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DRUG RECORD

 

TAXANES

OVERVIEW
Taxanes

 

The taxanes or taxoids are a closely related group of antineoplastic agents that have a unique mechanism of action as inhibitors of mitosis and which are widely used in the therapy of ovarian, breast, lung, esophageal, bladder and head and neck cancers.  Two taxanes are in clinical use, paclitaxel (Taxol) and docetaxel (Taxotere).  Paclitaxel was the first compound in this chemical group and was initially isolated from the bark of the Western yew tree.  Docetaxel is a semisynthetic analogue of paclitaxel and a derivative of extracts from needles of the European Yew (Taxus baccata) that has somewhat better pharmacokinetics and different side effects than paclitaxel.  The taxanes are similar to the vinca alkaloids in that they bind to tubulin and cause inhibition of mitosis.  However, the taxanes bind at a different site than the vinca alkaloids and cause inhibition of mitosis by prevention of degradation of microtubules, rather than prevention of their assembly.  Both paclitaxel and docetaxel are given intravenously, usually every 1 to 3 weeks.  While both agents have many side effects and can be associated with serum enzyme elevations during treatment, they have not been convincingly linked to clinically apparent liver injury with jaundice.


The two taxanes are discussed separately, but references to their hepatotoxicity and safety are given together at the end of this Overview section.

 

Drug Class:  Antineoplastic Agents

 

Drugs in the Subclass, Taxanes:  Cabazitaxel, Docetaxel, Paclitaxel

 

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REFERENCES
Taxanes

 

References updated: 04 December 2013

  1. Zimmerman HJ. Hepatotoxic effects of oncotherapeutic and immunosuppressive agents. In, Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999, pp.673-708.  (Textbook of hepatotoxicity published in 1999; paclitaxel and docetaxel are not mentioned).

  2. DeLeve LD. Cancer chemotherapy. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, pp. 549-68.  (Review of hepatotoxicity of cancer chemotherapeutic agents; the taxanes are not specifically discussed).

  3. Chabner BA, Bertino J, Clearly J, Ortiz T, Lane A, Supko JG, Ryan DP. Taxanes. Cytotoxic agents. Chemotherapy of neoplastic diseases. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 1707-9.  (Textbook of pharmacology and therapeutics).

  4. Onetto N, Canetta R, Winograd B, Catane R, Dougan M, Grechko J, Burroughs J, Rozencweig M. Overview of Taxol safety. J Natl Cancer Inst Monogr 1993;(15): 131-9. PubMed Citation  (Among 655 patients treated with paclitaxel, dose limiting toxicities included bone marrow suppression [especially neutropenia], mucositis, neuropathy and rarely cardiomyopathy; hypersensitivity reactions can be controlled with premedication; liver test abnormalities were dose dependent with any AST elevations in 7-26% of patients and values >5 times ULN in only 2% of those receiving the highest dose).

  5. Rowinsky EK, Eisenhauer EA, Chaudhry V, Arbuck SG, Donehower RC. Clinical toxicities encountered with paclitaxel(Taxol). Semin Oncol 1993; 20 (4 Suppl 3): 1-15. PubMed Citation  (Extensive review of toxicities of paclitaxel; according to data on file with the sponsor, elevations of AST, Alk P and bilirubin >5 times the ULN occurred in <1% of 402 patients in phase II and III trials).

  6. Horikoshi N, Inoue K, Aiba K, Mukaiyama T, Ogihara A, Sumida T, Akatsuka Y, et al. [Phase I study of paclitaxel]. Gan To Kagaku Ryoho 1994; 21: 2407-14. Japanese. PubMed Citation

  7. Blaney SM, Seibel NL, O'Brien M, Reaman GH, Berg SL, Adamson PC, Poplack DG, et al. Phase I trial of docetaxel administered as a 1-hour infusion in children with refractory solid tumors: a collaborative pediatric branch, National Cancer Institute and Children's Cancer Group trial. J Clin Oncol 1997; 15: 1538-43. PubMed Citation  (44 children with refractory solid tumors were given 103 courses of docetaxel every 21 days; major dose limiting toxicities were neutropenia, mild ALT elevations [<3 times ULN] occurred, but frequency and details were not given).

