TY - JOUR
AU - Hainsworth, John D.
AB - Abstract Learning Objectives After completing this course, the reader will be able to: Describe the efficacy of weekly docetaxel in various solid tumors, particularly in comparison with docetaxel administered every 3 weeks. List the common treatment-related toxicities of weekly docetaxel. Effectively manage the common toxicities related to weekly docetaxel. Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com Docetaxel (Taxotere®; Aventis Pharmaceuticals Inc.; Bridgewater, NJ) is a highly effective chemotherapeutic agent with proven efficacy in a number of solid tumors. However, myelosuppression can be a substantial concern when docetaxel is administered every 3 weeks. Myelosuppression can be particularly problematic in older patients and those being treated with palliative intent. Weekly dosing of docetaxel has been investigated in an effort to reduce toxicity and has been identified as a safe and effective regimen in clinical trials. Weekly docetaxel is generally administered at doses ranging from 30–40 mg/m2/week for 6 of 8 weeks or for 3 of 4 weeks. With weekly dosing, though efficacy is comparable, myelosuppression is substantially less, and the overall tolerability profile is better than with every-3-week dosing. Fatigue is a common toxicity associated with weekly docetaxel; other adverse effects that are seen in a minority of patients include hyperlacrimation, nail toxicity, and alopecia. These side effects are dose related and can generally be managed through dose reductions or alterations in the weekly schedule. Because of the favorable tolerability profile, weekly docetaxel is under investigation in combination with other chemotherapeutic agents and with novel targeted agents in a variety of tumor types. The results of these ongoing studies will further define the place of weekly docetaxel in cancer therapy. Docetaxel, Weekly, Taxanes, Administration, Side-effect management Introduction Docetaxel (Taxotere®; Aventis Pharmaceuticals Inc.; Bridgewater, NJ) is a semisynthetic taxane with proven efficacy in a variety of solid tumors, including breast cancer, non-small cell lung cancer (NSCLC), and prostate cancer [1–8]. The recommended single-agent dose ranges from 60–100 mg/m2 i.v. over 1 hour every 3 weeks. When administered at the higher end of this dose range, the majority of patients develop grade 3–4 neutropenia. Myelosuppression and its complications can be particularly problematic for older patients and for patients receiving palliative treatment, such as those with advanced breast cancer or NSCLC. Attempts to reduce the incidence of myelosuppression have resulted in the evaluation of weekly docetaxel regimens, which maintain dose intensity while altering the tolerability profile. Indeed, results from numerous clinical trials demonstrate that weekly dosing of docetaxel dramatically reduces the incidence of myelosuppression. In fact, there are fewer acute toxicities and the dose-limiting toxicities, namely fatigue and asthenia, appear to be cumulative. Although the safety profile is better with weekly administration of docetaxel, the efficacy appears comparable with that achieved with an every-3-week (q3w) schedule, as evidenced by results of randomized trials [9–12]. The current article reviews the results of clinical trials that have evaluated weekly docetaxel regimens and focuses on the unique tolerability profile associated with this dosing strategy. Useful strategies for managing the most common side effects reported in association with this regimen are also discussed. Weekly Docetaxel: Clinical Overview Phase I trials evaluating weekly docetaxel demonstrated activity and tolerability [13–16]. In the first of these trials, docetaxel was administered as a 1-hour i.v. infusion to patients with refractory, advanced disease on days 1 and 8 of a 3-week cycle [13]. The maximum-tolerated dose (MTD) was determined to be 110 mg/m2 per course (55 mg/m2 per dose), and hematologic toxicities were not significantly less. Other phase I trials evaluated more protracted regimens. We evaluated weekly docetaxel