Docetaxel (Taxotere) isa semisynthetic taxoid that possesses significant activity as a single
ABSTRACT: Docetaxel (Taxotere) isa semisynthetic taxoid that possesses significant activity as a singleagent in the treatment of patients with non-small-cell lung cancer. Inpatients with advanced non-small-cell lung cancer who had previously failedcisplatin (Platinol)-based chemotherapy, 100 mg/m² of docetaxel administeredas an intravenous infusion over 1 hour, once every 3 weeks, produced amedian response rate of 17% (of the intent-to-treat population) and mediansurvival of 9 months. The present report describes the preliminary resultsfrom three phase II trials performed in the United States, France, and Australia,examining the combination of docetaxel and cisplatin in patients with advancednon-small-cell lung cancer. One trial (Australian) studied docetaxel administeredas a 1-hour intravenous infusion followed by a 30-minute infusion of cisplatinon days 1, 22, and then every 3 weeks. The French and US trials administereddocetaxel every 3 weeks, but gave cisplatin on days 1, 22, and then every6 weeks. Major response rates ranged from 30% to 51% and median estimatedsurvival ranged from 9 to 10.5 months. Based on the results of these trials,the recommended dose for future phase II and III trials in patients withadvanced non-small-cell lung cancer is either 75 mg/m² of docetaxeland 75 mg/m² of cisplatin, or 65 mg/m² of docetaxel and 100 mg/m²of cisplatin, with docetaxel being administered once every 3 weeks andcisplatin on days 1, 22, and then every 6 weeks. [ONCOLOGY 11(Suppl 7):27-30,1997]
The introduction of several new chemotherapeutic agents has encouragedthe development of combination regimens with the potential for enhancedactivity in patients with non-small-cell lung cancer. Based on older studiesthat demonstrated some improvement in survival with cisplatin (Platinol)-basedregimens, nearly all the new agents have been tested in combination withcisplatin. This paper outlines the rationale and current progress in thedevelopment of combination chemotherapy regimens using docetaxel (Taxotere)plus cisplatin in non-small-cell lung cancer.
Docetaxel is a new agent with established activity in several malignancies,including non-small-cell lung cancer. As with paclitaxel (Taxol), evidenceof its single-agent activity is based on several single-arm phase II trialsrather than on random-assignment comparison studies. Both taxoids shareseveral preclinical and clinical features; however, their differences havethe potential to result in varying clinical outcomes.
Testing of docetaxel as a single agent involved different schedulesin typically escalating dosing steps. While the most prominent toxicitywas myelosuppression, especially neutropenia, other side effects of a moreunusual nature, such as finger nail changes, skin rash, and fluid retention,were observed in many of the trials. The majority of these side effectshave been relatively easy to prevent or ameliorate, largely through theuse of short courses of corticosteroids.
The schedule that appeared to have the greatest clinical activity, basedon dose-intensity and activity in preclinical models, was intravenous injectiongiven over 1 hour every 3 weeks. Neutropenia continued to be the most commondose-limiting toxicity of docetaxel at doses in the 75 to 100 mg/m²range in the every 3-week trial schedule.
Fluid retention was an unexpected side effect, occurring after severaladministrations of docetaxel. This effect was noted as edema or pleuraleffusion, even in patients with evidence of major clinical response.Prevention or marked diminution of the frequency and severity of fluidretention is now achieved with the prophylactic use of corticosteroids.
In a recent prospective evaluation, fluid retention was not apparentin any of the 33 patients receiving a twice-daily oral dose of 8 mg ofdexamethasone, beginning 1 day prior to docetaxel and continuing for 3or 4 more days. Fluid accumulation or edema generally cleared whilepatients continued on trial, with several of the patients continuing fora year on the every-3-week chemotherapy plus the dexamethasone regimen.
