Yew

Scientific Name(s): Taxus bacatta L. and T. cuspidata Sieb. and Zucc. The native species of the United States, T. canadensis Marsh. is found throughout the eastern United States; other species found in North America include T. floridana Nutt. and the Pacific yew, T. brevifolia Nutt. Family: Taxaceae

Common Name(s): Yew , ground hemlock

Uses

The yew plant has been used to treat rheumatism, liver and urinary tract conditions, and, most recently, cancer. The efficacy of paclitaxel as an antitumor agent is well documented.

Dosing

Despite abundant clinical literature on paclitaxel as an antitumor drug, crude preparations of yew needles or bark should not be used because of their cardiotoxic taxanes. A number of different dosing regimens have been employed for paclitaxel for a variety of different tumor types (see Uses and Pharmacology).

Contraindications

Contraindications have not yet been determined.

Pregnancy/Lactation

There are no adequate and well-controlled studies of taxanes in pregnant women. However, animal studies have demonstrated embryo and fetotoxicity as indicated by intrauterine mortality, increased resorptions, and increased fetal deaths. Animal studies also have demonstrated high concentrations of taxenes in milk. Use in lactating women is not recommended.

Interactions

Paclitaxel is metabolized extensively by the CYP enzyme family. Formal drug interaction studies have been performed with numerous agents. With the exclusion of other chemotherapy agents, few of these interactions appear to be clinically significant.

Adverse Reactions

The ingestion of the plant results in dizziness, dry mouth, mydriasis, and abdominal cramping. Rash and pale, cyanotic skin may develop. Eventually, ingestion may result in death. Use of taxanes as antitumor agents is associated with hematologic and neuromuscular effects, hypersensitivity, fatigue, edema, and hair and skin changes.

Toxicology

Excluding the red aril, most of the plant is poisonous.

Botany

This evergreen is found throughout woods and forests and often is used as an ornamental hedge. The trunk supports a crown of spreading branches with long, narrow, dark green, shiny leaves. It is dioecious, with male and female flowers being produced on different trees. The ovoid seed is black and is surrounded by a red, fleshy covering called the aril. Yews flower in March and April.

History

The Celts coated their arrows with yew sap as a nerve poison. The alkaloid taxine has been used as an antispasmodic. A tincture of the leaves has been used to treat rheumatism and liver and urinary tract conditions. 1

Chemistry

The entire plant, with the exception of the red, fleshy aril, contains many taxane alkaloids, of which the best known is taxine. 2 Other alkaloids (eg, milossine, ephedrine), the glycoside taxicatin, taxol and its derivatives, 3 and pigments are found throughout the plant. Bristol-Myers Squibb received FDA approval to market Taxol 4 as an antineoplastic agent for ovarian and breast cancers, and concern has been raised regarding the environmental impact of debarking Pacific yew trees to harvest the drug. Consequently, methods have been developed to produce paclitaxel from precursors found in the leaves, twigs, and needles of yews common in Europe and Asia, and there are efforts to synthesize paclitaxel from pinene, a common compound found in pine trees. In yew plants, paclitaxel content varies from 0.00003% to 0.069% of the plant. 5 The approved generic name, paclitaxel, was previously taxol. Taxol is now the trademarked brand name for paclitaxel.

Uses and Pharmacology

The compound paclitaxel is an anticancer agent that is available commercially in the United States and a number of other countries. It is derived from several species of yew, but primarily comes from the European yew, T. baccata . It has a novel mechanism of action causing mitotic abnormalities and arrest, and promoting microtubule polymerization into aggregated structures resulting in the inhibition of cell replication. 6

Mechanism of action

Paclitaxel and other taxanes distinguish themselves from previously known tubulin poisons both in the site of their interaction with β-tubulin and their stabilizing effect on microtubules. Taxanes block microtubule polymerization. Several important studies have demonstrated that microtubules must be in a dynamic state of polymerization and depolymerization to function properly, thus explaining how agents with reciprocal effects on microtubule polymerization can cause mitotic arrest. 7