administered for six consecutive weeks during an 8-week cycle in patients with advanced, refractory malignancies [14]. The docetaxel dose was escalated from 20 mg/m2/week to 52 mg/m2/week in six dose cohorts. Fatigue and asthenia were dose limiting, and 43 mg/m2/week was determined to be the MTD. Grade 3–4 toxicities were uncommon at doses below the MTD, and hematologic toxicities were mild at all dose levels. Similar results were seen in other phase I studies [15, 16]. Of note, responses were seen in refractory patients, providing evidence of clinical activity with these dosing strategies. Based on the results of phase I studies, doses of 36–42 mg/m2/week were recommended for evaluation in phase II clinical trials [14–16]. Numerous phase II trials have now been conducted to evaluate the safety and efficacy of weekly, single-agent docetaxel in a variety of solid tumors, including metastatic breast cancer (MBC), prostate cancer, and NSCLC (Tables 1–3) [5, 6, 17–39]. Table 1 Activity of weekly docetaxel in phase II clinical trials in metastatic breast cancer Study . n of patients . Line of therapy . Regimen (mg/m2 q wk for 6 of 8 weeks) . Overall response rate (%) . Stemmler et al. [17] 100 First (15%) or higher 35a 42 Jackisch et al. [18] 60 First (6%) or higher 35–40 29 Loeffler et al. [19] 41 Second or higher 40 48 Comandone et al. [20] 40 Second or higher 40b 19 Aihara et al. [21] 37 Second 40c 38 Hainsworth et al. [22] 36 First (75%) or higher 36 36 Stemmler et al. [23] 35 Second or higher 35a 34 Ramos et al. [24] 31 First (29%) or higher 36–40 41 Rittershaus et al. [25] 30 Second or higher 35 13 Lück et al. [26] 30 Third or higher 35d 16 Fornasiero et al. [27] 30 Second or higher 35b 20e Burstein et al. [28] 29 First (79%) or higher 40 41 Nistico et al. [29] 25 First (20%) or higher 40d 53 Climent et al. [30] 14 Second or higher 35d 36 Study . n of patients . Line of therapy . Regimen (mg/m2 q wk for 6 of 8 weeks) . Overall response rate (%) . Stemmler et al. [17] 100 First (15%) or higher 35a 42 Jackisch et al. [18] 60 First (6%) or higher 35–40 29 Loeffler et al. [19] 41 Second or higher 40 48 Comandone et al. [20] 40 Second or higher 40b 19 Aihara et al. [21] 37 Second 40c 38 Hainsworth et al. [22] 36 First (75%) or higher 36 36 Stemmler et al. [23] 35 Second or higher 35a 34 Ramos et al. [24] 31 First (29%) or higher 36–40 41 Rittershaus et al. [25] 30 Second or higher 35 13 Lück et al. [26] 30 Third or higher 35d 16 Fornasiero et al. [27] 30 Second or higher 35b 20e Burstein et al. [28] 29 First (79%) or higher 40 41 Nistico et al. [29] 25 First (20%) or higher 40d 53 Climent et al. [30] 14 Second or higher 35d 36 aAfter first cycle, cycles consisted of 3 weeks of treatment with 2 weeks of rest. bAdministered for 6 of 7 weeks. cAdministered for 3 of 4 weeks. dAdministered every week continuously. ePartial remission >50%. Open in new tab Table 1 Activity of weekly docetaxel in phase II clinical trials in metastatic breast cancer Study . n of patients . Line of therapy . Regimen (mg/m2 q wk for 6 of 8 weeks) . Overall response rate (%) . Stemmler et al. [17] 100 First (15%) or higher 35a 42 Jackisch et al. [18] 60 First (6%) or higher 35–40 29 Loeffler et al. [19] 41 Second or higher 40 48 Comandone et al. [20] 40 Second or higher 40b 19 Aihara et al. [21] 37 Second 40c 38 Hainsworth et al. [22] 36 First (75%) or higher 36 36 Stemmler et al. [23] 35 Second or higher 35a 34 Ramos et al. [24] 31 First (29%) or higher 36–40 41 Rittershaus et al. [25] 30 Second or higher 35 13 Lück et al. [26] 30 Third or higher 35d 16 Fornasiero et al. [27] 30 Second or higher 35b 20e Burstein et al. [28] 29 First (79%) or higher 40 41 Nistico et al. [29] 25 First (20%) or higher 40d 53 Climent et al. [30] 14 Second or higher 35d 36 Study . n of patients . Line of therapy . Regimen (mg/m2 q wk for 6 of 8 weeks) . Overall response rate (%) . Stemmler et al. [17] 100 First (15%) or higher 35a 42 Jackisch et al. [18] 60 First (6%) or higher 35–40 29 Loeffler et al. [19] 41 Second or higher 40 48 Comandone et al. [20] 40 Second or higher 40b 19 Aihara et al. [21] 37 Second 40c 38 