Single-Agent Docetaxel Activity
A number of phase II studies have been completed in different settingsusing the every 3-week schedule of docetaxel. Five studies have shown aconsistent high degree of activity, with the median survival reported inthe range of 7 to 13 months.[4-8] It is also of interest that the responseand survival rates were similar in two studies conducted at the same institution,but using different doses of docetaxel (100 or 75 mg/m²) on the sameschedule.[4,5] Although the studies are small, they suggest that the lowerdose range may be equivalent to the higher dose while producing less toxicity.If this lower dose is equally effective, it could have relevance for combinationtrials.
Docetaxel has also been tested in patients who have previously beentreated with cisplatin-containing regimens.[8,9] The observed 17% responserate is remarkable in that no other single agent has been reported to producea major response rate over 10% in previously treated patients. The estimatedsurvival of the patients in these two trials is 8 months. As a group, thesepatients had good prognostic factors at the time of enlistment, with themajority being women and with a high overall performance status. Theseresults suggest that docetaxel may not be very cross-resistant with cisplatin,which would be important in the design of combination studies.
At present, random-assignment studies with docetaxel have not been completed.Two trials based on the data from the studies with previously treated patientsare continuing to enlist patients. The first of these is an internationalstudy in which patients previously treated with cisplatin regimens areassigned to receive either docetaxel or supportive care. Enlistment inthis study has been relatively slow, while the second trial in this population,comparing docetaxel with either vinorelbine (Navelbine) or ifosfamide (Ifex),has had more rapid case accession. These trials should clarify the roleof docetaxel in a second-line setting, and will also outline the activityof the comparator agents in previously treated patients.
There are several reasons for using docetaxel in combination chemotherapy.While many agents could be combined with docetaxel, the selection of cisplatinis logical, based on the survival advantages previously demonstrated withcisplatin-based combinations.[10-14] Additionally, large, multicenter random-assignmenttrials have shown that the agents added to cisplatin (when the dose ofcisplatin is kept the same in comparison arms) can also influence survival.[15-17]
The side-effect profile of cisplatin makes it both logical and difficultfor use with docetaxel. Cisplatin is attractive for combining with anyagent due to its relatively mild degree of myelosuppression. This factoroften allows the cisplatin and the accompanying agents to be given at ornear their full phase II single-agent doses. However, the risk of emesis,nephrotoxicity, and fatigue makes cisplatin a difficult agent. Good supportivecare techniques have reduced the former risks;[18,19] however, the astheniaassociated with this agent has not been easy to control. While combiningdocetaxel with several other agents could be interesting, the greatestclinical experience has been with the cisplatin/docetaxel combination.The results of these studies will be discussed in the next section.
Docetaxel Plus Cisplatin Trials
There are reports of three trials in which docetaxel was combined withcisplatin in patients with advanced non-small-cell lung cancer previouslyuntreated with chemotherapy.[20-23] Several similarities exist among thesetrials, allowing for a better overall view of the activity of the regimen.These similarities include the characteristics of the patients enlistedinto the studies. All three studies share an every-3-week treatment regimenand at least one common dose level in each trial. Each study incorporatedboth phase I and phase II objectives. The trials were each single-institutionstudies, conducted in the United States, France, and Australia.
While generally similar, there were some differences among the trials,such as different combination dose levels. The Australian trial continuedwith both docetaxel and cisplatin given every 3 weeks, while in the Frenchand the US studies, docetaxel was administered every 3 weeks, but cisplatinwas administered on days 1 and 22, and every 6 weeks thereafter. The preliminaryresults of the trials are outlined in Table1.
The US trial explored four dose levels.[20,21] The only dose-limitingtoxicity was neutropenia, as seen in Table2. With the prophylactic dexamethasone regimen, outlined earlier inthis report, fluid retention and rash were not of clinical significancein any of the patients treated, with several receiving docetaxel for upto 1 year.
In the phase I portion, it was concluded that 85 mg/m² of docetaxelwas too high when combined with cisplatin. When giving cisplatin at 100mg/m², the investigators favor using docetaxel at 65 mg/m², althoughdoses of 75 mg/m² of docetaxel can be given. If the latter dose ofdocetaxel is used, this trial recommends a cisplatin dose of 75 mg/m².The 50% complete and partial response rate observed (with the majorityof patients treated at 75 mg/m² of each agent), was encouraging, aswas the projected median survival of 10 months. All patients were treatedon an outpatient basis; neither growth factors nor prophylactic antibioticswere used.
