Abstract

BACKGROUND

Paclitaxel was first derived from the bark of the yew tree (Taxus brevifolia). It was discovered as part of a National Cancer Institute program screen of plants and natural products with putative anticancer activity during the 1960s.^1–9 Paclitaxel works by suppressing spindle microtube dynamics, which results in the blockage of the metaphase-anaphase transitions, inhibition of mitosis, and induction of apoptosis in a broad spectrum of cancer cells. Paclitaxel also displayed additional anticancer activities, including the suppression of cell proliferation and antiangiogenic effects. However, since the growth of normal body cells may also be affected, other adverse effects (AEs) will also occur.^8–18

Two different chemotherapy drugs contain paclitaxel—paclitaxel and nabpaclitaxel— and the US Food and Drug Administration (FDA) recognizes them as separate entities.^19–21 Taxol (paclitaxel) was approved by the FDA in 1992 for treating advanced ovarian cancer.²⁰ It has since been approved for the treatment of metastatic breast cancer, AIDS-related Kaposi sarcoma (as an orphan drug), non-small cell lung cancer (NSCLC), and cervical cancers (in combination with bevacizumab) in 1994, 1997, 1999, and 2014, respectively.²¹ Since 2002, a generic version of Taxol, known as paclitaxel injectable, has been FDA-approved from different manufacturers. According to the National Cancer Institute, a combination of carboplatin and Taxol is approved to treat carcinoma of unknown primary, cervical, endometrial, NSCLC, ovarian, and thymoma cancers.¹⁹ Abraxane (nab-paclitaxel) was FDA-approved to treat metastatic breast cancer in 2005. It was later approved for first-line treatment of advanced NSCLC and late-stage pancreatic cancer in 2012 and 2013, respectively. In 2018 and 2020, both Taxol and Abraxane were approved for first-line treatment of metastatic squamous cell NSCLC in combination with carboplatin and pembrolizumab and metastatic triple-negative breast cancer in combination with pembrolizumab, respectively.^22–26 In 2019, Abraxane was approved with atezolizumab to treat metastatic triple-negative breast cancer, but this approval was withdrawn in 2021. In 2022, a generic version of Abraxane, known as paclitaxel protein-bound, was released in the United States. Furthermore, paclitaxel-containing formulations also are being studied in the treatment of other types of cancer.^19–32

One of the main limitations of paclitaxel is its low solubility in water, which complicates its drug supply. To distribute this hydrophobic anticancer drug efficiently, paclitaxel is formulated and administered to patients via polyethoxylated castor oil or albumin-bound (nab-paclitaxel). However, polyethoxylated castor oil induces complement activation and is the cause of common hypersensitivity reactions related to paclitaxel use.^2,17,33–38 Therefore, many alternatives to polyethoxylated castor oil have been researched.

Since 2000, new paclitaxel formulations have emerged using nanomedicine techniques. The difference between these formulations is the drug vehicle. Different paclitaxel-based nano-technological vehicles have been developed and approved, such as albumin-based nanoparticles, polymeric lipidic nanoparticles, polymeric micelles, and liposomes, with many others in clinical trial phases.^3,37 Albumin-based nanoparticles have a high response rate (33%), whereas the response rate for polyethoxylated castor oil is 25% in patients with metastatic breast cancer.^33,39–52 The use of paclitaxel dimer nanoparticles also has been proposed as a method for increasing drug solubility.^33,53

Paclitaxel is metabolized by cytochrome P450 (CYP) isoenzymes 2C8 and 3A4. When administering paclitaxel with known inhibitors, inducers, or substrates of CYP2C8 or CYP3A4, caution is required.^19–22 Regulations for CYP research were not issued until 2008, so potential interactions between paclitaxel and other drugs have not been extensively evaluated in clinical trials. A study of 12 kinase inhibitors showed strong inhibition of CYP2C8 and/or CYP3A4 pathways by these inhibitors, which could alter the ratio of paclitaxel metabolites in vivo, leading to clinically relevant changes.⁵⁴ Differential metabolism has been linked to paclitaxel-induced neurotoxicity in patients with cancer.⁵⁵ Nonetheless, variants in the CYP2C8, CYP3A4, CYP3A5, and ABCB1 genes do not account for significant interindividual variability in paclitaxel pharmacokinetics.⁵⁶ In liver microsomes, losartan inhibited paclitaxel metabolism when used at concentrations > 50 μmol/L.⁵⁷ Many drug-drug interaction (DDI) studies of CYP2C8 and CYP3A4 have shown similar results for paclitaxel.^58–64