Paclitaxel binds to the β-subunit of tubulin, producing unnaturally stable microtubules that prevent depolymerization and cause cell death. The actual mechanisms that lead to cell death remain unclear but may include activation of several intracellular signal transduction pathways essential for apoptosis. Paclitaxel binds to the N-terminal 31 amino acids of β-tubulin and produces abnormal asters, for which centrioles are not necessary. Paclitaxel-treated cells are not prevented from traversing from cell cycle stage G 2 into mitosis, but their primary effects occur in late G 2 and early mitosis. Cell death after exposure to paclitaxel appears to involve apopotic mechanisms, including classic features such as DNA fragmentation, cell volume shrinkage, and membrane-bound apoptotic bodies. Induction of bcl-2 phosphorylation facilitating apoptosis and inhibition of angiogenesis also is considered an important function of the antitumor activity of the taxanes. 8

Peripheral neurotoxicity has been associated with tubulin drugs. Microtubules are essential for axonal transport in neurons, and tubulin-binding drugs have been shown to directly perturb microtubule formation in Schwann cells and the axons of sciatic nerve. Although manageable and reversible, this toxicity can preclude repeated courses of therapy. 7

Although paclitaxel is one of the most broadly active antitumor agents, the majority of patients with advanced disease do not enter long-term remission. Both drug efflux pumps and alteration in tubulin can play a role in resistance. Taxanes are good substrates for the 170kDa P-glycoprotein (Pgp) efflux pump encoded by the multidrug resistance mdr gene, thus playing a role in sensitivity to these compounds in vitro. Alterations in tubulin function have been well documented as mechanisms of resistance to tubulin-binding agents. Recent studies have demonstrated changes in tubulin expression and mutations in β-tubulin that affect paclitaxel polymerization. 7

Breast cancer
Animal data

Research reveals no animal data regarding the use of taxanes for metastatic breast cancer.

Clinical data

A review evaluating taxane-containing regimens for metastatic breast cancer showed that they are associated with a statistically significant improvement in overall survival. Taxane-containing regimens were associated with a greater degree of leukopenia and neurotoxicity, but there was less nausea and vomiting than the control group; the overall impact on quality of life did not appear to differ in any of the trials. 9

Response

In 14 studies evaluating taxane-containing regimens with nontaxane regimens, a statistically significant difference in favor of taxane-containing regimens with an odds ratio of 1.29 is seen. If analysis is limited to trials of first-line therapy, there remains a significant difference in favor of the taxane-containing regimens. Ten studies evaluating single-agent taxane- vs nontaxane-containing regimens demonstrated no detectable difference between regimens. Restricting the trials to those involving first-line therapy suggests a benefit in favor of nontaxane-containing regimens. 9

Overall survival

Data from 12 studies evaluating a taxane-containing regimen with nontaxane regimens showed a statistically significant difference in favor of the taxane-containing regimens, with a 10% reduction in the risk of death or an absolute improvement in survival of 5%. If the analysis is limited to women receiving first-line therapy for metastatic disease, the difference is no longer statistically significant. Ten studies evaluating single-agent taxane- vs nontaxane-containing regimens suggest a benefit in favor of taxanes, although this was not statistically significant. 9

Time to progression

Data from 11 studies showed a statistically significant difference in favor of taxane-containing regimens, with a 13% reduction in the risk of progression or an absolute improvement in progression-free survival of 6.5%. If the analysis is limited to women receiving first-line chemotherapy, there is no detectable difference between taxane- and nontaxane-containing regimens. 9

Skin cancer
Animal data

Research reveals no animal data regarding the use of paclitaxel for skin cancer.

Clinical data

A study evaluating the efficacy of paclitaxel vs paclitaxel plus carboplatin was terminated early because of a poor response. The response rate in a study of 35 patients with histologically advanced metastatic melanoma (stage IV) was less than 10%. 10

Gastric cancer
Animal data

Research reveals no animal data regarding the use of paclitaxel for gastric cancer.

