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Second-Line Chemotherapy with a Modified Schedule of Docetaxel in Elderly Patients with Advanced-Stage Non-Small-Cell Lung Cancer
original contribution Second-Line Chemotherapy with a Modified Schedule of Docetaxel in Elderly Patients with Advanced-Stage Non−Small-Cell Lung Cancer Carmelo Tibaldi,1 Ilaria Bernardini,1 Antonio Chella,2 Francesa Russo,1 Enrico Vasile,1 Michele Malventi,3 Alfredo Falcone1,4 Abstract PURPOSE: In patients with advanced-stage non−small-cell lung cancer (NSCLC) pretreated with chemotherapy, docetaxel 75 mg/m2 every 3 weeks prolongs survival compared with best supportive care alone or chemotherapy with ifosfamide or vinorelbine. Neutropenia is the dose-limiting toxicity of this schedule, and thus limits its use in elderly patients. Therefore, we studied a modified schedule of docetaxel in order to reduce the toxicity of this regimen and to improve the compliance to treatment in an elderly population, while maintaining the same dose intensity of the original regimen. PATIENTS AND METHODS: Thirty-three elderly patients (aged ≥ 70 years) with advanced-stage NSCLC, Eastern Cooperative Oncology Group performance status 0-2, and a median age of 74 years (range, 70-83 years) who had progressed after 1 line of chemotherapy were treated with docetaxel 37.5 mg/m2 on days 1 and 8 every 3 weeks for a maximum of 6 courses. RESULTS: Seven of 33 patients (21.2%; 95% confidence interval, 8.98%-38.91%) exhibited a partial response (according to the intent-to-treat analysis), 12 patients (36.3%) exhibited stable disease, and 14 patients (42.4%) exhibited progression. Grade 3 (National Cancer Institute Common Toxicity Criteria) neutropenia and anemia were observed in 9% and 3% of patients, respectively. The main nonhematologic toxicity consisted of grade 3 nausea/vomiting, diarrhea, and asthenia in 6% of patients each, and grade 3 nail toxicity in 3% of patients. CONCLUSION: Our modified schedule of docetaxel is an active and well-tolerated second-line treatment in elderly patients with advanced-stage NSCLC and has a favorable toxicity profile. Clinical Lung Cancer, Vol. 7, No. 6, 401-405, 2006
Introduction Lung cancer is the leading cause of cancer-related deaths in Western countries. Non−small-cell lung cancer (NSCLC) accounts for > 80% of primary lung cancers, and approximately two thirds of patients with NSCLC are in an advanced stage at diagnosis.1 Most malignancies, including lung cancer, occur in elderly patients, with almost 30% diagnosed in patients aged > 70 years.2 The role of second-line chemotherapy after initial Division of Medical Oncology, Civil Hospital, Livorno, Italy Division of Pneumology, Cisanello Hospital, Pisa, Italy 3Division of Radiology, Civil Hospital, Livorno, Italy 4Department of Oncology, Transplants and Advanced Technologies, University of Pisa, Italy 1 2
Submitted: Feb 20, 2006; Revised: Mar 23, 2006; Accepted: Apr 5, 2006 Address for correspondence: Carmelo Tibaldi, MD, U.O. Oncologia Medica, Presidio Ospedaliero, Viale Alfieri, 36, 57100 Livorno, Italy Fax: 39-586-223457; e-mail: [email protected]
Key words: Best supportive care, Dexamethasone, Performance status, Toxicity treatment remained largely undefined until the final data of 2 randomized phase III trials were published. In the first trial, reported by Shepherd et al, 204 patients with advanced-stage NSCLC, who were previously treated with ≥ 1 platinum-based chemotherapy regimen, were randomized to receive docetaxel 100 mg/m2 (n = 49), docetaxel 75 mg/m2 (n = 55), or best supportive care (n = 100).3 Overall survival was significantly longer for patients receiving docetaxel than for those receiving best supportive care (7 months vs. 4.6 months; P = 0.047); the 1-year survival rates for chemotherapy and best supportive care were 29% and 19%, respectively. The difference was more pronounced for docetaxel 75 mg/m2 compared with best supportive care (7.5 months vs. 4.6 months; P = 0.01; 1-year survival, 37% vs. 11%; P = 0.003). In the second trial, reported by Fossella et al, 373 patients were randomized to receive docetaxel 100 mg/m2 (n = 125), docetaxel 75 mg/m2 (n = 125), or a control regimen consisting of vinorelbine or
Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by CIG Media Group, LP, ISSN #1525-7304, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA 978-750-8400.