The goals of this study are to investigate prescribed drugs used with paclitaxel and determine patient outcomes through several Military Health System (MHS) databases. The investigation focused on (1) the functions of paclitaxel; (2) identifying AEs that patients experienced; (3) evaluating differences when paclitaxel is used alone vs concomitantly and between the completed vs discontinued treatment groups; (4) identifying all drugs used during paclitaxel treatment; and (5) evaluating DDIs with antidepressants (that have an FDA boxed warning and are known to have DDIs confirmed in previous publications) and other drugs.^65–67

The Walter Reed National Military Medical Center in Bethesda, Maryland, 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 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 and currently 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 the CAPER record represents an ambulatory encounter at a military treatment facility (MTF). CAPER includes data from 2003 to 2024.

Each observation in the PDTS record represents a prescription filled for an MHS beneficiary at an MTF through the TRICARE mail-order program or a US retail pharmacy. Missing from this record are prescriptions filled at international civilian pharmacies and inpatient pharmacy prescriptions. The MHS Data Repository PDTS record is available from 2002 to 2024. The legacy Composite Health Care System is being replaced by GENESIS at MTFs.

RESULTS

The JPC provided 702 entries for 687 patients with a mean age of 56 years (range, 2 months to 88 years) who were treated with paclitaxel from March 1996 to October 2021. Fifteen patients had duplicate entries because they had multiple cancer sites or occurrences. There were 623 patients (89%) who received paclitaxel for FDA-approved indications. The most common types of cancer identified were 344 patients with breast cancer (49%), 91 patients with lung cancer (13%), 79 patients with ovarian cancer (11%), and 75 patients with endometrial cancer (11%) (Table 1). Seventy-nine patients (11%) received paclitaxel for cancers that were not for FDA-approved indications, including 19 for cancers of the fallopian tube (3%) and 17 for esophageal cancer (2%) (Table 2).

TABLE 1

Uses of Paclitaxel by Cancer Location^a

Cancer location	No. (%)
Total	623 (89)
Breast	344 (49)
Upper-outer quadrant	130 (19)
Overlapping lesion	73 (10)
Breast not otherwise specified	45 (6)
Upper-inner quadrant	41 (6)
Lower-inner quadrant	23 (3)
Lower-outer quadrant	21 (3)
Central portion	9 (1)
Axillary tail	2 (< 1)
Lung	91 (13)
Upper lobe	37 (5)
Lower lobe	34 (5)
Lung not otherwise specified	8 (1)
Main bronchus	6 (1)
Middle lobe	5 (1)
Overlapping lesion	1 (< 1)
Ovary	79 (11)
Endometrial	75 (11)
Endometrium	67 (10)
Corpus uteri	6 (1)
Fundus uteri	1 (< 1)
Overlapping lesion	1 (< 1)
Cervical	15 (2)
Cervix uteri	13 (2)
Endocervix	1 (< 1)
Overlapping lesion	1 (< 1)
Pancreatic	13 (2)
Head of pancreas	7 (1)
Body of pancreas	2 (< 1)
Tail of pancreas	2 (< 1)
Pancreas not otherwise specified	2 (< 1)
Connective, subcutaneous, and other soft tissue	4 (1)
Head, face, and neck	2 (< 1)
Upper limb and shoulder	1 (< 1)
Trunk not otherwise specified	1 (< 1)
Thymus	2 (< 1)

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^a687 patients were prescribed paclitaxel; 15 patients had multiple cancer sites, making 702 entries from March 18, 1996, to October 1, 2021.