Hainsworth et al. [22] 36 First (75%) or higher 36 36 Stemmler et al. [23] 35 Second or higher 35a 34 Ramos et al. [24] 31 First (29%) or higher 36–40 41 Rittershaus et al. [25] 30 Second or higher 35 13 Lück et al. [26] 30 Third or higher 35d 16 Fornasiero et al. [27] 30 Second or higher 35b 20e Burstein et al. [28] 29 First (79%) or higher 40 41 Nistico et al. [29] 25 First (20%) or higher 40d 53 Climent et al. [30] 14 Second or higher 35d 36 aAfter first cycle, cycles consisted of 3 weeks of treatment with 2 weeks of rest. bAdministered for 6 of 7 weeks. cAdministered for 3 of 4 weeks. dAdministered every week continuously. ePartial remission >50%. Open in new tab Table 2 Activity of weekly docetaxel in phase II clinical trials in prostate cancer Study . n of patients . Patient population . Regimen (mg/m2/wk for 6 of 8 weeks) . Response rate (%) . Berry et al. [5] 60 HRPC 36 41 (PSA) Beer et al. [6] 25 HRPC 36 46 (PSA) Petrioli et al. [31] 27 HRPC 25a 48 (palliative) Oh et al. [32] 15 High-risk 35b 67 (PSA) Study . n of patients . Patient population . Regimen (mg/m2/wk for 6 of 8 weeks) . Response rate (%) . Berry et al. [5] 60 HRPC 36 41 (PSA) Beer et al. [6] 25 HRPC 36 46 (PSA) Petrioli et al. [31] 27 HRPC 25a 48 (palliative) Oh et al. [32] 15 High-risk 35b 67 (PSA) aAdministered every week continuously. bAdministered weekly in the neoadjuvant setting. Open in new tab Table 2 Activity of weekly docetaxel in phase II clinical trials in prostate cancer Study . n of patients . Patient population . Regimen (mg/m2/wk for 6 of 8 weeks) . Response rate (%) . Berry et al. [5] 60 HRPC 36 41 (PSA) Beer et al. [6] 25 HRPC 36 46 (PSA) Petrioli et al. [31] 27 HRPC 25a 48 (palliative) Oh et al. [32] 15 High-risk 35b 67 (PSA) Study . n of patients . Patient population . Regimen (mg/m2/wk for 6 of 8 weeks) . Response rate (%) . Berry et al. [5] 60 HRPC 36 41 (PSA) Beer et al. [6] 25 HRPC 36 46 (PSA) Petrioli et al. [31] 27 HRPC 25a 48 (palliative) Oh et al. [32] 15 High-risk 35b 67 (PSA) aAdministered every week continuously. bAdministered weekly in the neoadjuvant setting. Open in new tab Table 3 Activity of weekly docetaxel in phase II clinical trials in NSCLC Study . n of patients . Line of therapy . Regimen (mg/m2 q wk for 6 of 8 weeks) . Objective response rate (%) . Hainsworth et al. [33] 39 First 36 18 Serke et al. [34] 36 Second 35 11 Garcia-Lopez et al. [35] 26 Second 43 17.4 Valerio et al. [36] 16 Second or higher 40 12.5 Lilenbaum et al. [37] 30 Second 36 10 Gomez et al. [38] 24 Second or higher 36 22 Petrioli et al. [39] 26 Third 25a 23 Study . n of patients . Line of therapy . Regimen (mg/m2 q wk for 6 of 8 weeks) . Objective response rate (%) . Hainsworth et al. [33] 39 First 36 18 Serke et al. [34] 36 Second 35 11 Garcia-Lopez et al. [35] 26 Second 43 17.4 Valerio et al. [36] 16 Second or higher 40 12.5 Lilenbaum et al. [37] 30 Second 36 10 Gomez et al. [38] 24 Second or higher 36 22 Petrioli et al. [39] 26 Third 25a 23 aAdministered weekly continuously. Open in new tab Table 3 Activity of weekly docetaxel in phase II clinical trials in NSCLC Study . n of patients . Line of therapy . Regimen (mg/m2 q wk for 6 of 8 weeks) . Objective response rate (%) . Hainsworth et al. [33] 39 First 36 18 Serke et al. [34] 36 Second 35 11 Garcia-Lopez et al. [35] 26 Second 43 17.4 Valerio et al. [36] 16 Second or higher 40 12.5 Lilenbaum et al. [37] 30 Second 36 10 Gomez et al. [38] 24 Second or higher 36 22 Petrioli et al. [39] 26 Third 25a 23 Study . n of patients . Line of therapy . Regimen (mg/m2 q wk for 6 of 8 weeks) . Objective response rate (%) . Hainsworth et al. [33] 39 First 36 18 Serke et al. [34] 36 Second 35 11 Garcia-Lopez et al. [35] 26 Second 43 17.4 Valerio et al. [36] 16 Second or higher 40 12.5 Lilenbaum et al. [37] 30 Second 36 10 Gomez et al. [38] 24 Second or higher 36 22 Petrioli et al. [39] 26 Third 25a 23 aAdministered weekly continuously. Open in new tab In phase II trials of women with MBC, weekly docetaxel produced objective responses in 29%–53% of patients when used as first-line or salvage therapy (Table 1) [17–30]. As expected, response rates