlotinib or gefitinib.

Data Extraction Analysis

The Surveillance, Epidemiology, and End Results Program Coding and Staging Manual 2016 and the International Classification of Diseases for Oncology (ICD-O) were used to decode disease and cancer types.^15,16 Data sorting and analysis were performed using Microsoft Excel. The percentage for the total was calculated by using the total number of patients or data available within the gefitinib and erlotinib groups divided by total number of patients or data variables. The subgroup percentage was calculated by using the number of patients or data available within the subgroup divided by the total number of patients in that subgroup.

In alone vs concomitant and completed vs discontinued treatment groups, a 2-tailed, 2-sample z test was used to calculate P to determine statistical significance (P < .05) using a statistics website.¹⁷ Concomitant was defined as erlotinib or gefitinib taken with other medication(s) before, after, or at the same time as cancer therapy. For the retrospective data analysis, physicians’ notes with “.”, “,”, “/”, “;”, (period, comma, forward slash, semicolon) or space between medication names were interpreted as concurrent, while “+”, “-/+” (plus, minus/plus), or and between drug names were interpreted as combined. Completed treatment was defined as erlotinib or gefitinib as the last medication the patient took without recorded AEs; switching or experiencing AEs was defined as discontinued treatment.

Results

Erlotinib

The Joint Pathology Center provided 387 entries for 382 patients aged 21 to 93 years (mean, 65 years) who were treated systemically with erlotinib from January 1, 2001, to December 31, 2020. Five patients had duplicate entries because they had different cancer sites. There were 287 patients (74%) with lung cancer, 61 (16%) with pancreatic cancer, and 39 (10%) with other cancers. For lung cancer, there were 118 patients (30%) for the upper lobe, 78 (20%) for the lower lobe, and 60 (16%) not otherwise specified (NOS). Other lung cancer sites had fewer patients: 21 (5%) middle lobe lung, 6 (2%) overlapping lung lesion(s), and 4 (1%) main bronchus of the lung. For pancreatic cancer, there were 27 patients (7%) for the head of the pancreas, 10 (3%) pancreas NOS, 9 (2%) body of the pancreas, 9 (2%) tail of the pancreas, 4 (1%) overlapping lesions of the pancreas, 1 (< 1%) pancreatic duct, and 1 (< 1%) other specified parts of the pancreas

There were 342 patients (88%) who were aged > 50 years; 186 male patients (48%) and 201 female patients (52%). There were 293 patients (76%) who had a cancer diagnosis of stage III or IV disease and 94 (24%) who had a cancer diagnosis of stage ≤ II (combination of data for stage 0, 1, and 2, not applicable, and unknown). For their systemic treatment, 161 patients (42%) were treated with erlotinib alone and 226 (58%) received erlotinib concomitantly with additional chemotherapy.

Among the 123 patients who discontinued their treatment, 101 switched treatment with no AEs notes, 22 died or experienced fatigue with blurry vision, constipation, nonspecific gastrointestinal effects, grade-4 diarrhea (as defined by the Common Terminology Criteria for Adverse Events), or developed a pleural fluid, pneumonitis, renal failure, skin swelling and facial rash, and unknown AEs of discontinuation. Patients who discontinued treatment because of unknown AEs had physicians’ notes that detailed emergency department visits, peripheral vascular disease, progressive disease, and treatment cessation, but did not specify the exact symptom(s) that led to discontinuation. The causes of death are unknown because they were not detailed in the available notes or databases. The overall results in this retrospective review cannot establish causality between taking erlotinib or gefitinib and death.

Gefitinib

In September 2021, the Joint Pathology Center provided 33 entries for 33 patients who were systemically treated with gefitinib from January 1, 2002, to December 31, 2017. The patient ages ranged from 49 to 89 years with a mean age of 66 years. There were 31 (94%) and 2 (6%) patients with lung and other cancers, respectively. The upper lobe, lower lobe, and lung NOS had the most patients: 14 (42%), 8 (24%), and 6 (18%), respectively.