TABLE 2

Off-Label Uses of Paclitaxel by Cancer Location^a

Cancer location	No. (%)
Total	79 (11)
Fallopian	19 (3)
Fallopian tube	18 (3)
Female genital tract not otherwise specified	1 (< 1)
Esophageal	17 (2)
Lower third of esophagus	7 (1)
Esophagus not otherwise specified	7 (1)
Cervical esophagus	1 (< 1)
Thoracic esophagus	1 (< 1)
Middle third of esophagus	1 (< 1)
Stomach	6 (1)
Cardia not otherwise specified	4 (1)
Stomach not otherwise specified	2 (< 1)
Larynx	2 (< 1)
Glottis	1 (< 1)
Supraglottis	1 (< 1)
Total	33 (5)
Unknown primary site	7 (1)
Peritoneum not otherwise specified	6 (1)
Kidney not otherwise specified	4 (1)
Uterus not otherwise specified	3 (< 1)
Tonsil not otherwise specified	3 (< 1)
Anal canal	2 (< 1)
Glans penis	1 (< 1)
Prostate gland	1 (< 1)
Undescended testis	1 (< 1)
Posterior wall of bladder	1 (< 1)
Urethra	1 (< 1)
Lower gum	1 (< 1)
Cheek mucosa	1 (< 1)
Parotid gland	1 (< 1)

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^a687 patients were prescribed paclitaxel; 15 patients had multiple cancer sites, making 702 entries from March 18, 1996, to October 1, 2021.

There were 477 patients (68%) aged > 50 years. A total of 304 patients (43%) had a stage III or IV cancer diagnosis and 398 (57%) had stage II or lower (combination of data for stages 0, I, and II; not applicable; and unknown) cancer diagnosis. For systemic treatment, 16 patients (2%) were treated with paclitaxel alone and 686 patients (98%) received paclitaxel concomitantly with additional chemotherapy: 59 patients (9%) in the before or after group, 410 patients (58%) had a 2-drug combination, 212 patients (30%) had a 3-drug combination, and 5 patients (1%) had a 4-drug combination. In addition, for doublet therapies, paclitaxel combined with carboplatin, trastuzumab, gemcitabine, or cisplatin had more patients (318, 58, 12, and 11, respectively) than other combinations (≤ 4 patients). For triplet therapies, paclitaxel combined with doxorubicin plus cyclophosphamide or carboplatin plus bevacizumab had more patients (174 and 20, respectively) than other combinations, including quadruplet therapies (≤ 4 patients) (Table 3).

TABLE 3

Paclitaxel Use in Military Health System Cancer Registry Database

Drugs	Total, No. (%)	Completed without AEs, No. (%)	Discontinued with AEs, No. (%)
Total	702 (100)	338 (48)	364 (52)
Treatment
Alone	16 (2)	16 (5)	0 (0)
Concomitant	686 (98)	322 (95)	364 (100)
Before or after	59 (8)	4 (1)	55 (15)
Paclitaxel + other medications	627 (89)	318 (94)	309 (85)
Paclitaxel + 1 medication	410 (58)	222 (66)	188 (52)
Carboplatin	318 (45)	182 (54)	136 (37)
Trastuzumab	58 (8)	23 (7)	35 (10)
Gemcitabine	12 (2)	6 (2)	6 (2)
Cisplatin	11 (2)	6 (2)	5 (1)
Trastuzumab-dttb	4 (1)	1 (< 1)	3 (1)
Bevacizumab	3 (< 1)	1 (< 1)	2 (1)
Cetuximab	2 (< 1)	2 (1)	0 (0)
Cyclophosphamide	1 (< 1)	0 (0)	1 (< 1)
Ramucirumab	1 (< 1)	1 (< 1)	1 (< 1)
Paclitaxel + 2 medications	212 (30)	93 (28)	119 (33)
Doxorubicin + cyclophosphamide	174 (25)	78 (23)	96 (26)
Carboplatin + bevacizumab	20 (3)	6 (2)	14 (4)
Ifosfamide (IFEX) + cisplatin	4 (1)	2 (1)	2 (1)
Carboplatin + trastuzumab	3 (< 1)	1 (< 1)	2 (1)
Cisplatin + bevacizumab	3 (< 1)	2 (1)	1 (< 1)
Trastuzumab + pertuzumab	2 (< 1)	1 (< 1)	1 (< 1)
Carboplatin + etoposide	1 (< 1)	1 (< 1)	0 (0)
Carboplatin + fluorouracil (5FU)	1 (< 1)	1 (< 1)	0 (0)
Gemcitabine + cisplatin	1 (< 1)	0 (0)	1 (< 1)
Trastuzumab-dttb + pertuzumab	1 (< 1)	0 (0)	1 (< 1)
Carboplatin + pembrolizumab	1 (< 1)	0 (0)	1 (< 1)
Cisplatin + pembrolizumab	1 (< 1)	1 (< 1)	0 (0)
Paclitaxel + 3 medications	5 (1)	3 (1)	2 (1)
Carboplatin + trastuzumab + pertuzumab	2 (< 1)	2 (1)	0 (0)
Carboplatin + doxorubicin + cyclophosphamide	1 (< 1)	0 (0)	1 (< 1)
Doxorubicin + cyclophosphamide + pegfilgrastim	1 (< 1)	1 (< 1)	0 (0)
Doxorubicin, cyclophosphamide + pembrolizumab	1 (< 1)	0 (0)	1 (< 1)
Cancers
Cancer with FDA-approved indication	546 (78)	241 (71)	305 (84)
Off-label or other cancers	156 (22)	97 (29)	59 (16)
Stage 0, I, II, not applicable, or unknown	398 (57)	196 (58)	202 (55)
Stage III or IV	304 (43)	142 (42)	162 (45)
Age
≤ 50 y	225 (32)	102 (30)	123 (34)
> 50 y	477 (68)	236 (70)	241 (66)