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Modified Schedule of Docetaxel in Advanced-Stage NSCLC ifosfamide (n = 123).4 Patients who received docetaxel had a longer time to progression (TTP) and a greater progression-free survival at 26 weeks; the 1-year survival was significantly greater with docetaxel 75 mg/m2 than with the control treatment (32% vs. 19%; P = 0.025). In light of these results, docetaxel 75 mg/m2 became the standard treatment of advanced-stage NSCLC in the second-line setting. Grade 3/4 neutropenia was the most important toxicity reported by both trials and occurred with docetaxel 75 mg/m2 in 67.3% of patients in the first trial and in 54% of patients (grade 4 neutropenia) in the second. Febrile neutropenia was reported in 1.8% and 8% of the patients, respectively. Grade 3/4 asthenia was the main nonhematologic side effect and was observed in 11% and 18% of patients. Although there was no age limit for enrollment in either trial, the median age of the patients was 61 years (range, 37-73 years) and 59 years (range not reported), respectively.3,4 Moreover, neither trial reported the number of enrolled patients aged > 70 years. In this subset of elderly patients, a treatment with docetaxel 75 mg/m2 every 3 weeks could be too toxic because of the age-related reduction in bone marrow reserves in these patients and the potential enhanced risk of hematologic toxicity. On this basis, we carried out a phase II study in patients aged ≥ 70 years with advanced-stage NSCLC who had progressed after 1 line of chemotherapy. A modified schedule of docetaxel was used to study the activity and toxicity of this treatment while maintaining the same dose intensity as the original regimen.
Patients and Methods Patient Selection Criteria Patients aged ≥ 70 years with histologically or cytologically confirmed NSCLC who had been pretreated with 1 line of chemotherapy and had measurable clinical stage IIIB disease (cytologically positive pleural effusion or metastatic supraclavicular lymph nodes) or stage IV disease were eligible if they met the following criteria: Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 2, life expectancy > 3 months, adequate bone marrow reserve (leukocyte count ≥ 4,000/μL; platelet count ≥ 100,000/μL), adequate hepatic function (bilirubin level ≤ 1.5 mg/dL), and renal function (creatinine level ≤ 1.5 mg/dL). Previous radiation therapy was allowed provided that the irradiated area was not the only source of measurable disease and that radiation therapy had been completed before chemotherapy was initiated. Patients were excluded for the presence of active infections, concomitant malignancy or a second primary malignancy except in situ carcinoma of the cervix or adequately treated basal cell carcinoma of the skin, recent myocardial infarction, unstable angina, symptomatic brain metastases, or hypercalcemia. A written informed consent was obtained from each patient before enrollment. The protocol was approved by the internal review board of our institution, and the trial was conducted according to the Declaration of Helsinki of the World Medical Association. Treatment The chemotherapy regimen consisted of docetaxel 37.5 mg/m2 in 500 mL of normal saline administered intravenously over
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60 minutes on days 1 and 8 every 3 weeks for a maximum of 6 courses. Premedication consisted of 20 mg dexamethasone intravenously and 5-hydroxytryptamine-3 receptor antagonists as antiemetic prophylaxis. Patients whose white blood cell count, neutrophil count, and platelet count were ≥ 3500/μL, 1500/μL, and 100,000/μL, respectively, received chemotherapy on day 1. In patients with white blood cell count, neutrophil count, and platelet count < 3500/μL, 1500/μL, and 100,000/μL, respectively, administration of docetaxel was delayed 1 week or until recovery. A dose delay for > 3 weeks resulted in withdrawal from the study. The dose of docetaxel was modified on day 8 according to hematologic and nonhematologic toxicities as follows: if neutrophil count was > 1500/μL and platelet count was > 100,000/μL, docetaxel was administered at full dose; for neutrophil count 1000-1490/μL or platelet count 75,00099,000/μL, the docetaxel dose was reduced by 25%; for neutrophil count 500-990/μL or platelet count 50,000-74,000/μL, docetaxel was reduced by 50%; for neutrophil count < 500/μL or platelet count < 50,000/μL, docetaxel was omitted. If grade 2 (National Cancer Institute Common Toxicity Criteria [NCI-CTC])5 nonhematologic toxicity (except for alopecia) was observed, the dose of docetaxel was omitted until resolution and then administered at the next cycle with doses reduced by 25%-50%. In case of grade 2 neurologic toxicity or grade 4 nonhematologic toxicity, the patient was withdrawn from the study. The planned dose intensity of the study was 25 mg/m2 per week. Delivered dose intensity, expressed as mg/m2 per week, was defined as the ratio of the actual total dose received in relation to the duration (number of weeks) of treatment. Relative dose intensity was expressed as the ratio of delivered dose intensity in relation to