were slightly lower (range 13%–48%) for patients being treated with second-line or third-line therapy (Table 1) [17–30]. These response rates compare favorably to the response rates seen in the pivotal randomized trials (46% and 30%, with median survival times of 4.3 months and 15 months), which were conducted in patients with MBC previously treated with an anthracycline- or alkylating agent-containing regimen to evaluate docetaxel every 3 weeks [1, 40]. In hormone-refractory prostate cancer (HRPC), prostate-specific antigen (PSA) responses (≥50% decline in PSA lasting at least 4 weeks) were reported in 41%–46% of patients receiving weekly docetaxel in phase II trials (Table 2) [5, 6]. In addition, 48% of patients in two trials had improvements in symptoms [6, 31]. In phase II trials of patients with NSCLC, the objective response rate ranged from 10%–23% in patients with previously treated advanced or metastatic disease and was 18% in chemotherapy-naïve patients (Table 3) [33–39]. Of note, noncomparative trials conducted specifically in older patients or in those with poor performance status scores have shown that the activity and toxicity of weekly docetaxel are similar to those seen in younger patients [22, 33]. These findings are supported by a pooled analysis of data from two trials in HRPC, in which efficacy and tolerability were compared between men 70 years of age and older and those under age 70 [41]. There were no differences in key efficacy and toxicity end points (including PSA and measurable disease response rates, time to progression, overall survival, and incidence and severity of hematologic and nonhematologic toxicities) between younger and older patients, lending support to the use of weekly docetaxel as an effective and well-tolerated alternative for older patients requiring chemotherapy. Randomized comparisons of weekly and q3w docetaxel regimens conducted in patients with NSCLC [11, 12] and MBC [9, 10] demonstrate that clinical activity is maintained with the weekly regimen. The Spanish Lung Cancer Group conducted a phase III trial comparing second-line docetaxel administered at 36 mg/m2 for six consecutive weeks of an 8-week cycle with docetaxel administered at 75 mg/m2 q3w in patients with advanced or metastatic NSCLC [11]. A total of 179 patients with performance status scores ≤2 were enrolled. The response rates were 9% and 11%, respectively, and median overall survival times were similar (6.1 months and 6.3 months, respectively). The incidence of grade 3–4 hematologic toxicities was lower in the weekly arm (14% versus 24%), and leukopenia, dose delays, and dose reductions were more common with q3w dosing. In another randomized phase III trial, docetaxel administered at 33.3 mg/m2/week for 6 weeks followed by 2 weeks rest was compared with docetaxel administered at 75 mg/m2 q3w as second-line treatment in 220 patients with advanced NSCLC [12]. Quality of life (QOL) was the primary end point. Responses were seen in 5.5% and 2.7% of patients, respectively, and median overall survival did not differ between groups (23.9 weeks versus 29.1 weeks, respectively). Rates of grade 3–4 leukopenia, neutropenia, and febrile neutropenia were significantly less with weekly therapy. Although global QOL was not better with the weekly regimen, there were improvements in specific QOL domains, including cognitive function, pain, cough, and hair loss. The levels of activity seen in those trials are similar to those produced with conventional docetaxel schedules (75 mg/m2 q3w) in the phase III second-line registrational trials [3, 4]. Two randomized trials comparing weekly docetaxel with q3w administration have been conducted in patients with MBC. Investigators in Europe compared weekly docetaxel (40 mg/m2/week × 6 followed by 2 weeks rest) with standard docetaxel (100 mg/m2 q3w) in 83 MBC patients [9]. The overall response rates (44% versus 38%) and times to treatment failure (3.7 months versus 4.4 months) were comparable between treatment groups. There were trends toward lower rates of grade 3–4 neutropenia (2.5% versus 17.9%; p = 0.057) and febrile neutropenia (5% versus 17.9%; p = 0.088) that favored weekly docetaxel. Similarly, investigators in Egypt conducted a pilot study to compare weekly docetaxel (35 mg/m2/week × 6 followed by 2 weeks rest) with q3w administration (100 mg/m2) in 30 women with advanced breast cancer [10]. Rates of overall response (87% versus 73%) and median times to progression (5.6 months versus 4.6 months) were similar, and the incidence of neutropenia was significantly lower in the weekly group (p = 0.02). In conclusion, the results of these phase III trials in advanced breast and lung cancer confirm observations from phase II trials, showing similar efficacies and less neutropenia with weekly docetaxel administration schedules. When docetaxel is administered weekly at doses of 30–35 mg/m2, the dose intensity (i.e., mg/m2/week administered) is similar to common q3w dosing schedules. The similar efficacies reported with these two schedules are, therefore, not surprising. Weekly Docetaxel: Tolerability Reviewing the clinical trial data, it is clear that the side-effect profile of docetaxel is better when a lower dose is administered weekly than with a standard q3w dosing. The incidence of hematologic toxicities is less [9–12] and, in randomized trials, there was less fatigue [10], nausea/vomiting [10], diarrhea [11], stomatitis [9], neurotoxicity [9], and fluid retention [9, 10] with weekly dosing than with q3w dosing. Due to better tolerability, weekly dosing is an important alternative administration schedule for docetaxel in elderly patients and in those with a poor performance status. With prolonged treatment administration that is possible due to the superior tolerability profile of weekly docetaxel, other cumulative toxicities emerge. The most commonly reported events relating to weekly docetaxel are identified and management strategies summarized in Table 4. Table 4 Management of toxicity associated with weekly docetaxel Toxicity (Grade ≥2) . Clinical observations . Management . Fatigue (common) Cumulative; highly dose dependent 3 of 4 weeks better than 6 of 8 weeks; consider modest
 dose reduction (e.g., from 35 to 30 mg/m2) Hyperlacrimation (<15%) Cumulative; can result in permanent lacrimal duct stenosis Early ophthalmologic consult; lacrimal duct stint Nail toxicity (<15%) Cumulative; dose dependent Symptomatic management; dose reduction sometimes helpful Alopecia Dose dependent (25 mg/m2, none; 30 mg/m2, occasional; 
 35 mg/m2, common) Select lower initial docetaxel dose if
 problematic Toxicity (Grade ≥2) . Clinical observations . Management . Fatigue (common) Cumulative; highly dose dependent 3 of 4 weeks better than 6 of 8 weeks; consider modest
 dose reduction (e.g., from 35 to 30 mg/m2) Hyperlacrimation (<15%) Cumulative; can result in permanent lacrimal duct stenosis Early ophthalmologic consult; lacrimal duct stint Nail toxicity (<15%) Cumulative; dose dependent Symptomatic management; dose reduction sometimes helpful Alopecia Dose dependent (25 mg/m2, none; 30 mg/m2, occasional; 
 35 mg/m2, common) Select lower initial docetaxel dose if
 problematic Open in new tab Table 4 Management of toxicity associated with weekly docetaxel Toxicity (Grade ≥2) . Clinical observations . Management . Fatigue (common) Cumulative; highly dose dependent 3 of 4 weeks better than 6 of 8 weeks; consider modest
 dose reduction (e.g., from 35 to 30 mg/m2) Hyperlacrimation (<15%) Cumulative; can result in permanent lacrimal duct stenosis Early ophthalmologic consult; lacrimal duct stint Nail toxicity (<15%) Cumulative; dose dependent Symptomatic management; dose reduction sometimes helpful Alopecia Dose dependent (25 mg/m2, none; 30 mg/m2, occasional; 
 35 mg/m2, common) Select lower initial docetaxel dose if
 problematic Toxicity (Grade ≥2) . Clinical observations . Management . Fatigue (common) Cumulative; highly dose dependent 3 of 4 weeks better than 6 of 8 weeks; consider modest
 dose reduction (e.g., from 35 to 30 mg/m2) Hyperlacrimation (<15%) Cumulative; can result in permanent lacrimal duct stenosis Early ophthalmologic consult; lacrimal duct stint Nail toxicity (<15%) Cumulative; dose dependent Symptomatic management; dose reduction sometimes helpful Alopecia Dose dependent (25 mg/m2, none; 30 mg/m2, occasional; 