Clinical data

In a study of 60 patients with histologically confirmed gastric cancer who previously had received at most 1 chemotherapy regimen, paclitaxel (210 mg/m 2 ) every 3 weeks for a median of 3 courses achieved an overall response rate of 23% (complete response 0%, partial response 23%). Paclitaxel demonstrated a response rate of 26% in patients who had received prior chemotherapy and 21% in those with no prior chemotherapy. 11

Nonsquamous carcinomas of the uterine cervix
Animal data

Research reveals no animal data regarding the use of taxanes for nonsquamous carcinomas of the uterine cervix.

Clinical data

In a trial of 42 assessable patients, a starting dose of paclitaxel 170 mg/m 2 (135 ng/m 2 for patients with prior pelvic radiation) was given as a 24-hour continuous infusion every 3 weeks. Responding patients received a median of 6 cycles (range, 5 to 12 cycles). The primary and dose-limiting toxicity was neutropenia. 12

Prevention of restenosis
Clinical data

Trials of paclitaxel-coated stents have shown significant reduction in restenosis. Implantation of a paclitaxel-eluting stent, as compared with a bare metal stent, reduced the primary end point of the risk of target-vessel revascularization at 9 months 61% and lowered the risk of target-lesion revascularization 73%. The use of a paclitaxel-eluting stent reduced the risk of binary restenosis 77% within the stent and 70% in the analysis segment. 13

The paclitaxel-eluting stent (TAXUS I) trial showed no restenosis in the paclitaxel stent group at 12 months compared with 10% for the standard stent group. This difference was reflected in the revascularization of the target lesion in both groups (0% vs 10%). Results were maintained for 24 months. The TAXUS II trial confirmed the reduction of restenosis. The Asian Paclitaxel-Eluting Stent Clinical Trial (ASPECT) demonstrated that angiographic restenosis decreased from 27% in the uncoated stent group to 4% in the paclitaxel stent group. No increase in subacute stent thrombosis or restenosis at the edges of the stent have been reported in published randomized trials. 14

Other uses

An in vitro study has demonstrated that paclitaxel exerts very potent, dose-dependent, inhibitory effects on human gall bladder epithelial cells, pancreatic adenocarcinoma cells, and fibroblasts. The effect tends to be more efficient in the adenocarcinoma cells in comparison with epithelial cells or fibroblasts, especially after prolonged incubation (72 hours). 15

In rats, paclitaxel has been shown to have immunosuppressive potential that can be used effectively to inhibit allograft rejection. A short course of paclitaxel treatment was able to improve heart allograft survival by 2 to 3 weeks. Low-dose paclitaxel and cyclosporine acted synergistically and supported allograft survival approximately 3 weeks longer than either of the 2 drugs alone at the same individual dose. 16

Dosage

Despite abundant clinical literature on paclitaxel as an antitumor drug, crude preparations of yew needles or bark should not be used because of their cardiotoxicity caused by taxanes.

Pregnancy/Lactation

Information regarding safety and efficacy in pregnancy and lactation is lacking. Avoid use.

Interactions

Paclitaxel is metabolized extensively by the CYP enzyme family. Paclitaxel is metabolized by both CYP3A4 and CYP2C8 isoenzymes, causing differences in the potential for drug interactions. Formal drug interaction studies have been performed with numerous agents. With the exclusion of other chemotherapy agents, few of these interactions appear to be clinically significant. Cisplatin appears to alter the clearance of paclitaxel. Paclitaxel alters the clearance of doxorubicin, worsening cardiac toxicity, neutropenia, and mucositis when paclitaxel precedes doxorubicin. 8

Adverse Reactions

Hematological

The dose-limiting toxicity of paclitaxel is neutropenia or, more specifically, febrile neutropenia. Paclitaxel at doses of 250 mg/m 2 given over 24 hours has a 16% to 36% incidence of febrile neutropenia. When given as a shorter infusion (1- or 3-hour) paclitaxel 250 mg/m 2 is associated with a significantly lower incidence of febrile neutropenia (less than or equal to 5%).