the planned dose intensity. Evaluation Criteria Pretreatment evaluation included medical history, physical examination, assessment of PS, complete blood cell count with differential, routine chemistry, chest radiograph, and computed tomography (CT) scan of the chest and abdomen. During treatment, a complete blood cell count was performed weekly. Eastern Cooperative Oncology Group PS was evaluated at each cycle. Assessment of tumor response was carried out with CT scan every 3 cycles. Responses were assessed using standard Response Evalutaion Criteria in Solid Tumors.6 Patients were considered evaluable for response if they had received ≥ 3 courses of chemotherapy. The best overall response for each patient was reported, and all responses were reviewed by an independent radiologist and had to be confirmed ≥ 28 days after the initial documentation of response. Hematologic toxicity was recorded weekly, and nonhematologic toxicities were recorded on days 1 and 8 of every course of treatment. The worst toxicity grade for each patient in all cycles was reported. Toxicities were assessed using NCI-CTC, version 2.0.5 Statisical Analysis Because overall response rate was the target, Simon’s optimal 2-stage design for phase II trials was used to calculate the sample size: with α = 0.05 and β = 0.2, p0 (clinically uninteresting true response rate) and p1 (sufficiently promising true response rate)
Carmelo Tibaldi et al Table 1 Patient Characteristics (N = 33) Characteristic Median Age, Years (Range)
Value (%)
Figure 1 Kaplan-Meier Curve of Overall Survival and Time to Progression
74 (70-83)
100 Median TTP, 4 Months (95% CI, 2.5-5.7)
Sex 29 (88)
Female
4 (12)
ECOG PS 0
3 (9)
1
22 (67)
2
8 (24)
80 Probability (%)
Male
Median OS, 6 Months (95% CI, 4-9.7)
60 40 20
Histology Adenocarcinoma
10 (30)
Squamous cell
15 (46)
Other*
8 (24)
0
5
10
15
20
Months
First-line Chemotherapy Platinum-based doublets
17 (52)
Monotherapy (Gemcitabine or Vinorelbine)
16 (49)
Response to First-Line Chemotherapy Partial response
12 (36)
Stable disease
6 (18)
Progressive disease
15 (46)
Number of Metastatic Sites 1
2 (6)
2
15 (46)
3
16 (49)
Number of Comorbidities 0
5 (15)
1
12 (36)
2
7 (21)
3
9 (27)
*Other histologies included large-cell carcinoma and undifferentiated NSCLC.
were set at 5% and 20%, respectively. The drug combination was considered of interest if ≥ 3 responses were observed out of 29 evaluable patients. Time to progression was calculated from the date of registration to the date of clinical and/or radiologic evidence of progression or death, whichever occurred first. Survival was calculated from registration to death or last follow-up. Survival and TTP were estimated using the KaplanMeier method.7 Data were analysed using SPSS/PC version 11.5 statistics software.
Results Patient Characteristics From July 2002 to February 2005, a total of 33 patients entered the study. Twenty-nine patients (88%) were men, and 4 (12%) were women; median age was 74 years (range, 70-83 years). Three patients (9%) had PS 0, 22 patients (67%) had PS 1, and 8 patients (24%) had PS 2. Squamous cell carcinoma was the most frequent histology (n = 15); 10 patients had adeno-
Abbreviations: CI = confidence interval; OS = overall survival
carcinoma, 4 patients had large-cell carcinoma, and 4 patients had undifferentiated NSCLC. All patients had stage IV disease. Patient characteristics are summarized in Table 1. Dose Administration Thirty-three patients received a total of 132 cycles. The median number of courses was 4 (range, 1-6 courses). The delivered dose intensity was 20.6 mg/m2 per week, and the relative dose intensity was 82.4%. Twenty treatment delays (15% of the courses) were reported. The reasons for the delays were 4 episodes of grade 2 mucositis, 1 episode of grade 3 diarrhea, 2 episodes of grade 2 diarrhea, 2 episodes of grade 2 skin toxicity, and 7 other reasons not related to toxicity. Only 2 patients discontinued treatment because of grade 3 diarrhea and allergic reaction to docetaxel. The docetaxel dose was reduced by 25% in 20 administrations and by 50% in 2 administrations. Response and Survival Twenty-nine patients were evaluable for response. Four patients were not evaluable for the following reasons: 1 patient refused to continue chemotherapy after the first cycle, 1 patient reported herpes zoster syndrome and discontinued treatment before the first evaluation, 1 patient experienced an allergic reaction after the second administration of docetaxel and discontinued treatment. We observed 1 early death during the first month of chemotherapy that was not correlated to toxicity but presumably to tumor progression. Overall response rate according to the intent-to-treat analysis was 21.2% (7 of 33 patients; 95% confidence interval, 8.98%38.91%); 12 patients (36.3%) had stable disease, and 14 patients (42.5%) had progressive disease. Among the patients with PS 2, we observed 3 with partial response, 1 with stable disease, and 4 with progressive disease. Median TTP was 4 months (range, 1-24 months), and median duration of survival was 6 months (range, 1-24 months). The 1-year survival rate was 22.2% (Figure 1).