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Abbreviations: AE, adverse event; FDA, US Food and Drug Administration.

Patients were more likely to discontinue paclitaxel if they received concomitant treatment. None of the 16 patients receiving paclitaxel monotherapy experienced AEs, whereas 364 of 686 patients (53%) treated concomitantly discontinued (P < .001). Comparisons of 1 drug vs combination (2 to 4 drugs) and use for treating cancers that were FDA-approved indications vs off-label use were significant (P < .001), whereas comparisons of stage II or lower vs stage III and IV cancer and of those aged ≤ 50 years vs aged > 50 years were not significant (P = .50 and P = .30, respectively) (Table 4).

TABLE 4

Adverse Event-Related Discontinuations^a

Criteria	Paclitaxel use
	Adverse events, No.	Patients, No.	Patients, %	P value
Treatment
Alone	0	16	0	< .001
Concomitant	364	686	53
1 medication (alone, before, or after)	55	75	73	< .001
Combination (2 – 4 drugs)	309	627	49
Cancers
Food and Drug Administration-approved cancer indication	305	546	56	< .001
Others (off-label)	59	156	38
Stage 0, I, II, not applicable, or unknown	202	398	51	.50
Stage III and IV	162	304	53
Age
≤ 50 y	123	225	55	.30
> 50 y	241	477	51

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^aCalculated with 2-tailed, 2-sample z test between groups: alone vs concomitant, 1 drug vs combinations, lung vs other cancers, stages ≤ II vs III and IV, and ≤ 50 y vs > 50 y.

Among the 364 patients who had concomitant treatment and had discontinued their treatment, 332 (91%) switched treatments with no AEs documented and 32 (9%) experienced fatigue with pneumonia, mucositis, neuropathy, neurotoxicity, neutropenia, pneumonitis, allergic or hypersensitivity reaction, or an unknown AE. Patients who discontinued treatment because of unknown AEs had a physician’s note that detailed progressive disease, a significant decline in performance status, and another unknown adverse effect due to a previous sinus tract infection and infectious colitis (Table 5).

TABLE 5

Adverse Event-Related Discontinuations (N = 364)

Adverse event	Alone, No.	Concomitant, No. (%)
Adverse events	0	32 (9)
Fatigue and pneumonia	—	1 (< 1)
Mucositis	—	1 (< 1)
Neuropathy	—	4 (1)
Neurotoxicity	—	1 (< 1)
Neutropenia	—	2 (1)
Pneumonitis	—	3 (1)
Reaction of allergic or hypersensitivity	—	8 (2)
Unknown	—	12 (3)
No documentation	0	332 (91)
Changed treatment	0	332 (91)

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Management Analysis and Reporting Tool Database

MHS data analysts provided data on diagnoses for 639 patients among 687 submitted diagnoses, with 294 patients completing and 345 discontinuing paclitaxel treatment. Patients in the completed treatment group had 3 to 258 unique health conditions documented, while patients in the discontinued treatment group had 4 to 181 unique health conditions documented. The MHS reported 3808 unique diagnosis conditions for the completed group and 3714 for the discontinued group (P = .02).