When given as a prolonged infusion (eg, 140 mg/m 2 over 96 hours) the incidence of severe (grade 4) neutropenia appears to be approximately double that seen with a 3-hour infusion. The severity of neutropenia is dependent on the number of prior chemotherapy regimens that a patient has received and generally is higher in patients with metastatic disease.

With paclitaxel, the neutropenia is not cumulative. White blood cell count begins to fall approximately 5 to 7 days after administration and reach nadir between days 7 to 14 with nearly every patient recovering by day 21. Thrombocytopenia and anemia are not commonly experienced with paclitaxel, but mild cases have been reported. 8

Neuromuscular

Cumulative peripheral neuropathy is seen with paclitaxel, exhibiting stocking-glove distribution and manifesting as a sensory neuropathy progressing to motor loss with continued administration.

The severity and incidence appear to be related to the length of infusion, with shorter infusions being associated with a higher incidence of severe neuropathies. Myalgias and/or arthralgias are seen beginning approximately 48 to 72 hours after administration, with an expected duration of 48 to 72 hours. 8

Fatigue

Asthenia and fatigue are seen quite frequently with paclitaxel (4% to 15% and 34% to 73%, respectively). This often is categorized with the myalgias and arthralgias commonly seen with paclitaxel and is difficult to distinguish as a separate entity. Patients in the early trials with paclitaxel also were pretreated more heavily and had multiple sites of metastases, factors that also may contribute to fatigue. 8

Skin and hair

Total body alopecia is seen with paclitaxel and occurs approximately 10 to 14 days after therapy begins. Skin and nail changes consisted of dry skin, nail ridging, and onycholysis. Currently, taxanes are classified as irritants, but if extravasated, have been associated rarely with ulceration. No specific antidotes have been identified to assist with management of extravasation of taxanes. 8

Edema

A small number of patients receiving paclitaxel have reported mild peripheral edema in the trials to date. Weight gain is the first sign of fluid retention and should be monitored closely with each course of therapy. Early treatment with diuretics appears to be effective in limiting the severity of toxicity. Patients with congestive heart failure or other comorbid conditions require particularly close monitoring for this effect. 8

Hypersensitivity reactions

Hypersensitivity reactions are seen with paclitaxel, ranging from a mild rash to severe anaphylactic reactions and often associated with hypotension. They are believed to be caused by the vehicles in which the drugs are solubilized; however, do not discount a contribution of the drugs themselves. Prolonging infusions and adding premedication with corticosteroids, H 1 - and H 2 - antagonists have helped reduce the incidence of this adverse effect to less than 3% with paclitaxel. Close monitoring for the first 30 to 60 minutes of the infusion has been shown to be adequate as most of these reactions occur within the first 10 minutes of the infusion. If a patient has an allergic reaction to paclitaxel, rechallenge has been accomplished successfully by employing a more rigorous premedication regimen and/or slowing the infusion rate; however, this method of rechallenge has failed in some patients. 8

Cardiovascular

Asymptomatic bradycardia is the most common cardiac manifestation of paclitaxel toxicity and is estimated to occur in approximately 30% of patients. More severe bradyarrhythmias and heart block also have been reported but occur less frequently. Patients with a history of cardiac rhythm disorders or patients on medication that may predispose them to these effects should be monitored closely. 8

Gastrointestinal

GI effects of the taxanes generally are minimal and include mild nausea, mucositis, diarrhea, and elevations in liver function tests. Standard premedication regimens do not include separate antiemetics because of the low emetogenic potential of these agents. Prolonged infusions of paclitaxel are associated with increased mucositis and diarrhea. There have been a few reports of neutropenic enterocolitis (typhlitis) after paclitaxel administration when given in high doses or in combination with doxorubicin or cyclophosphamide. 8