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Modified Schedule of Docetaxel in Advanced-Stage NSCLC Table 2
Hematologic and Nonhematologic Toxicity Per Patient Grade 1
Grade 2
Grade 3
Neutropenia
Toxicity
6
3
9
Thrombocytopenia
3
0
0
Anemia
27
18
3
Nausea/Vomiting
36
3
6
Diarrhea
36
21
6
Mucositis
42
24
0
Asthenia
45
21
6
Nail Toxicity
15
0
3
Skin Toxicity
3
3
0
Table 3 Hematologic Toxicity in Trials with Weekly and Every-3-Week Docetaxel Grade 3/4 Toxicity (%) Study Tibaldi
Gridelli et al13
Camps et al14
Values are percentages. There were no grade 4 toxicities. Patients were graded according to the NCI-CTC.
Toxicity All patients were evaluable for toxicity. Observed toxicities were mild with good compliance to treatment. No grade 4 hematologic toxicity was observed, and grade 3 neutropenia and anemia were reported in 9% and 3% of patients, respectively. No patients developed febrile neutropenia or hemorrhages. Nonhematologic toxicity consisted mainly of grade 3 nausea/ vomiting, grade 3 diarrhea, grade 3 asthenia occurring in 6% of patients, and grade 3 nail toxicity occurring in 3% of patients. No treatment-related deaths occurred. Patients with PS 2 had comparable grade 3/4 toxicity (1 episode of grade 3 diarrhea and 1 episode of grade 3 anemia). Hematologic and nonhematologic toxicities are summarized in Table 2.
Discussion Docetaxel 75 mg/m2 once every 3 weeks is considered the standard of care in second-line treatment of advanced-stage NSCLC8; however, severe myelosuppression is common and a concern. Because of myelosuppression, there is a subset of patients who are not expected to tolerate the full-dose every3-week regimen. In general, these patients have a poor PS, comorbidities, and poor hematologic reserve, similar to many elderly patients. Futhermore, tolerability data of docetaxel at a full-dose every-3-week regimen in elderly patients with NSCLC are inconsistent or lacking. In our study, a modified schedule of docetaxel proved to be active and showed an interesting response rate of 21.2% (95% confidence interval, 8.98%-38.91%) that was in line with the activity data of the initial phase II studies carried out with docetaxel at 75-100 mg/m2 once every 3 weeks.9-12 Although the planned dose intensity of our regimen was the same as in the original every-3-week regimen (25 mg/m2 per week), the observed hematologic toxicities were mild and acceptable with grade 3 neutropenia and anemia occurring in only 9% and 3% of patients, respectively. Nonhematologic toxicities consisted of grade 3 nausea/vomiting, diarrhea, and asthenia in 6% of patients and grade 3 nail toxicity in 3% of patients. The favorable toxicity profile of our schedule produced good compliance to the treatment and, consequently, an optimal relative
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Schuette et al15
Gervais et al17
Regimen 37.5 mg/m2 for 2
Neutropenia Thrombocytopenia Anemia 9
0
3
33.3 mg/m2 for 6 weeks every 8 weeks
2
1
0
75 mg/m2 every 3 weeks
19
1
3
36 mg/m2 for 6 weeks every 8 weeks
4
1
6
75 mg/m2 every 3 weeks
12
0
3
35 mg/m2 for 3 weeks every 4 weeks
5
0
1
75 mg/m2 every 3 weeks
21
0
6
40 mg/m2 for 6 weeks every 8 weeks
16
NR
13
75 mg/m2 every 3 weeks
48
NR
10
weeks every 3 weeks
Abbreviation: NR = not reported Patients were graded according to the NCI-CTC.