There were 31 patients (94%) who were aged > 50 years; 15 were male (45%) and 18 were female (55%). There were 26 patients (79%) who had a cancer diagnosis of stage III or IV disease. Nineteen patients (58%) were treated with gefitinib alone, and 14 (42%) were treated with gefitinib concomitantly with additional chemotherapy. Thirty-one patients (94%) were treated for lung cancer (Table 2). Thirty-three patients are a small sample size to determine whether patients were likely to stop gefitinib if used concomitantly with other drugs. Among the patients treated with gefitinib monotherapy, 5% (n = 1) stopped treatment, whereas 29% (n = 4) of patients treated concomitantly discontinued treatment (P = .06). All comparisons for gefitinib yielded insignificant P values. Physicians’ notes indicated that the reasons for gefitinib discontinuation were life-altering pruritis and unknown (progressive disease outcome) (Table 3).

Management Analysis and Reporting Tool Database

MHS data analysts provided data on diagnoses for 348 patients among 415 submitted, with 232 and 112 patients completing and discontinuing erlotinib or gefitinib treatment, respectively. Each patient had 1 to 104 (completed treatment group) and 1 to 157 (discontinued treatment group) unique health conditions documented. The MHS reported 1319 unique-diagnosis conditions for the completed group and 1266 for the discontinued group. Patients with additional health issues stopped chemotherapy use more often than those without; P < .001 for the completed group (232 patients, 1319 diagnoses) vs the discontinued group (112 patients, 1266 diagnoses). The mean (SD) number of diagnoses was 19 (17) for the completed and 30 (22) for the discontinued treatment groups (Figure).

MHS data was provided for patients who filled erlotinib (n = 240) or gefitinib (n = 18). Among the 258 patients, there were 179 and 79 patients in the completed and discontinued treatment groups, respectively. Each patient filled 1 to 75 (for the completed treatment group) and 3 to 103 (for the discontinued treatment group) prescription drugs. There were 805 unique-filled prescriptions for the completed and 670 for the discontinued group. Patients in the discontinued group filled more prescriptions than those who completed treatment; P < .001 for the completed group (179 patients,805 drugs) vs the discontinued group (79 patients, 670 drugs).

The mean (SD) number of filled prescription drugs was 19 (11) for the completed group and 29 (18) for the discontinued treatment group. The 5 most filled prescriptions with erlotinib from 258 patients with PDTS data were ondansetron (151 prescriptions, 10 recorded AEs), dexamethasone (119 prescriptions, 9 recorded AEs), prochlorperazine (105 prescriptions, 15 recorded AEs), oxycodone (99 prescriptions, 1 AE), and docusate (96 prescriptions, 7 recorded AEs).

Discussion

The difference between erlotinib and gefitinib data can be attributed to the FDA approval date and gefitinib’s association with a higher frequency of hepatotoxicity.^18-20 The FDA designated gefitinib as an orphan drug for EGFR mutation–positive NSCLC treatment. Gefitinib first received accelerated approval in 2003 for the treatment of locally advanced or metastatic NSCLC. Gefitinib then was voluntarily withdrawn from the market following confirmatory clinical trials that did not verify clinical benefit.

The current approval is for a different patient population—previously untreated, metastatic EGFR exon 19 or 21 L858R mutation—than the 2003 approval.^4,6 There was no record of gefitinib use after 2017 in our study.

Erlotinib is a reversible EGFR-TKI that is approved by the FDA as first-line (maintenance) or second-line treatment (after progression following at least 1 earlier chemotherapy regimen) for patients with metastatic NSCLC who harbor EGFR exon 19 deletions or exon 21 L858R substitution mutations, as detected by an FDA-approved test.³ Since 2005, the FDA also approved erlotinib for first-line treatment of patients with locally advanced, unresectable, or metastatic pancreatic cancer in combination with gemcitabine.³ Without FDA indication, erlotinib is used for colorectal, head and neck, ovarian carcinoma, pancreatic carcinoma, and breast cancer.²¹

Erlotinib and gefitinib are not considered first-line treatments in EGFR exon 19 or 21–mutated NSCLC because osimertinib was approved in 2018. Targeted therapies for EGFR mutation continue to advance at a fast pace, with amivantamab and mobocertinib now FDA approved for EGFR exon 20 insertion–mutated NSCLC.