The mean (SD) number of diagnoses was 51 (31) for the completed and 55 (28) for the discontinued treatment groups (Figure). Among 639 patients who received paclitaxel, the top 5 diagnoses were administrative, including encounters for other administrative examinations; antineoplastic chemotherapy; administrative examination for unspecified; other specified counseling; and adjustment and management of vascular access device. The database does not differentiate between administrative and clinically significant diagnoses.

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FIGURE

Diagnoses and Prescriptions for Patients Receiving Paclitaxel by Treatment Outcome

Mean and SD shown for each distribution; patients who discontinued treatment had more diagnosed medical issues compared with those who completed treatment; patients who took paclitaxel concomitantly with a greater number of prescription drugs had a higher rate of treatment discontinuation than those who received fewer filled prescriptions

MHS data analysts provided data for 336 of 687 submitted patients who were prescribed paclitaxel; 46 patients had no PDTS data, and 305 patients had PDTS data without paclitaxel, Taxol, or Abraxane dispensed. Medications that were filled outside the chemotherapy period were removed by evaluating the dispensed date and day of supply. Among these 336 patients, 151 completed the treatment and 185 discontinued, with 14 patients experiencing documented AEs. Patients in the completed treatment group filled 9 to 56 prescriptions while patients in the discontinued treatment group filled 6 to 70 prescriptions. Patients in the discontinued group filled more prescriptions than those who completed treatment: 793 vs 591, respectively (P = .34).

The mean (SD) number of filled prescription drugs was 24 (9) for the completed and 34 (12) for the discontinued treatment group. The 5 most filled prescriptions with paclitaxel from 336 patients with PDTS data were dexamethasone (324 prescriptions with 14 recorded AEs), diphenhydramine (296 prescriptions with 12 recorded AEs), ondansetron (277 prescriptions with 11 recorded AEs), prochlorperazine (265 prescriptions with 12 recorded AEs), and sodium chloride (232 prescriptions with 11 recorded AEs).

DISCUSSION

As a retrospective review, this study is more limited in the strength of its conclusions when compared to randomized control trials. The DoD Cancer Registry Program only contains information about cancer types, stages, treatment regimens, and physicians’ notes. Therefore, noncancer drugs are based solely on the PDTS database. In most cases, physicians’ notes on AEs were not detailed. There was no distinction between initial vs later lines of therapy and dosage reductions. The change in status or appearance of a new medical condition did not indicate whether paclitaxel caused the changes to develop or directly worsen a pre-existing condition. The PDTS records prescriptions filled, but that may not reflect patients taking prescriptions.

CONCLUSIONS

This retrospective study discusses the use of paclitaxel in the MHS and the potential DDIs associated with it. The study population consisted mostly of active-duty personnel, who are required to be healthy or have controlled or nonactive medical diagnoses and be physically fit. This group is mixed with dependents and retirees that are more reflective of the average US population. As a result, this patient population is healthier than the general population, with a lower prevalence of common illnesses such as diabetes and obesity. The study aimed to identify drugs used alongside paclitaxel treatment. While further research is needed to identify potential DDIs among patients who experienced AEs, in vitro testing will need to be conducted before confirming causality. The low number of AEs experienced by only 32 of 702 patients (5%), with no deaths during paclitaxel treatment, indicates that the drug is generally well tolerated. Although this study cannot conclude that concomitant use with noncancer drugs led to the discontinuation of paclitaxel, we can conclude that there seems to be no significant DDIs identified between paclitaxel and antidepressants. This comprehensive overview provides clinicians with a complete picture of paclitaxel use for 27 years (1996–2022), enabling them to make informed decisions about paclitaxel treatment.

Acknowledgments

Footnotes

References