  8. Von Hoff DD. The taxoids: same roots, different drugs. Semin Oncol 1997; 4(4 Suppl 13): S13-3-S13-10. PubMed Citation  (Review of the development of paclitaxel and docetaxel, clinical use, efficacy and toxicity stressing the differences between the two taxoids, which are due largely to differences in pharmacokinetics).

  9. Picus J, Schultz M. Docetaxel (Taxotere) as monotherapy in the treatment of hormone-refractory prostate cancer: preliminary results. Semin Oncol 1999; 26 (5 Suppl 17): 14-8. PubMed Citation  (35 patients with prostate cancer were treated with docetaxel every 3 weeks [average of 6 cycles]; one had marked ALT elevations, but also had liver metastases).

  10. Crown J. A review of the efficacy and safety of docetaxel as monotherapy in metastatic breast cancer. Semin Oncol 1999; 26 (1 Suppl 3): 5-9. PubMed Citation  (Brief review of safety and efficacy of docetaxel in advanced breast cancer; no discussion of hepatotoxicity or ALT elevations).

  11. Burris HA 3rd. Single-agent docetaxel(Taxotere) in randomized phase III trials. Semin Oncol 1999; 26(3 Suppl 9): 1-6. PubMed Citation  (Review of 3 randomized trials of docetaxel vs standard chemotherapy in women with breast cancer; adverse events were common, but hepatotoxicity was not mentioned).

  12. Fumoleau P. Efficacy and safety of docetaxel in clinical trials. Am J Health Syst Pharm 1997; 54(24 Suppl 2): S19-24. PubMed Citation  (Overall response rates to docetaxel and paclitaxel in advanced breast cancer ranged from 29-68% of patients; major dose related toxicities included neutropenia, mucositis, cardiomyopathy and fluid retention; hepatotoxicity was not mentioned).

  13. Alexandre J, Bleuzen P, Bonneterre J, Sutherland W, Misset JL, Guastalla J, Viens P, et al. Factors predicting for efficacy and safety of docetaxel in a compassionate-use cohort of 825 heavily pretreated advanced breast cancer patients. J Clin Oncol 2000; 18: 562-73. PubMed Citation  (Among 825 patients with breast cancer undergoing therapy with docetaxel, the risk for febrile neutropenia was increased in those with liver dysfunction as defined by ALT or AST >1.5 and Alk P >3 times ULN [odds ratio 1.86]).

  14. Colomer R, Llombart A, Lluch A, Ojeda B, Barnadas A, Carañ V, Fernáez Y, et al. Paclitaxel/gemcitabine administered every two weeks in advanced breast cancer: preliminary results of a phase II trial. Semin Oncol 2000; 27 (1 Suppl 2): 20-4. PubMed Citation  (Among 43 women with metastatic breast cancer treated with paclitaxel and gemcitabine for up to 8 cycles, 41% had serum aminotransferase elevations which were above 5 times ULN in 5%).

  15. De Pas T, de Braud F, Danesi R, Sessa C, Catania C, Curigliano G, Fogli S, et al. Phase I and pharmacologic study of weekly gemcitabine and paclitaxel in chemo-naï patients with advanced non-small-cell lung cancer. Ann Oncol 2000; 11: 821-7. PubMed Citation  (Among 35 patients with lung cancer given escalating doses of gemcitabine and paclitaxel, 33% of first and 20% of all cycles were associated with aminotransferase elevations >5 times ULN, but all were asymptomatic and reversible, although some led to dose reduction).

  16. Patnaik A, Warner E, Michael M, Egorin MJ, Moore MJ, Siu LL, Fracasso PM, et al. Phase I dose-finding and pharmacokinetic study of paclitaxel and carboplatin with oral valspodar in patients with advanced solid tumors. J Clin Oncol 2000; 18: 3677-89. PubMed Citation  (Among 58 patients with advanced cancers treated with cycles of paclitaxel, carboplatin and valspodar, 3 had aminotransferase elevations >5 times ULN, two of which were dose limiting).

  17. Douillard JY, Lerouge D, Monnier A, Bennouna J, Haller AM, Sun XS, Assouline D, et al. Combined paclitaxel and gemcitabine as first-line treatment in metastatic non-small cell lung cancer: a multicentre phase II study. Br J Cancer 2001; 84: 1179-84. PubMed Citation  (Among 54 patients with advanced lung cancer treated with cycles of paclitaxel and gemcitabine, 98% had some elevation in liver tests and 9% had ALT elevations of >5 times ULN, but all were asymptomatic and self-limited).