Erlotinib Use

Thirty-nine patients (10%) in this study were prescribed erlotinib for off-label indications. Erlotinib was used alone or in combination with bevacizumab, capecitabine, cisplatin, denosumab, docetaxel, gemcitabine, and the MEK-inhibitor selumetinib. Erlotinib combined with cisplatin, denosumab, docetaxel, and gemcitabine had no recorded AEs, with 10 data entries for gemcitabine and 1 for other drugs. Three patients received bevacizumab and erlotinib, and 1 patient (diagnosed with kidney NOS) showed rash or facial swelling/erythema and diffuse body itching then stable disease after 2 cycles.

One patient (diagnosed with cancer located at the pancreas head) was bridged with capecitabine and erlotinib when going on a vacation, then received FOLFIRINOX (a combination chemotherapy regimen containing folinic acid [leucovorin], fluorouracil, irinotecan, and oxaliplatin), which led to significant fatigue, blurry vision, and constipation. One patient was treated for lung NOS with the MEK-inhibitor selumetinib plus erlotinib and developed pneumonitis following treatment.

Because oncologists followed guidelines and protocols in systemic treatment, DDIs of erlotinib concurrently (before or after) and in combination with cancer drugs were unlikely. Further investigation is needed for several 1:1:1 DDIs with noncancer drugs. A retrospective overview is not a randomized clinical study; therefore, analysis is limited. Data from the MHS were obtained solely from notes from physicians who treated the patients; therefore, exact information explaining whether a patient completed treatment or had to withdraw could not be extrapolated (ie, blood/plasma samples were not obtained to confirm).

Discontinued Treatment

The reasons for treatment discontinuation with erlotinib or gefitinib varied among patients, with no consistent AE or cause. Most data were for switching treatments after discontinuing treatment with erlotinib (101 of 123 patients) and gefitinib (2 of 5 patients). This is not surprising given the widely recognized pillars of therapy for NSCLC: chemotherapy, target therapy, and immunotherapy.²² From the MHS records, the reasons patients switched treatment of erlotinib or gefitinib were not listed or listed as due to negative EGFR testing, lack of responsiveness, or enrollment in a different treatment.

Physicians’ notes on AEs were not detailed in most cases. Notes for gastrointestinal effects, life-altering pruritis, intolerance, peripheral vascular disease, pneumonitis, and progressive disease described the change in status or appearance of a new medical condition but did not indicate whether erlotinib or gefitinib caused the changes or worsened a pre-existing condition.

The causes of AEs were not described in the available notes or the databases. This retrospective data analysis only focused on identifying drugs involved with erlotinib and gefitinib treatment; further mapping of DDIs among patients experiencing AEs needs to be performed, then in vitro data testing before researchers can reach a conclusion.

DDIs With Antidepressants

We used the PDTS database to evaluate patients who experienced AEs, excluding patients who switched treatment. Thirteen patients filled a prescription for erlotinib and reported taking 220 cancer and noncancer prescription drugs. One patient (pruritis) was taking gefitinib along with 16 noncancer prescription drugs.