Toxicology

Excluding the red aril, most of the plant is poisonous. Following ingestion, symptoms of dizziness, dry mouth, mydriasis, and abdominal cramping develop rapidly. A rash may appear, and the skin can become pale and cyanotic. Bradycardia, hypotension, and dyspnea may be accompanied by coma, leading to death caused by respiratory or cardiac failure. A number of deaths in humans have been reported following the ingestion of yew leaves or teas brewed from yew. The administration of digoxin-specific FAB antibody fragments has been associated with the improvement of cardiac conduction abnormalities following ingestion of yew leaves and berries. 2 General supportive measures also have been suggested for the management of yew intoxication. The stomach should be emptied and a charcoal slurry administered. Treat the patient symptomatically. 6

There are no adequate and well-controlled studies of taxanes in pregnant women. However, animal studies have demonstrated embryo and fetotoxicity, as indicated by intrauterine mortality, increased resorptions, and increased fetal deaths. Animal studies also have demonstrated high concentrations of taxenes in milk. Use in lactating women is not recommended. 17

Bibliography

1. Schauenberg P, Paris F. Guide to Medicinal Plants . New Canaan, CT: Keats Publishing; 1990.
2. Cummins RO, Haulman J, Quan L, Graves JR, Peterson D, Horan S. Near-fatal yew berry intoxication treated with external cardiac pacing and digoxin-specific FAB antibody fragments. Ann Emerg Med . 1990;19:38-43.
3. Senilh V, et al. J Nat Prod . 1984;47:131.
4. Olin BR, ed, et al. Drug Facts and Comparisons . St. Louis, MO: Facts and Comparisons, Inc., 1993.
5. Vidensek N, Lim P, Campbell A, Carlson C. Taxol content in bark, wood, root, leaf, twig, and seedling from several Taxus specis. J Nat Prod . 1990;53:1609-1610.
6. Haller DG, Misset JL. Docetaxel in advanced gastric cancer. Anticancer Drugs . 2002;13:451-460.
7. Wood KW, Cornwell WE, Jackson JR. Past and future of the mitotic spindle as an oncology target. Curr Opin Pharmacol . 2001;1:370-377.
8. Michaud LB, Vaero V, Hortobagyi G. Risks and benefits of taxanes in breast and ovarian cancer. Drug Saf . 2000;23:401-428.
9. Ghersi D, Wilcken N, Simes J, Donoghue E. Taxane containing regimens for metastatic breast cancer. Cochrane Database Syst Rev . 2003;(3):CD003366.
10. Zimpfer-Rechner C, Hofmann U, Figl R, et al. Randomized phase II study of weekly paclitaxel versus paclitaxel and carboplatin as second-line therapy in disseminated melanoma: a multicentre trial of the Dermatologic Co-operative Oncology Group (DeCOG). Melanoma Res . 2003;13:531-536.
11. Yamada Y, Shirao K, Ohtsu A, et al. Phase II trial of paclitaxel by 3-hour infusion for advanced gastric cancer with short premedication for prophylaxis against paclitaxel-associated hypersensitivity reactions. Ann Oncol . 2001;12:1133-1137.
12. Curtin JP, Blessing JA, Webster KD, et al. Paclitaxel, an active agent in nonsquamous carcinomas of the uterine cervix: a Gynecologic Oncology Group Study. J Clin Oncol . 2001;19:1275-1278.
13. Stone GW, Ellis SG, Cox DA, et al. A polymer-based, paclitaxel-eluting stent in patients with coronary artery disease. N Engl J Med . 2004;350:221-231.
14. Bhargava B, Karthikeyan G, Abizaid AS, Mehran R. New approaches to preventing restenosis. BMJ . 2003;327:274-279.
15. Kalinowski M, Alfke H, Kleb B, Dürfeld F, Joachin Wagner H. Paclitaxel inhibits proliferation of cell lines responsible for metal stent obstruction: possible topical application in malignant bile duct obstructions. Invest Radiol . 2002;37:399-404.
16. Tange S, Scherer MN, Graeb C, et al. The antineoplastic drug Paclitaxel has immunosuppressive properties that can effectively promote allograft survival in a rat heart transplant model. Transplantation . 2002;73:216-223.
17. Taxol [package insert]. Princeton, NJ: Bristol-Myers Squibb Co; March 2003. Available at http://www.taxol.com/txpi.html

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