 35 mg/m2, common) Select lower initial docetaxel dose if
 problematic Open in new tab Fatigue/Asthenia Fatigue is the most common treatment-related toxicity associated with weekly docetaxel therapy. In a phase I study, fatigue/asthenia was the dose-limiting toxicity at a weekly dose of 52 mg/m2/week; 36 mg/m2/week was the dose recommended for phase II trials [14]. In phase II trials, the incidence of grade 3 fatigue has ranged from 2.5%–29% [5, 20, 22, 28, 33, 36], and grade 4 fatigue has been occasionally reported [33, 37]. The occurrence of fatigue is related to the weekly docetaxel dose and duration of therapy. Burstein and colleagues noted that fatigue improved after the dose was reduced from 40 mg/m2/week to 30 mg/m2/week [28]. Lilenbaum and colleagues reported a 33% incidence of grade 3–4 fatigue in their phase II trial, and they noted that most cases occurred at the end of the 6-week treatment cycle [37]. Moreover, fatigue was partially reversible during the 2-week treatment break, leading the authors to hypothesize that altering the treatment schedule to three weekly doses followed by a week of rest may decrease the incidence of fatigue. Aihara and colleagues studied this regimen in patients with MBC, and, in fact, they reported no cases of grade 3–4 fatigue with this schedule [21]. About a third of patients (35%) in that study experienced mild fatigue only. Thus, at this time, we recommend the use of a 3-out-of-4-weeks schedule to minimize the level of fatigue experienced during weekly docetaxel therapy. If fatigue occurs with this dosing schedule, a modest dose reduction often results in substantial improvement [22, 28, 33]. Hyperlacrimation Excessive tearing is generally mild and manageable [15, 16] and usually occurs only after many weeks of therapy [15, 28]. In a phase I trial [15], five patients developed hyperlacrimation at a median cumulative docetaxel dose of 300 mg/m2. However, ophthalmologic exam revealed no abnormalities of the conjunctiva or lacrimal apparatus. Similarly, in a phase II trial in which nearly half the patients (n = 14/29) reported excessive tearing, the onset was related to the length of therapy, occurring at a median cumulative dose of 400 mg/m2, and physical exam revealed no abnormalities [28]. The authors of that study reported that some patients also experienced symptoms of mild conjunctivitis in association with hyperlacrimation; artificial tears/ocular moisturizers helped relieve these symptoms [28]. Anecdotal reports have suggested a role for steroid eyedrops when symptoms are mild; however, no controlled studies of steroids have been completed, and this treatment is ineffective for patients with moderate or severe symptoms. Although hyperlacrimation is generally mild and manageable, it is possible for permanent ocular damage to occur. Recently, researchers have identified canalicular stenosis as the probable cause of weekly docetaxel-associated hyperlacrimation [42]. Fourteen patients with MBC who developed hyperlacrimation during weekly docetaxel therapy were referred for comprehensive ophthalmologic examinations, which included probing and irrigation of the tear drainage apparatus [42]. Hyperlacrimation occurred, on average, after 7 weeks of therapy (range 4–16 weeks), and all patients were experiencing a negative impact on their activities of daily living related to the excessive tearing. Seven patients were found to have moderate canalicular stenosis, and the other seven were found to have severe stenosis. The mean cumulative dose of docetaxel at the time hyperlacrimation was diagnosed was higher in patients with severe stenosis (501 mg/m2) than in those with moderate stenosis (399 mg/m2; p = 0.09). Eleven patients underwent bicanalicular silicone intubation or dacryocystorhinostomy to reverse the lacrimal outflow blockage; surgery was successful in all treated patients. The three patients who refused surgery remained symptomatic. The authors of that study suggested that canalicular