|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Originally published as JCO Early Release 10.1200/JCO.2003.05.099 on June 13 2003 © 2003 American Society for Clinical Oncology
Dose-Intense Paclitaxel: Déjà Vu All Over Again?Institute for Drug Development, Cancer Therapy and Research Center, and University of Texas Health Science Center, San Antonio, TX IN CANCER chemotherapy, the majority of treatments for patients with solid malignancies has less than ideal efficacy. One strategy for maximizing the therapeutic benefit of anticancer chemotherapy is to administer all drugs at their optimal doses and schedules. However, despite substantial clinical experience, the optimal administration regimen for most chemotherapeutic agents remains elusive. For example, fluorouracil has been in clinical use for over 40 years, yet many questions remain concerning the best way to administer this drug.1 One approach is to use all drugs at the absolute highest tolerable dose. This strategy is historically well-grounded; for example, the traditional cancer chemotherapy phase I trial is designed as a clinical experiment to define the maximally tolerated dose.2 Typically, the recommended phase II dose is then defined as the highest dose level with an acceptable incidence of toxicity. This definition implicitly assumes that the best dose for further testing is the one that most narrowly avoids producing severe toxicity. For agents with steep dose-response curves and narrow therapeutic windows, this strategy has served us well in defining tolerable dosing schemes that have subsequently demonstrated clinical benefit. Much of developmental chemotherapy in oncology has been driven by the fundamental concept that more is better.3 Over the past two decades, several developments in the field of cancer chemotherapy have supported the strategic approach of using drugs at their highest tolerable doses, a practice that has been referred to as pushing "the outer edge of the dosing envelope."4 First, there was the recognition that administered dose-intensity, which is defined as the amount of drug administered per unit time (expressed in units of mg/m2/wk), could independently predict antitumor response in some solid malignancies, such as breast cancer.5 For agents in which the relationship between dose and response is steep, Hryniuk and Levine6 and others7 argued eloquently for enhancing dose-intensity, even at the expense of modest increases in treatment-related toxicity. More recently, the concept of dose-dense chemotherapy has evolved to describe regimens using high drug doses combined with shortened time intervals between treatments.8 The value of dose-dense chemotherapy in the adjuvant treatment of breast cancer remains an active area of debate.9–11 Second, the development of colony-stimulating growth factors has rendered the routine use of increased doses of myelosuppressive agents in standard regimens a practical option. Finally, the development of high-dose chemotherapy with stem-cell support has allowed the use of previously unthinkable doses of chemotherapy, an approach that explores the "outer edge of the outer edge of the dosing envelope."4 In advanced breast cancer patients, impressive response rates and favorable clinical outcomes, compared with historical controls,12 led to the extensive exploration of high-dose chemotherapy in the treatment of a wide variety of solid malignancies. By the early 1990s, these developments reinforced the widely held notion in cancer chemotherapy that more is better and its unstated corollary that most is best. This reasoning led to the initiation of a study reported by Omura et al13 in this issue of the Journal of Clinical Oncology that evaluates dose-intense paclitaxel chemotherapy in patients with advanced ovarian cancer. More recently, the luster of dose-intense chemotherapy has been tarnished by critical commentaries deriding the indiscriminant use of colony-stimulating factors to enhance dose-intensity in the absence of supportive scientific data.14 Even more damaging was the subsequent failure of high-dose chemotherapy to show clear benefit in patients with advanced breast cancer.15,16 Nonetheless, such dose-intense approaches have dominated strategic thinking in anticancer drug development for a number of years, and it is against this historical landscape that the study by Omura et al13 must be viewed. Paclitaxel is an active and useful agent in the treatment of a variety of solid malignancies, particularly advanced ovarian cancer. In preclinical studies, paclitaxel produces a number of concentration-dependent effects, including acute cytotoxicity with and without apoptosis, radiosensitization, microtubule bundle formation, increase in tubulin polymer mass, and stabilization of microtubules against depolymerization.17 As paclitaxel concentrations increase, its mechanism of cytotoxic action may also vary. For example, in laboratory studies, paclitaxel concentrations up to 330 nmol/L enhance polymerized microtubule mass and stabilize microtubule bundle formation in association with cell growth arrest.18 These high concentrations of paclitaxel are also associated with the induction of cell death via a Raf-1–dependent pathway.19 In contrast, at lower concentrations (< 10 nmol/L), paclitaxel induces growth inhibition independent of microtubular mass18 and causes mitotic arrest by a Raf-1–dependent pathway.19 Thus, paclitaxel can induce a variety of concentration-dependent effects in human tumor cell lines over a range of clinically achievable concentrations