  18. Tomassini E, Muhizi J, al Raheb K, Steinbach G, Bemer M, Platini C. [Fulminant hepatocellular necrosis following administration of docetaxel]. Presse Med 2001; 30: 634. French. PubMed Citation  (52 year old woman with metastatic breast cancer developed jaundice and stupor 72 hours after an initial infusion of docetaxel [bilirubin 6.8 mg/dL, ALT 5540 U/L, GGT 116 U/L, protime 18 sec], with death from multiorgan failure and autopsy showing massive necrosis).

  19. Venturini M, Del Mastro L, Garrone O, Angiolini C, Merlano M, Bergaglio M, Tolino G, et al. Phase I, dose-finding study of capecitabine in combination with docetaxel and epirubicin as first-line chemotherapy for advanced breast cancer. Ann Oncol 2002; 13: 546-52. PubMed Citation  (Among 23 women with advanced breast cancer treated with 139 cycles of docetaxel, capecitabine and epirubicin, 2 were withdrawn because of hepatic toxicity).

  20. Yeo W, Mok TS, Tse KK, Kwan WH, Lam KC, Ho WM, Chiu SK, et al. Phase II study of docetaxel and epirubicin in Chinese patients with metastatic breast cancer. Anticancer Drugs 2002; 13: 655-62. PubMed Citation  (Among 46 patients treated with docetaxel and epirubicin, 6 [13%] developed abnormal ALT levels including two with hepatitis B reactivation, the 4 without hepatitis B being mild and transient).

  21. Sundar S, Chan SY. Cholestatic jaundice and pseudomembranous colitis following combination therapy with doxorubicin and docetaxel. Anticancer Drugs 2003; 14: 327-9. PubMed Citation  (45 year old woman with advanced breast cancer developed febrile neutropenia after 2 cycles of docetaxel and doxorubicin with subsequent pseudo-membranous colitis and jaundice [peak bilirubin 5.3 mg/dL, ALT 46 U/L, Alk P 3436 U/L], resolving within 2 months).

  22. Markman M, Zanotti K, Webster K, Belinson J, Rose P. Toxicity associated with carboplatin/paclitaxel/Irinotecan use in advanced ovarian cancer: preliminary analysis. Oncology (Williston Park) 2003; 17 (5 Suppl 5): 34-5. PubMed Citation  (Among 26 women with advanced ovarian cancer given paclitaxel, carboplatin and irinotecan, 1[4%] developed transient ALT elevations >5 times ULN).

  23. Harries M, O'Donnell A, Scurr M, Reade S, Cole C, Judson I, Greystoke A, et al. Phase I/II study of DHA-paclitaxel in combination with carboplatin in patients with advanced malignant solid tumours. Br J Cancer 2004; 91: 1651-5. PubMed Citation  (Among 15 patients with advanced solid cancers given carboplatin and paclitaxel conjugated to fatty acids, 5 [33%] developed transient ALT elevations >5 times ULN).

  24. Pelegrí, Calvo L, Mayordomo JI, FloriáJ, Váuez S, Arcusa A, Martn-Richard M, et al.; Spanish Group for Breast Cancer Research (GEICAM). Gemcitabine plus docetaxel administered every other week as first-line treatment of metastatic breast cancer: preliminary results from a phase II trial. Semin Oncol 2004; 31 (2 Suppl 5): 20-4. PubMed Citation  (Among 35 patients with metastatic breast cancer treated with up to 10 cycles of docetaxel and gemcitabine, 51% had aminotransferase elevations, which were >5 times ULN in 6%, but largely asymptomatic and self-limited).

  25. Goodin S, Medina P, Capanna T, Shih WJ, Abraham S, Winnie J, Doyle-Lindrud S, et al. Effect of docetaxel in patients with hormone-dependent prostate-specific antigen progression after local therapy for prostate cancer. J Clin Oncol 2005; 23: 3352-7. PubMed Citation  (Among 25 patients with advanced prostate cancer given docetaxel in 3 week cycles, one had dose reduction for ALT elevations >5 times ULN).

  26. Kaira K, Takise A, Minato K, Iwasaki Y, Ishihara S, Takei Y, Tsuchiya S, et al. Phase II study of weekly docetaxel and cisplatin in patients with non-small cell lung cancer. Anticancer Drugs 2005; 16: 455-60. PubMed Citation  (Among 40 patients with lung cancer treated with weekly docetaxel and cisplatin, 2 had ALT elevations >5 times ULN leading to dose reduction in 1).