stenosis may be caused by the secretion of docetaxel into tears, which results in chronic canalicular inflammation, or by chronic inflammation and subsequent fibrosis of the mucous membranes that line the canaliculi. They also cautioned that once anatomic narrowing of the canaliculi occurs, it appears to be irreversible without surgical intervention. Patients receiving weekly docetaxel should be advised, therefore, to report any ocular changes so that hyperlacrimation can be managed promptly. Early ophthalmologic consultation is recommended, and early intervention may be appropriate. The placement of a lacrimal duct stent is an uncomplicated outpatient procedure that provides palliative benefit and allows continuation of weekly docetaxel. Nail Toxicity Nail bed toxicity, manifested by pain and, occasionally, onycholysis is a bothersome side effect for about 10%–20% of patients treated with weekly docetaxel. It, too, appears to be cumulative and dose dependent. Onycholysis and onychomelanosis, which were preceded by local tenderness, were noted to occur after three to four treatment cycles at the 100-mg/m2 dose level when docetaxel was given on days 1 and 8 of a 3-week cycle in a phase I trial [13]. Grade 2 nail toxicity, defined as pain in the nailbeds or partial or complete loss of the nail on the National Cancer Institute Common Toxicity Criteria scale, was reported in 7%–30% of patients in phase II clinical trials [6, 21, 23, 26, 28, 32]. In only one study was it reported that nail toxicity necessitated discontinuation of weekly docetaxel treatment (n = 1/35) [23]. Although there is no known preventive treatment for onycholysis, a temporary interruption of docetaxel therapy followed by resumption at a lower weekly dose may be helpful. Patients may also benefit from keeping their nails clean and trimmed and wearing protective gloves during cleaning or gardening. The use of a nail hardener at the first sign of any nail weakening may also be beneficial. Alopecia The development of alopecia is dependent on the dose of docetaxel. In early studies, the incidence of alopecia was lower with weekly docetaxel than with traditional q3w dosing [14]. Additionally, the incidence was greatest in those phase I trials that evaluated higher weekly doses of docetaxel. Fifty percent of patients developed grade 2 alopecia when a weekly dose of 40 mg/m2/week or more was administered for several weeks [15], and alopecia occurred in 100% of patients treated with 55 mg/m2 on days 1 and 8 of a 3-week cycle in another phase I trial [13]. However, it was also noted that alopecia could develop later during the course of treatment. One patient developed alopecia after 8 months of weekly dosing [14]. Other patients experience a gradual but cumulative loss of hair during the first 3–4 months of treatment. Severe alopecia is uncommon with weekly docetaxel doses ≤30 mg/m2. Therefore, dosing can be adjusted for patients who have special concerns about this toxicity. Weekly Docetaxel: Steroid Prophylaxis Steroid premedication is recommended with q3w docetaxel administration schedules in order to reduce the incidence and severity of fluid retention as well as the severity of hypersensitivity reactions. The recommended regimen is dexamethasone (Decadron®; Merck & Company, Inc.; West Point, PA) at a dose of 8 mg twice daily for 3 days starting 1 day prior to docetaxel administration. A variety of prophylactic corticosteroid regimens have been selected empirically in clinical trials of weekly docetaxel; however, the weekly use of steroid premedication raises concerns regarding several steroid-related side effects, including iatrogenic Cushing's syndrome, hyperglycemia, and opportunistic infections. Most clinical trials with weekly docetaxel have used dexamethasone at doses of 4–8 mg given orally every 12 hours for three doses, beginning the evening before docetaxel administration. Since edema and fluid retention have been rarely reported in association with weekly docetaxel, there has been interest in reducing the steroid prophylaxis used in this setting. In one recent trial, steroid prophylaxis