dose intensity of docetaxel equal to 82.4%. It is noteworthy that these tolerability data were observed in an unselected patient population, 24% of whom had poor general conditions (PS 2). Our tolerability data are consistent with those reported in recent randomized phase III trials that compared docetaxel 75 mg/m2 every 3 weeks with a weekly schedule in second-line advanced-stage NSCLC. In the first trial, reported by Gridelli et al, 220 patients with advanced-stage NSCLC, aged < 75 years (median age, 63 years), were randomized to receive docetaxel 75 mg/m2 on day 1 every 3 weeks for 6 cycles or docetaxel 33.3 mg/m2 for 6 weeks followed by 2 weeks of rest for 2 cycles. The primary endpoint of the study was quality of life (QOL). Quality of life patterns generally favored the weekly arm; the every-3-week docetaxel regimen caused more leukopenia, neutropenia, febrile neutropenia, and hair loss.13 The second trial, carried out by the Spanish Lung Cancer Group, randomized 246 patients (median age, 62.3 years) to docetaxel 75 mg/m2 once every 3 weeks or docetaxel 36 mg/m2 for 6 weeks in an 8-week course; median survival, the primary endpoint of the study, was equivalent in both arms. Grade 3/4 leukopenia and neutropenia were more frequent in the every-3-week arm than in the weekly arm (11% vs. 4.5% and 8.8% vs. 2.3%, respectively).14 Overall survival was also the primary endpoint of the third trial, which compared docetaxel 75 mg/m2 once every 3 weeks with docetaxel 35 mg/m2 for 3 weeks, followed by 1 week without therapy, in 215 patients (median age, 63 years).15 These data also indicated that there was similar efficacy with weekly docetaxel but significantly less severe toxicity in terms of leukopenia, neutropenia, and anemia. Severe fatigue was the most common complaint after weekly treatment and occurred mainly at the end of the 6 consecutive treatment weeks and
Carmelo Tibaldi et al partly regressed during the 2-week rest interval.16 However, it is not clear whether the incidence of fatigue is actually increased by the weekly schedule. Indeed, studies from Gridelli et al and Camps et al observed no difference in the incidence of asthenia between the 2 schedules.13,14 In contrast, Gervais et al reported that severe asthenia was more common with the weekly regimen (11.1% vs. 4.8%; Table 3).17 In a phase II study carried out with weekly docetaxel as first-line chemotherapy in elderly patients with advanced-stage NSCLC, severe asthenia was reported in 50% of patients.18 In our study we observed severe asthenia (grade 3) in only 6% of patients. Our toxicity data are comparable with those observed in a randomized phase II study carried out in elderly patients and/or patients with poor PS NSCLC who are chemotherapynaive treated with docetaxel weekly or every 3 weeks.19 Another important aspect of our regimen is that, with respect to the 8-week schedule, the number of admissions to the hospital is lower, and this is remarkable especially in the elderly population; likewise, the incidence of corticosteroid-related complications caused by premedication (eg, hyperglycaemia or peptic/duodenal ulcers) was reduced. Recently, in a large phase III study involving 571 patients, a new drug, pemetrexed, was found equivalent to every-3-week docetaxel as second-line treatment for advanced-stage NSCLC.20 In this study by Hanna et al, survival, response rate, and QOL results were similar, but pemetrexed was less toxic. Severe myelosuppresion was significantly lower in the pemetrexed arm than in the docetaxel arm, so this drug could be of interest for treatment of elderly patients. Notably, patients receiving pemetrexed required regular folic acid and vitamin B12 supplements to reduce hematologic and nonhematologic toxicity.
Conclusion Our modified schedule of docetaxel is an active and well-tolerated treatment regimen in elderly patients with advanced-stage NSCLC who are candidates for second-line chemotherapy, and could represent a valuable choice. Future trials should better define the best strategy in terms of efficacy, toxicity, QOL, and economic analysis in this subset of elderly patients with NSCLC.