  27. Cao Y, Wang ZQ, Guo Y, Feng FY, Hu XH, Xiong JP, Tang GD, et al. [A randomized control clinical trial of Euruikang(docetaxel) in treatment of advanced non-small cell lung cancer(NSCLC)]. Ai Zheng 2006; 25: 999-1002. Chinese. PubMed Citation

  28. Kasahara K, Kimura H, Shibata K, Araya T, Sone T, Oribe Y, Furusho S, et al. A phase II study of combination chemotherapy with docetaxel and carboplatin for patients with advanced or metastatic non-small cell lung cancer. Anticancer Res 2006; 26: 3723-8. PubMed Citation  (Among 40 patients with advanced lung cancer treated with docetaxel and carboplatin, 6 [15%] had ALT elevations which were above 5 times ULN in one).

  29. Liu DG, Peng RJ, Feng FY, Hu XH, Tang GD, Xiong JP, Zhao HY, et al. [Randomized controlled trial of two kinds of home-produced docetaxel in China for advanced breast cancer]. Ai Zheng 2006; 25: 1557-60. Chinese. PubMed Citation  (Comparison of two formulations of docetaxel in 67 patients with advanced breast cancer found that transient ALT and AST elevations were common).

  30. Sinibaldi VJ, Elza-Brown K, Schmidt J, Eisenberger MA, Rosenbaum E, Denmeade SR, Pili R, et al. Phase II evaluation of docetaxel plus exisulind in patients with androgen independent prostate carcinoma. Am J Clin Oncol 2006; 29: 395-8. PubMed Citation  (Among 14 patients with prostate cancer treated with docetaxel and exisulind, 21% had aminotransferase elevations above 5 times ULN).

  31. Aoki H, Ishidoya S, Ito A, Endoh M, Shimazui T, Arai Y. Experience of the treatment with gemcitabine, docetaxel, and carboplatin(GDC) chemotherapy for patients with small-cell carcinoma of the prostate. Int J Urol 2006; 13: 1254-8. PubMed Citation  (Two patients with advanced prostate cancer were treated with docetaxel in combination with gemcitabine and carboplatin; one developed acute liver failure several months after a fifth cycle which was attributed to herpes zoster).

  32. Ohlmann CH, Kohlmorgen S, Sahi D, Engelmann U, Heidenreich A. [Lethal course after chemotherapy with docetaxel. Acute liver failure with accompanying erythema multiforme major]. Urologe A 2007; 46: 1425-7. German. PubMed Citation  (67 year old man with prostate cancer developed Stevens-Johnson Syndrome, neutropenia and thrombocytopenia after 5 weekly infusions of docetaxel, with subsequent rise in liver tests and jaundice that progressed to hepatic failure and death; few details provided).

  33. Bailey HH, Alberti DB, Thomas JP, Mulkerin DL, Binger KA, Gottardis MM, Martell RE, et al. Phase I trial of weekly paclitaxel and BMS-214662 in patients with advanced solid tumors. Clin Cancer Res 2007; 13: 3623-9. PubMed Citation  (Among 26 patients with advanced cancer treated with paclitaxel and an experimental farnesyl transferase inhibitor, 3 developed febrile neutropenia and raised ALT levels 1 to 3 days after the infusions, not attributed to paclitaxel).

  34. Chen JP, Lo Y, Yu CJ, Hsu C, Shih JY, Yang CH. Predictors of toxicity of weekly docetaxel in chemotherapy-treated non-small cell lung cancers. Lung Cancer 2008; 60: 92-7. PubMed Citation  (Retrospective analysis of toxicity of 455 cycles of docetaxel in 155 patients with non-small cell lung cancer; 67 patients were withdrawn for toxicity, 2 were liver related; preexisting hepatitis B and C were risk factors for toxicity).

  35. James J, Murry DJ, Treston AM, Storniolo AM, Sledge GW, Sidor C, Miller KD. Phase I safety, pharmacokinetic and pharmacodynamic studies of 2-methoxyestradiol alone or in combination with docetaxel in patients with locally recurrent or metastatic breast cancer. Invest New Drugs 2007; 25: 41-8. PubMed Citation  (Among 15 women with advanced breast cancer treated with docetaxel and 2-methoxyestradiol, 3 [20%] had ALT elevations, which resolved with dose reductions in 2 and stopping docetaxel in 1).