was compared with no prophylaxis in patients receiving weekly docetaxel for MBC [17]. A total of 34 patients were randomized to weekly docetaxel (35 mg/m2/week for 6 weeks followed by 2 weeks rest, with additional cycles given for three consecutive weeks followed by 2 weeks rest) with dexamethasone (8 mg prior to docetaxel) or no steroid premedication. Another 76 patients received weekly docetaxel with dexamethasone prophylaxis in a nonrandomized fashion. The identical docetaxel-related toxicities were then compared in the 93 patients who received prophylaxis versus the 17 patients who did not. Dexamethasone prophylaxis was associated with a lower incidence of several nonhematologic toxicities, including nail changes (13% versus 35%; p = 0.004), fluid retention (3% versus 12%; p = 0.017), and conjunctivitis or hyperlacrimation (10% versus 18%; not significant). The incidence of infection was not increased by corticosteroid treatment. These findings demonstrate the continued importance of steroid prophylaxis; however, a single 8-mg dexamethasone dose given prior to weekly docetaxel is effective for minimizing nonhematologic toxicities. We are currently using a single dose of dexamethasone (4–8 mg i.v. or orally) administered prior to each weekly docetaxel dose at our center. Conclusion Docetaxel can be safely administered on a weekly basis as an alternative to traditional q3w dosing. In randomized trials published to date, weekly dosing is as effective as traditional q3w dosing. Moreover, weekly dosing is associated with a significantly better tolerability profile. Myelosuppression is dramatically less, which may be particularly important for patients being treated with palliative intent, as well as for older patients and patients with poor performance statuses. Trials conducted in older patients and in patients with poor performance statuses demonstrate that weekly docetaxel is a safe and effective option for these patients. Because of the favorable tolerability profile, weekly docetaxel is being studied in combination with other chemotherapeutic agents in various tumor types. For some patients, the greater number of office visits to receive weekly docetaxel (as opposed to q3w docetaxel) may make this schedule less attractive. However, the superior toxicity profile with weekly docetaxel usually offsets this less convenient schedule. As a single agent, weekly docetaxel has shown activity in advanced lung cancer, metastatic breast cancer, and prostate cancer. Most of the common toxicities associated with weekly dosing, such as fatigue, excessive tearing, nail changes, and alopecia, are cumulative toxicities, and are related both to the weekly dose administered and to the total cumulative docetaxel dose. Most of these side effects can be managed or minimized by making minor changes in the docetaxel dose or schedule. Thus, weekly docetaxel, with its high level of clinical activity and superior tolerability profile, provides an excellent therapeutic alternative to standard chemotherapy dosing. Results of ongoing clinical trials that incorporate weekly docetaxel into combination regimens and others that compare it with traditional dosing will further aid in our understanding of its role in cancer therapy. Acknowledgments Support came from Aventis Pharmaceuticals Inc., Bridgewater, NJ. References 1 S Chan , K Friedrichs, D Noel et al. Prospective randomized trial of docetaxel versus doxorubicin in patients with metastatic breast cancer . J Clin Oncol 1999 ; 17 : 2341 – 2354 . Google Scholar Crossref Search ADS PubMed WorldCat 2 M Martin , T Pienkowski, J Mackey et al. 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Google Scholar Crossref Search ADS PubMed WorldCat © 2004 AlphaMed Press This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)
TI - Practical Aspects of Weekly Docetaxel Administration Schedules
JF - The Oncologist
DO - 10.1634/theoncologist.9-5-538
DA - 2004-09-01
UR - https://www.deepdyve.com/lp/oxford-university-press/practical-aspects-of-weekly-docetaxel-administration-schedules-luc5WOx7q7
SP - 538
EP - 545
VL - 9
IS - 5
DP - DeepDyve
ER -