References 1. Parkin DM. Global cancer statistics in the year 2000. Lancet Oncol 2001; 2:533-543. 2. Lee-chiong TL Jr, Matthay RA. Lung cancer in the elderly patient. Clin Chest Med 1993; 14:453-478. 3. Shepherd FA, Dancey J, Damlau R, et al. Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol 2000; 18:2095-2103. 4. Fossella FV, Devore R, Kerr RN, et al. Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small-cell lung cancer previously treated with platinum-containing chemotherapy regimens. J Clin Oncol 2000; 18:2354-2362. 5. National Cancer Institute. Cancer therapy evaluation programs (CTEP) common toxicity criteria-version 2.0. Bethesda (MD) (1999): Division of cancer treatment and diagnosis, national cancer institute. Available at: http://ctep.cancer.gov/reporting/ctc. html. Accessed January 2002. 6. Therasse P, Arbuck G, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 2000; 92:205-216. 7. Kaplan E, Meier P. Non-parametric estimation from incomplete observations. J Am Stat Assoc 1993; 53:1245-1252. 8. Pfister DG, Johnson DH, Azzoli CG, et al. American society of clinical oncology treatment of unresectable non-small-cell-lung cancer guideline: update 2003. J Clin Oncol 2004; 22:330-353. 9. Fossella FV, Lee JS, Shin DM, et al. Phase II study of docetaxel for advanced or metastatic platinum-refractory non-small-cell lung cancer. J Clin Oncol 1995; 13:645-651. 10. Gandara DR, Vokes E, Green M, et al. Activity of docetaxel in platinum treated non small cell lung cancer: Results of a phase II multicenter trial. J Clin Oncol 2000; 18:131-135. 11. Alexopoulos K, Kouroussis C, Androulakis N, et al. Docetaxel and granulocyte colony-stimulating factor in patients with advanced non small cell lung cancer previously treated with platinum-based chemotherapy; a multicenter phase II trial. Cancer Chemother Pharmacol 1999; 43:257-262. 12. Gridelli C, Frontini l, Barletta E, et al. Single agent docetaxel plus granulocyte-colony stimulating factor (G-CSF) in previously treated patients with advanced non small cell lung cancer. A phase II study and review of the literature. Anticancer Res 2000; 20:1077-1084. 13. Gridelli C, Gallo C, Di Maio M, et al. A randomized clinical trial of two docetaxel regimens (weekly vs 3 week) in the second-line treatment of non small cell lung cancer. The distal 01 study. Br J Cancer 2004; 91:1996-2004. 14. Camps C, Massutti B, Jimenez AM, et al. Randomized phase III study of 3-weekly versus weekly docetaxel in pretreated advanced non-small-cell lung cancer: a Spanish Lung Cancer Group trial. Ann Oncol 2006; 17:467-472. 15. Schuette W, Nagel S, Blankenburg T, et al. Phase III study of second-line chemotherapy for advanced non-small-cell lung cancer with weekly compared with 3-weekly docetaxel. J Clin Oncol 2005; 23:8389-8395. 16. Engels FK, Verweij J. Docetaxel administration schedule: from fever to tears? A review of randomised studies. Eur J Cancer 2005; 41:1117-1126. 17. Gervais R, Ducolone A, Breton JL, et al. Phase II randomized trial comparing docetaxel given every 3 weeks with weekly schedule as second-line therapy in patients with advanced non-small-cell lung cancer (NSCLC). Ann Oncol 2005; 16:90-96. 18. Le Caer H, Gimenez C, Fournel P, et al. A multicenter phase II study of docetaxel (D) or docetaxel/gemcitabine (G) weekly in advanced non-small cell lung cancer (NSCLC) in elderly and/or poor performance status (PS) patients (pts). (GFPC 0202). J Clin Oncol 2005; 23(16 suppl):657s (Abstract #7150). 19. Lilenbaum R, Rubin M, Samuel J, et al. A phase II randomized trial of docetaxel weekly or every 3 weeks in elderly and/or poor performance status (PS) patients (pts) with advanced non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 2004; 23:627 (Abstract # 7057). 20. Hanna N, Shepherd FA, Fossella FV, et al. Randomized phase III trial of pemetrexed versus docetaxel in patients with non small cell lung cancer previously treated with chemotherapy. J Clin Oncol 2004; 22:1589-1597.