  36. Pignata S, Breda E, Scambia G, Pisano C, Zagonel V, Lorusso D, Greggi S, et al. A phase II study of weekly carboplatin and paclitaxel as first-line treatment of elderly patients with advanced ovarian cancer. A Multicentre Italian Trial in Ovarian cancer(MITO-5) study. Crit Rev Oncol Hematol 2008; 66: 229-36. PubMed Citation  (Among 27 elderly women with advanced ovarian cancer treated with weekly infusions of carboplatin and paclitaxel, one had ALT increase above 5 times ULN during first course, but without jaundice, and she subsequently tolerated 5 more courses).

  37. Minami H, Kawada K, Sasaki Y, Tahara M, Igarashi T, Itoh K, Fujii H, et al. Population pharmacokinetics of docetaxel in patients with hepatic dysfunction treated in an oncology practice. Cancer Sci 2009; 100: 144-9. PubMed Citation  (Analysis of pharmacokinetics of docetaxel in 200 patients found that liver test abnormalities were associated with delayed clearance and recommended 20-40% reduction in dose).

  38. Campone M, Levy V, Bourbouloux E, Berton Rigaud D, Bootle D, Dutreix C, Zoellner U, et al. Safety and pharmacokinetics of paclitaxel and the oral mTOR inhibitor everolimus in advanced solid tumours. Br J Cancer 2009; 100: 315-21. PubMed Citation  (Among 16 patients with advanced malignancies treated with paclitaxel and oral everolimus, one developed transient ALT elevations >5 times ULN).

  39. Sun Q, Liu C, Zhong H, Zhong B, Xu H, Shen W, Wang D. Multi-center phase II trial of weekly paclitaxel plus cisplatin combination chemotherapy in patients with advanced gastric and gastro-esophageal cancer. Jpn J Clin Oncol 2009; 39: 237-43. PubMed Citation  (Among 49 patients with gastrointestinal cancers treated with cyclic regimens of paclitaxel and cisplatin, 9 [18%] developed transient ALT elevations which were greater than 5 times ULN in 1 [2%], but none had jaundice).

  40. Kobayashi K, Yokonishi T, Ito Y, Matsumoto T, Umemoto S, Osaka K, Nakamura M, et al. [Low-dose docetaxel, estramustine and dexamethasone combination chemotherapy for hormone-refractory prostate cancer]. Hinyokika Kiyo 2010; 56: 203-7. Japanese. PubMed Citation  (Among 62 patients with advanced prostate cancer treated with docetaxel, estramustine and dexamethasone for an average of 11 cycles, only 1 had transient ALT elevation >5 times ULN).

  41. Oshita F, Saito H, Murakami S, Kondo T, Yamada K. Phase II study of paclitaxel and irinotecan with intercalated gefitinib in patients with advanced non-small-cell lung cancer. Am J Clin Oncol 2010; 33: 66-9. PubMed Citation  (Among 16 patients with advanced non-small cell lung cancer treated with paclitaxel, irinotecan and gefitinib, 8 had ALT elevations [only one >5 times ULN], but none developed jaundice).

  42. Wang Z, Liang X, Yu J, Zheng X, Zhu Y, Yan Y, Dong N, et al. Non-genetic risk factors and predicting efficacy for docetaxel--drug-induced liver injury among metastatic breast cancer patients. J Gastroenterol Hepatol 2012; 27: 1348-52. PubMed Citation (Among 647 women with breast cancer treated with docetaxel, 67 [10%] developed liver injury [27% with jaundice], with a median time to onset of 14 days; risk factors were menopausal status, hepatitis B markers, and presence of liver metastases).

  43. Liang X, Zhang J, Zhu Y, Lu Y, Zhou X, Wang Z, Yu J, et al. Specific genetic polymorphisms of IL10-592 AA and IL10-819 TT genotypes lead to the key role for inducing docetaxel-induced liver injury in breast cancer patients. Clin Transl Oncol 2013; 15: 331-4. PubMed Citation  (Among 129 patients with metastatic breast cancer treated with docetaxel, there were significant associations between specific polymorphisms of IL10, but not tumor necrosis factor; although the associations were slight).

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Taxanes
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