The French trial used the same dosing interval for both agentsas in the US study. Interestingly, the French study found less neutropeniathan any of the other studies, and favored 75 mg/m² of docetaxel plus100 mg/m² of cisplatin. While the major response rate observedin this trial (30%) was the lowest among the 3 trials (Table1), it should be realized that the French study had the largest proportionof patients with stage IV non-small-cell lung cancer (85%); nonetheless,the median survival is similar to the other studies and is projected tobe 10 months.
The Australian trial--A response-rate intermediate between theFrench and US trials was reported in the Australian study, as was the amountof neutropenia. This group concluded that the 75 mg/m2-dose of bothagents, with each given every 3 weeks, was the phase II level. As in theother studies, their preliminary analysis predicts a 10-month median survival(Table 1).
To date, no random-assignment trials with docetaxel combination regimenshave been reported. This is appropriate in that data from the initial combinationstudies have only recently been available. The above trials indicate reproducibleand useful response rates with survival rates as high as or higher thanthose reported with other combination regimens.
The trials have outlined several possible dosing levels. Based on ourtrial and the other studies, we would make two recommendations for randomizedinvestigations. If cisplatin is given at 75 mg/m² then a 75 mg/m²dose of docetaxel appears to be appropriate. If cisplatin is given at the100 mg/m²dose level, then docetaxel should be given at a dose of 65mg/m². We recommend the every-3-week docetaxel schedule, with cisplatingiven on days 1, 22, and every 6 weeks thereafter.
The only prominent toxicity in the US trial was neutropenia. Fluid retentionof clinical significance was completely prevented by using dexamethasonewith each docetaxel course. Febrile neutropenia was treated effectivelywith a new all-oral outpatient regimen.
The results of these studies are encouraging, and outline schedulesof docetaxel that could also be useful in patients with other malignanciesand that could be combined with other chemotherapeutic agents. The cisplatin/docetaxelregimens warrant further study in lung cancer, in patients with advanceddisease, and as part of combined-modality investigations.
1. Burris H, Irvin R, Kuhn J, et al: Phase I clinical trial of Taxotereadministered as either a 2-hour or 6-hour intravenous infusion 3 weeks.J Clin Oncol 11:950-958, 1993.
2. Tomiak E, Piccart MJ, Karger J, et al: Phase I study of docetaxeladministered as a 1-hour intravenous infusion on a weekly basis. J ClinOncol 12:1458-1467, 1994.
3. Rittenberg CN, Gralla RJ, Cole JT, et al: Preventing docetaxel-inducedfluid retention: The efficacy of corticosteroids. Proc Am Soc Clin Oncol15:531, 1996.
4. Francis PA, Rigas JR, Kris MG, et al: Phase II trial of docetaxelin patients with stage III and IV non-small cell lung cancer. J Clin Oncol12:1232-1237, 1994.
5. Miller VA, Rigas JR, Francis PA, et al: Phase II trial of a 75-mg/m2dose of docetaxel with prednisone premedication for patients with advancednon-small-cell lung cancer. Cancer 75:968-972, 1995.
6. Fossella FV, Lee JS, Murphy WK, et al: Phase II study of docetaxelfor recurrent or metastatic non-small cell lung cancer. J Clin Oncol 12:1238-1244,1994.
7. Cerny T, Kaplan S, Pavlidis N, et al: Docetaxel (Taxotere) is activein non-small cell lung cancer: A phase II trial of the EORTC early clinicaltrials group (ECTG). Br J Cancer 70:384-387, 1994.
8. Burris HA, Eckardt J, Fields S, et al: Phase II trials of Taxoterein patients with non-small cell lung cancer (abstract 1116). Proc Am SocClin Oncol 12:335, 1993.
9. Fossella FV, Lee JS, Shin DM, et al: Phase II study of docetaxel(Taxotere) for advanced or metastatic platinum-refractory non-small celllung cancer. J Clin Oncol 13:645-651, 1995.