Selective serotonin reuptake inhibitors and other antidepressants have been implicated in CYP 2D6 inhibition and DDIs.^48,49 Losartan is a widely used antihypertensive drug with a favorable DDI profile.⁵⁰Erlotinib and gefitinib are primarily metabolized via CYP 2D6 and 3A4 pathways. DDIs from in vitro human hepatocytes assays revealed that gefitinib had significant metabolic changes in a 1:1 (P < .05) combination with paroxetine or sertraline, and a 1:1:1 combination with losartan and fluoxetine, fluvoxamine, paroxetine, or sertraline. Citalopram and venlafaxine seemed to be unaffected by any combination (P ≥ .05).⁵¹ Erlotinib with fluoxetine or losartan 1:1 yielded insignificant differences in metabolism for all drugs (P ≥ .05). Three drug combinations of 1:1:1 involving fluoxetine and losartan with erlotinib yielded significant degrees of inhibition of fluoxetine and losartan metabolism (P < .05) but not erlotinib.⁵²

Our data showed that 16 antidepressants (amitriptyline, bupropion, citalopram, desvenlafaxine, duloxetine, escitalopram, imipramine, fluoxetine, fluvoxamine, mirtazapine, nortriptyline, paroxetine, phenelzine, sertraline, trazodone, and venlafaxine) were recorded with concomitant erlotinib or gefitinib from initiation to completion of therapy or a buffer of 6 months from the first diagnosis date. Based on the date dispensed and days’ supply, only escitalopram could be used in combination with gefitinib treatment. The one patient who filled a prescription for gefitinib and escitalopram completed treatment without recorded AEs. PDTS database confirmed that patients experienced AEs with 5 antidepressants (amitriptyline, mirtazapine, paroxetine, trazodone, and venlafaxine) with concomitant erlotinib use.

Based on the date dispensed and days’ supply, only trazodone could be used in combination with erlotinib. PDTS database showed that cancer drugs (erlotinib and megestrol) and 39 noncancer drugs (including acetaminophen, azithromycin, dexamethasone, hydrocortisone, and polyethylene glycol) were filled by 1 patient whose physician noted skin rash. Another limitation of using databases to reflect clinical practice is that although megestrol is listed as a cancer drug by code in the PDTS database, it is not used for nonendometrial or gynecologic cancers. However, because of the PDTS database classification, megestrol is classified as a cancer drug in this retrospective review.

This retrospective review found no significant DDIs for erlotinib or gefitinib, with 1 antidepressant taken by 1 patient for each respective treatment. The degree of inhibition and induction for escitalopram and trazodone are categorized as weak, minimal, or none; therefore, while 1:1 DDIs might be little or no effect, 1:1:1 combination DDIs could have a different outcome. This retrospective data collection cannot be linked to the in­ vitro hepatocyte DDIs from erlotinib and gefitinib in previous studies.^51,52

Conclusions

This retrospective study describes erlotinib and gefitinib use in the MHS and their potential for DDIs. Because of military service requirements, people who are qualified to serve must be healthy or have either controlled or nonactive medical diagnoses and be physically fit. Consequently, our patient population had fewer common medical illnesses, such as diabetes and obesity, compared with the general population. Most noncancer drugs mentioned in this study are not known CYP metabolizers; therefore, recorded AEs alone cannot conclusively determine whether there is a DDI among erlotinib or gefitinib and noncancer drugs. Antidepressants generally are safe but have boxed warnings in the US for increased risk of suicidal ideation in young people.^53,54 This retrospective study did not find statistically significant DDIs for erlotinib or gefitinib with antidepressants. Based on this retrospective data analysis, future in vitro testing is needed to assess DDIs for erlotinib or gefitinib and cancer or noncancer drugs identified in this study.

Acknowledgments

The Department of Research Program funds at Walter Reed National Military Medical Center supported this protocol. We sincerely appreciate the contribution of data extraction from the Joint Pathology Center teams (Francisco J. Rentas, John D. McGeeney, Kimberly M. Greenfield, Beatriz A. Hallo, and Johnny P. Beason) and the MHS database personnel (Maj Ryan Costantino, Lee Ann Zarzabal, Brandon Jenkins, and Alex Rittel). We gratefully thank you for the protocol support from the Department of Research programs: CDR Wesley R. Campbell, CDR Ling Ye, Yaling Zhou, Elizabeth Schafer, Robert Roogow, Micah Stretch, Diane Beaner, Adrienne Woodard, David L. Evers, and Paula Amann.