In early clinical studies in recurrent or refractory ovarian cancer, 24-hour paclitaxel infusions were explored over doses ranging from 110 to 300 mg/m2.20 Hematopoietic growth factor support was typically used for doses These observations set the stage for the next logical step in paclitaxel’s development—an intergroup randomized phase III study of dose-intense paclitaxel in women with platinum-resistant ovarian cancer.13 In its original design, women with platinum-refractory ovarian cancer were randomly assigned to receive 24-hour paclitaxel infusions at doses of 135 mg/m2, 175 mg/m2, or 250 mg/m2 with filgrastim. The three primary end points were to measure objective response rates, progression-free survival, and overall survival. The efficacy of filgrastim was also examined at two dose levels, 5 or 10 µg/kg/d. Major problems developed during the conduct of the study, the most significant of which was slow accrual rate occurring after paclitaxel became commercially available. Consequently, the eligibility criteria were modified to include patients with platinum-sensitive disease, and the requirement for clinically measurable lesions was eliminated. Furthermore, the low-dose arm of 135 mg/m2 was closed after the accrual of only 77 patients. Despite these alterations, the results are clear. The response rate, a potential surrogate marker for clinical benefit, was significantly higher for the 250-mg/m2 arm compared with the 175-mg/m2 arm (36% v 27%, respectively; P = .0027), but progression-free survival (5.5 v 4.8 months, respectively) and overall survival (12.3 v 13.1 months, respectively) were unchanged. Toxicities such as thrombocytopenia, neuropathy, and myalgias were substantially greater for patients treated on the high-dose arm. The study conclusions were that paclitaxel response rates were significantly greater at 250 mg/m2 than at 175 mg/m2, but drug-related toxicities were also higher, with no survival benefit. Thus, there was no compelling reason to recommend doses of paclitaxel greater than 175 mg/m2 in the palliative treatment of women with advanced or refractory ovarian cancer. Finally, no benefit was observed for the higher dose of filgrastim in this same patient population.
How do these findings compare with data from other studies? The results of other clinical trials of dose-intense paclitaxel are listed in Table 1
Similar findings have been reported in randomized studies of paclitaxel dose-intensity in women with advanced breast cancer.24,25 No differences in response rates or median survival were found in a randomized study of 471 women with metastatic breast cancer, although the trend favored higher doses of paclitaxel.24 Administration of paclitaxel at 135 or 175 mg/m2 infused over 3 hours resulted in objective response rates of 22% versus 29%, respectively (P = .108), and median survival times of 10.5 versus 11.7 months, respectively (P = .088); additionally, progression-free survival time was significantly better for the high-dose group (3.0 v 4.2 months, respectively; P = .027). Dose-intensity was also tested using a higher paclitaxel dose range in a Cancer and Leukemia Group B study that randomly assigned 325 women with metastatic breast cancer to receive 3-hour infusions of 175, 210, or 250 mg/m2 of paclitaxel.25 Overall, the paclitaxel dose did not significantly influence the response rate (21% v 28% v 22%, respectively; P = .64) or the overall median survival time (3.8 v 4.1 v 4.8 months, respectively; P = .48). However, a significantly longer time to treatment failure was noted as the dose of paclitaxel was increased (3.8 v 4.1 v 4.8 months, respectively; P = .03). Increasing doses were also associated with higher rates of severe myelosuppression and moderate sensory neuropathies.25 When data from both of these breast cancer studies are analyzed, there is no evidence that paclitaxel doses greater than 175 mg/m2 infused over 3 hours offer any therapeutic benefit to women with metastatic breast cancer. Limited benefits for higher doses of paclitaxel have also been reported in non–small-cell lung cancer (NSCLC) and head and neck cancer. In NSCLC, Kosmidis et al26 treated 178 patients with paclitaxel at 175 or 225 mg/m2 infused over 3 hours in combination with carboplatin dosed to achieve an area under the curve of 6. The primary end point of tumor response rate was not significantly different for the low- and high-dose paclitaxel arms (25.6% v 31.8%, respectively; P = .733), and the secondary end point of median survival was not improved (9.5 v 11.4 months, respectively; P = .14). However, the median time to tumor progression significantly increased from 4.3 months in the low-dose arm to 6.4 months in the high-dose arm (P = .044), albeit at the expense of a greater incidence of neurologic toxicity and more severe leukopenia. Despite these results, these investigators favored the use of an intermediate dose of 200 mg/m2 of paclitaxel for future trials. Bonomi et al27 obtained nearly identical data from a three-arm randomized study of 599 patients