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Introduction Lung cancer is the leading cause of cancer-related deaths in Western countries. Non−small-cell lung cancer (NSCLC) accounts for > 80% of primary lung cancers, and approximately two thirds of patients with NSCLC are in an advanced stage at diagnosis.1 Most malignancies, including lung cancer, occur in elderly patients, with almost 30% diagnosed in patients aged > 70 years.2 The role of second-line chemotherapy after initial Division of Medical Oncology, Civil Hospital, Livorno, Italy Division of Pneumology, Cisanello Hospital, Pisa, Italy 3Division of Radiology, Civil Hospital, Livorno, Italy 4Department of Oncology, Transplants and Advanced Technologies, University of Pisa, Italy 1 2
Submitted: Feb 20, 2006; Revised: Mar 23, 2006; Accepted: Apr 5, 2006 Address for correspondence: Carmelo Tibaldi, MD, U.O. Oncologia Medica, Presidio Ospedaliero, Viale Alfieri, 36, 57100 Livorno, Italy Fax: 39-586-223457; e-mail: [email protected]
Key words: Best supportive care, Dexamethasone, Performance status, Toxicity treatment remained largely undefined until the final data of 2 randomized phase III trials were published. In the first trial, reported by Shepherd et al, 204 patients with advanced-stage NSCLC, who were previously treated with ≥ 1 platinum-based chemotherapy regimen, were randomized to receive docetaxel 100 mg/m2 (n = 49), docetaxel 75 mg/m2 (n = 55), or best supportive care (n = 100).3 Overall survival was significantly longer for patients receiving docetaxel than for those receiving best supportive care (7 months vs. 4.6 months; P = 0.047); the 1-year survival rates for chemotherapy and best supportive care were 29% and 19%, respectively. The difference was more pronounced for docetaxel 75 mg/m2 compared with best supportive care (7.5 months vs. 4.6 months; P = 0.01; 1-year survival, 37% vs. 11%; P = 0.003). In the second trial, reported by Fossella et al, 373 patients were randomized to receive docetaxel 100 mg/m2 (n = 125), docetaxel 75 mg/m2 (n = 125), or a control regimen consisting of vinorelbine or
Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by CIG Media Group, LP, ISSN #1525-7304, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA 978-750-8400.
Clinical Lung Cancer May 2006
401
Modified Schedule of Docetaxel in Advanced-Stage NSCLC ifosfamide (n = 123).4 Patients who received docetaxel had a longer time to progression (TTP) and a greater progression-free survival at 26 weeks; the 1-year survival was significantly greater with docetaxel 75 mg/m2 than with the control treatment (32% vs. 19%; P = 0.025). In light of these results, docetaxel 75 mg/m2 became the standard treatment of advanced-stage NSCLC in the second-line setting. Grade 3/4 neutropenia was the most important toxicity reported by both trials and occurred with docetaxel 75 mg/m2 in 67.3% of patients in the first trial and in 54% of patients (grade 4 neutropenia) in the second. Febrile neutropenia was reported in 1.8% and 8% of the patients, respectively. Grade 3/4 asthenia was the main nonhematologic side effect and was observed in 11% and 18% of patients. Although there was no age limit for enrollment in either trial, the median age of the patients was 61 years (range, 37-73 years) and 59 years (range not reported), respectively.3,4 Moreover, neither trial reported the number of enrolled patients aged > 70 years. In this subset of elderly patients, a treatment with docetaxel 75 mg/m2 every 3 weeks could be too toxic because of the age-related reduction in bone marrow reserves in these patients and the potential enhanced risk of hematologic toxicity. On this basis, we carried out a phase II study in patients aged ≥ 70 years with advanced-stage NSCLC who had progressed after 1 line of chemotherapy. A modified schedule of docetaxel was used to study the activity and toxicity of this treatment while maintaining the same dose intensity as the original regimen.