10. Gralla RJ, Casper ES, Kelsen DP, et al: Cisplatin and vindesinecombination chemotherapy for advanced carcinoma of the lung: A randomizedtrial investigating two dosage schedules. Ann Intern Med 95:414-420, 1981.
11. Kris MG, Gralla RJ, Kalman LA, et al: Randomized trial comparingvindesine plus cisplatin with vinblastine plus cisplatin in patients withnon-small cell lung cancer with an analysis of methods of response assessment.Cancer Treat Rep 69:387-395, 1985.
12. Rapp E, Pater J, William A, et al: Chemotherapy can prolong survivalin patients with advanced non small cell lung cancer: Report of a Canadianmulticenter randomized trial. J Clin Oncol 6:633-641, 1988.
13. Non-Small Cell Lung Cancer Collaborative Group: Chemotherapy innon-small cell lung cancer: A meta-analysis using updated data on individualpatients from 52 randomised clinical trials. Br Med J 311:899-909, 1995.
14. Souquet PJ, Chauvin F, Boissel JP, et al: Polychemotherapy in advancednon-small cell lung cancer: A meta-analysis. Lancet 342:19-21, 1993.
15. LeChevalier T, Brisgand D, Douillard JY, et al: Randomized studyof vinorelbine and cisplatin versus vindesine and cisplatin versus vinorelbinealone in advanced non-small cell lung cancer: Results of a European multicentertrial including 612 patients. J Clin Oncol 12:360-367, 1994.
16. Crino L, Clerici M, Figoli F, et al: Chemotherapy of advanced non-smallcell lung cancer: A comparison of three active regimens. A randomized trialof the Italian Oncology Group for Clinical Research (G.O.I.R.C.). Ann Oncol6:347-353, 1995.
17. Wozniak AJ, Crowley JJ, Balcerzak SP, et al: Randomized phase IIItrial of cisplatin (CDDP) vs. CDDP plus Navelbine (NVB) in treatment ofadvanced non-small cell lung cancer (NSCLC): Report of a Southwest OncologyGroup Study (SWOG-9308). Proc Am Soc Clin Oncol 15:374, 1996.
18. Gralla RJ: Adverse effects of treatment: Antiemetic therapy, inDeVita VT, Hellman S, Rosenberg SA (eds): Cancer, Principles and Practicesof Oncology, vol IV, pp 2338-2348. Philadelphia, JB Lippincott Co, 1993.
19. Hayes DM, Cvitkovic E, Goldberg RB, et al: High-dose cisplatinumdiamminedichloride: amelioration of renal toxicity by mannitol diuresis.Cancer 39:1372-1381, 1977.
20. Cole JT, Gralla RJ, Marques CB, et al: Phase I-II study of cisplatin+ docetaxel (Taxotere) in non-small cell lung cancer (NSCLC) (abstract1087). Proc Am Soc Clin Oncol 14:357, 1995.
21. Cole JT, Galla RJ, Rittenberg CN, et al: Defining the dose of docetaxel(Taxotere) in combination chemotherapy of non-small cell lung cancer: Preservingefficacy with lower dose regimens (abstract 1671). Proc Am Soc Clin Oncol16:465a, 1997.
22. Douillard FY, Monnier A, Ibrahim N, et al: Preliminary report ofa phase II study of docetaxel (Taxotere) and cisplatin in advanced non-smallcell lung cancer (NSCLC) (abstract 1096). Eur J Cancer 31A(suppl 5): S228,1995.
23. Zalcberg JR, Bishop JF, Millward MJ, et al: Preliminary resultsof the first phase II trial of docetaxel in combination with cisplatinin patients with metastatic or locally advanced non-small cell lung cancer(NSCLC) (abstract 1062). Proc Am Soc Clin Oncol 14:351, 1995.
24. Bizette GA, Gralla RJ, Robertson CL, et al: An effective twice dailyoral outpatient antibiotic regimen for febrile neutropenia in lower riskpatients (abstract 176). Proc Am Soc Clin Oncol 16:51a, 1997.