with NSCLC. Patients were treated with one of the following regimens: cisplatin 75 mg/m2 on day 1 plus etoposide 100 mg/m2 on days 1 to 3; cisplatin 75 mg/m2 plus low-dose paclitaxel at 135 mg/m2 over 24 hours; or cisplatin at 75 mg/m2 plus high-dose paclitaxel at 250 mg/m2 over 24 hours with 5 ìg/kg of filgrastim support. In a direct comparison of the low- versus high-dose paclitaxel arms, no significant differences in response rate (25.3% v 27.7%, respectively; P = .264) or median survival time (9.5 v 10.0 months, respectively; P = .931) were observed. The incidences of severe neurotoxicty and severe granulocytopenia were significantly greater for the high-dose paclitaxel arm. Thus, in NSCLC, there is no benefit to paclitaxel doses above 135 mg/m2 infused over 24 hours when combined with platinum. Finally, a study in advanced head and neck cancer randomly assigned 210 patients to receive cisplatin at 75 mg/m2 plus paclitaxel at either 135 mg/m2 or 200 mg/m2 over 24 hours with filgrastim support. No significant difference in response rate (35% v 36%, respectively) or median survival times (6.8 v 7.6 months, respectively P = .756) was seen when the low- and high-dose arms were compared. Toxicities were severe in both arms, with a combined overall toxic death rate of 10.5%. No paclitaxel dose-response effect was noted in this study, although the overall high toxicity precluded the recommendation of any of the regimens examined in this study. In summary, data from randomized studies in lung, ovarian, breast, and head and neck cancers form a convincing and highly consistent body of evidence that modest increases of paclitaxel dose-intensity above that associated with the conventional definition of the maximally tolerated dose without filgrastim support do not result in any improvement in overall survival. No paclitaxel dosing schedule is associated with a superior clinical outcome, and higher paclitaxel doses enhance toxicity. Furthermore, the plateau in paclitaxel’s antitumor activity occurs at doses that can be readily given without growth factor support.4 What is the basis for this lack of dose-response in standard paclitaxel chemotherapy regimens? At the pharmacologic level, there is evidence indicating that the duration of exposure, and not the maximal concentration, is the most important determinant of paclitaxel’s drug effect.29–33 Therefore, increasing the drug concentration above a threshold may not result in improved antitumor activity, but toxic effects may continue to increase. The absolute level of this threshold concentration likely varies with different cell types and may be inversely related to the duration of infusion. An attractive mechanistic hypothesis that may explain this threshold effect is the saturable binding of paclitaxel to sites on beta-tubulin.17 Exceeding this threshold should not generate any greater antimicrotubule effect. Proof of this theory is complicated by the difficulty in measuring saturable binding of paclitaxel to tubulin sites within tumor cells. Another factor may be the nonlinear pharmacokinetic profile of paclitaxel that is partially related to its unusual saturable tissue distribution process.34,35 If distribution of drug into the tumor compartment is saturable, then increasing dose and plasma drug concentrations may not correspond to increased drug concentrations within the active site compartment. Finally, paclitaxel commonly generates high ratios of tissue to plasma drug concentrations, again indicating that plasma drug concentration may not be highly informative concerning tumor and normal tissue drug concentrations at the pharmacologic site of action. All of these factors may contribute to a plateau effect, explaining the diminishing clinical benefit associated with higher doses of paclitaxel.
The observation by Omura et al13 that higher doses of paclitaxel generate significantly higher response rates but do not improve survival may at first be puzzling; however, theoretical models of cell growth can readily explain these findings. Gompertzian kinetics predict that tumor growth rates are rapid when the number of viable cells is low, but these rates decrease asymptotically as the tumor grows larger,36,37 as shown schematically in Figure 1
What dose and regimen should be used when administering paclitaxel to advanced cancer patients? In the palliative setting, there seems little value in escalating paclitaxel doses beyond 175 mg/m2 infused over 3 hours or 135 mg/m2 infused over 24 hours every 3 weeks. Are further studies of high doses of paclitaxel in the treatment of common solid tumors necessary? Given the growing need to develop and test many novel new therapies in well-designed clinical trials, precious clinical research resources should probably be allocated elsewhere. In this regard, the report by Omura et al13 should be considered the definitive study of dose-intense (but not dose-dense) paclitaxel in the palliative setting. More frequent administration of standard paclitaxel doses may still improve clinical outcomes. If the concept that more is better does not hold in this setting, then perhaps it is time to examine whether more often is better. This concept is being studied in breast cancer39,40 and is worthy of careful examination in patients with other malignancies.
Although the Omura study took longer to complete than initially anticipated, it is a well-conducted trial, and the findings are unequivocal.13 Dose-intense paclitaxel regimens generate significantly higher response rates but also cause more toxicity and, most importantly, do not convincingly improve clinical benefit, particularly survival. Thus, higher response rates in this setting are of dubious clinical benefit. When viewed in the context of the numerous related studies listed in Table 1
REFERENCES 1. Takimoto CH: The clinical pharmacology of the oral fluoropyrimidines. Curr Probl Cancer 25:134–213, 2001[CrossRef][Medline] 2. Leventhal BG, Wittes RE: Research Methods in Clinical Oncology. New York, NY, Raven Press, 1988
3. Hryniuk WM: More is better. J Clin Oncol 6:1365–1367, 1988
4. Rowinsky EK: On pushing the outer edge of the outer edge of paclitaxel’s dosing envelope. Clin Cancer Res 5:481–486, 1999 5. Hryniuk W, Bush H: The importance of dose intensity in chemotherapy of metastatic breast cancer. J Clin Oncol 2:1281–1288, 1984[Medline]
6. Hryniuk W, Levine MN: Analysis of dose intensity for adjuvant chemotherapy trials in stage II breast cancer. J Clin Oncol 4:1162–1170, 1986
7. DeVita VT: Dose-response is alive and well. J Clin Oncol 4:1157–1159, 1986 8. Hudis CA: Dose-dense paclitaxel-containing adjuvant therapy for breast cancer. Oncology (Huntingt) 12:16–18, 1998[Medline]
9. Biganzoli L, Piccart MJ: The bigger the better? Or what we know and what we still need to learn about anthracycline dose per course, dose density and cumulative dose in the treatment of breast cancer. Ann Oncol 8:1177–1182, 1997 10. Piccart MJ, Biganzoli L, Di Leo A: The impact of chemotherapy dose density and dose intensity on breast cancer outcome: What have we learned? Eur J Cancer 36:S4–10, 2000 (suppl 1)
11. Piccart MJ: Mathematics and oncology: A match for life? J Clin Oncol 21:1425–1428, 2003
12. Peters WP, Shpall EJ, Jones RB, et al: High-dose combination alkylating agents with bone marrow support as initial treatment for metastatic breast cancer. J Clin Oncol 6:1368–1376, 1988
13. Omura GA, Brady MF, Look KY, et al: Phase III trial of paclitaxel at two dose levels, the higher dose accompanied by filgrastim at two dose levels in platinum-pretreated epithelial ovarian cancer: An Intergroup Study. J Clin Oncol 21:2843–2848, 2003
14. American Society of Clinical Oncology: Recommendations for the use of hematopoietic colony-stimulating factors: Evidence-based, clinical practice guidelines. J Clin Oncol 12:2471–2508, 1994
15. Stadtmauer EA, O’Neill A, Goldstein LJ, et al: Conventional-dose chemotherapy compared with high-dose chemotherapy plus autologous hematopoietic stem-cell transplantation for metastatic breast cancer. Philadelphia Bone Marrow Transplant Group. N Engl J Med 342:1069–1076, 2000 16. Gerrero RM, Stein S, Stadtmauer EA: High-dose chemotherapy and stem cell support for breast cancer: Where are we now? Drugs Aging 19:475–485, 2002[CrossRef][Medline] 17. Rowinsky EK: The taxanes: Dosing and scheduling considerations. Oncology 11:7–19, 1997[Medline]
18. Jordan MA, Toso RJ, Thrower D, et al: Mechanism of mitotic block and inhibition of cell proliferation by Taxol at low concentrations. Proc Natl Acad Sci USA 90:9552–9556, 1993
19. Torres K, Horwitz SB: Mechanisms of Taxol-induced cell death are concentration dependent. Cancer Res 58:3620–3626, 1998
20. Rowinsky EK, Donehower RC: Paclitaxel (Taxol). N Engl J Med 332:1004–1014, 1995
21. Kohn EC, Sarosy G, Bicher A, et al: Dose-intense Taxol: High response rate in patients with platinum-resistant recurrent ovarian cancer. J Natl Cancer Inst 86:18–24, 1994
22. Eisenhauer EA, ten Bokkel Huinink WW, Swenerton KD, et al: European-Canadian randomized trial of paclitaxel in relapsed ovarian cancer: High-dose versus low-dose and long versus short infusion. J Clin Oncol 12:2654–2666, 1994 23. Rowinsky EK, Mackey MK, Goodman SN: Meta-analysis of paclitaxel dose-response and dose-intensity in recurrent or refractory ovarian cancer. Proc Am Soc Clinc Oncol 15:284, 1996 (abstr 770)
24. Nabholtz JM, Gelmon K, Bontenbal M, et al: Multicenter, randomized comparative study of two doses of paclitaxel in patients with metastatic breast cancer. J Clin Oncol 14:1858–1867, 1996 25. Winer E, Berry D, Duggan D, et al: Failure of higher dose paclitaxel to improve outcome in patients with metastatic breast cancer: Results from CALGB 9342. Proc Am Soc Clinc Oncol 17:101a, 1998 (abstr 388)
26. Kosmidis P, Mylonakis N, Skarlos D, et al: Paclitaxel (175 mg/m2) plus carboplatin (6 AUC) versus paclitaxel (225 mg/m2) plus carboplatin (6 AUC) in advanced non-small-cell lung cancer (NSCLC): A multicenter randomized trial. Hellenic Cooperative Oncology Group (HeCOG). Ann Oncol 11:799–805, 2000
27. Bonomi P, Kim K, Fairclough D, et al: Comparison of survival and quality of life in advanced non-small-cell lung cancer patients treated with two dose levels of paclitaxel combined with cisplatin versus etoposide with cisplatin: Results of an Eastern Cooperative Oncology Group trial. J Clin Oncol 18:623–631, 2000
28. Forastiere AA, Leong T, Rowinsky E, et al: Phase III comparison of high-dose paclitaxel + cisplatin + granulocyte colony-stimulating factor versus low-dose paclitaxel + cisplatin in advanced head and neck cancer: Eastern Cooperative Oncology Group Study E1393. J Clin Oncol 19:1088–1095, 2001 29. Georgiadis MS, Russell EK, Gazdar AF, et al: Paclitaxel cytotoxicity against human lung cancer cell lines increases with prolonged exposure durations. Clin Cancer Res 3:449–454, 1997[Abstract] 30. Liebmann J, Cook JA, Lipschultz C, et al: The influence of Cremophor EL on the cell cycle effects of paclitaxel (Taxol) in human tumor cell lines. Cancer Chemother Pharmacol 33:331–339, 1994[Medline]
31. Rowinsky EK, Donehower RC, Jones RJ, et al: Microtubule changes and cytotoxicity in leukemic cell lines treated with Taxol. Cancer Res 48:4093–4100, 1988 32. Helson L, Helson C, Malik S, et al: A saturation threshold for Taxol cytotoxicity in human glial and neuroblastoma cells. Anticancer Drugs 4:487–490, 1993[Medline] 33. Liebmann JE, Cook JA, Lipschultz C, et al: Cytotoxic studies of paclitaxel (Taxol) in human tumour cell lines. Br J Cancer 68:1104–1109, 1993[Medline] 34. Kearns CM, Gianni L, Egorin MJ: Paclitaxel pharmacokinetics and pharmacodynamics. Semin Oncol 22:16–23, 1995[Medline]
35. Gianni L, Kearns CM, Giani A, et al: Nonlinear pharmacokinetics and metabolism of paclitaxel and its pharmacokinetic/pharmacodynamic relationships in humans. J Clin Oncol 13:180–190, 1995 36. Norton L, Simon R, Brereton HD, et al: Predicting the course of Gompertzian growth. Nature 264:542–545, 1976[CrossRef][Medline]
37. Norton L: A Gompertzian model of human breast cancer growth. Cancer Res 48:7067–7071, 1988
38. Citron ML, Berry DA, Cirrincione C, et al: Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: First report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol 21:1431–1439, 2003 39. Hudis CA: The current state of adjuvant therapy for breast cancer: Focus on paclitaxel. Semin Oncol 26:1–5, 1999[Medline]
40. Norton L: Theoretical concepts and the emerging role of taxanes in adjuvant therapy. Oncologist 6:30–35, 2001
This article has been cited by other articles:
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
250 mg/m2. Although patient populations differed, response rates were apparently higher for paclitaxel doses greater than 175 mg/m2.