Patients and Methods Patient Selection Criteria Patients aged ≥ 70 years with histologically or cytologically confirmed NSCLC who had been pretreated with 1 line of chemotherapy and had measurable clinical stage IIIB disease (cytologically positive pleural effusion or metastatic supraclavicular lymph nodes) or stage IV disease were eligible if they met the following criteria: Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 2, life expectancy > 3 months, adequate bone marrow reserve (leukocyte count ≥ 4,000/μL; platelet count ≥ 100,000/μL), adequate hepatic function (bilirubin level ≤ 1.5 mg/dL), and renal function (creatinine level ≤ 1.5 mg/dL). Previous radiation therapy was allowed provided that the irradiated area was not the only source of measurable disease and that radiation therapy had been completed before chemotherapy was initiated. Patients were excluded for the presence of active infections, concomitant malignancy or a second primary malignancy except in situ carcinoma of the cervix or adequately treated basal cell carcinoma of the skin, recent myocardial infarction, unstable angina, symptomatic brain metastases, or hypercalcemia. A written informed consent was obtained from each patient before enrollment. The protocol was approved by the internal review board of our institution, and the trial was conducted according to the Declaration of Helsinki of the World Medical Association. Treatment The chemotherapy regimen consisted of docetaxel 37.5 mg/m2 in 500 mL of normal saline administered intravenously over
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60 minutes on days 1 and 8 every 3 weeks for a maximum of 6 courses. Premedication consisted of 20 mg dexamethasone intravenously and 5-hydroxytryptamine-3 receptor antagonists as antiemetic prophylaxis. Patients whose white blood cell count, neutrophil count, and platelet count were ≥ 3500/μL, 1500/μL, and 100,000/μL, respectively, received chemotherapy on day 1. In patients with white blood cell count, neutrophil count, and platelet count < 3500/μL, 1500/μL, and 100,000/μL, respectively, administration of docetaxel was delayed 1 week or until recovery. A dose delay for > 3 weeks resulted in withdrawal from the study. The dose of docetaxel was modified on day 8 according to hematologic and nonhematologic toxicities as follows: if neutrophil count was > 1500/μL and platelet count was > 100,000/μL, docetaxel was administered at full dose; for neutrophil count 1000-1490/μL or platelet count 75,00099,000/μL, the docetaxel dose was reduced by 25%; for neutrophil count 500-990/μL or platelet count 50,000-74,000/μL, docetaxel was reduced by 50%; for neutrophil count < 500/μL or platelet count < 50,000/μL, docetaxel was omitted. If grade 2 (National Cancer Institute Common Toxicity Criteria [NCI-CTC])5 nonhematologic toxicity (except for alopecia) was observed, the dose of docetaxel was omitted until resolution and then administered at the next cycle with doses reduced by 25%-50%. In case of grade 2 neurologic toxicity or grade 4 nonhematologic toxicity, the patient was withdrawn from the study. The planned dose intensity of the study was 25 mg/m2 per week. Delivered dose intensity, expressed as mg/m2 per week, was defined as the ratio of the actual total dose received in relation to the duration (number of weeks) of treatment. Relative dose intensity was expressed as the ratio of delivered dose intensity in relation to the planned dose intensity. Evaluation Criteria Pretreatment evaluation included medical history, physical examination, assessment of PS, complete blood cell count with differential, routine chemistry, chest radiograph, and computed tomography (CT) scan of the chest and abdomen. During treatment, a complete blood cell count was performed weekly. Eastern Cooperative Oncology Group PS was evaluated at each cycle. Assessment of tumor response was carried out with CT scan every 3 cycles. Responses were assessed using standard Response Evalutaion Criteria in Solid Tumors.6 Patients were considered evaluable for response if they had received ≥ 3 courses of chemotherapy. The best overall response for each patient was reported, and all responses were reviewed by an independent radiologist and had to be confirmed ≥ 28 days after the initial documentation of response. Hematologic toxicity was recorded weekly, and nonhematologic toxicities were recorded on days 1 and 8 of every course of treatment. The worst toxicity grade for each patient in all cycles was reported. Toxicities were assessed using NCI-CTC, version 2.0.5 Statisical Analysis Because overall response rate was the target, Simon’s optimal 2-stage design for phase II trials was used to calculate the sample size: with α = 0.05 and β = 0.2, p0 (clinically uninteresting true response rate) and p1 (sufficiently promising true response rate)
Carmelo Tibaldi et al Table 1 Patient Characteristics (N = 33) Characteristic Median Age, Years (Range)
Value (%)
Figure 1 Kaplan-Meier Curve of Overall Survival and Time to Progression
74 (70-83)
100 Median TTP, 4 Months (95% CI, 2.5-5.7)
Sex 29 (88)
Female
4 (12)
ECOG PS 0
3 (9)
1
22 (67)
2
8 (24)
80 Probability (%)
Male
Median OS, 6 Months (95% CI, 4-9.7)
60 40 20
Histology Adenocarcinoma
10 (30)
Squamous cell
15 (46)
Other*
8 (24)
0
5
10
15
20
Months
First-line Chemotherapy Platinum-based doublets
17 (52)
Monotherapy (Gemcitabine or Vinorelbine)
16 (49)
Response to First-Line Chemotherapy Partial response
12 (36)
Stable disease
6 (18)
Progressive disease
15 (46)
Number of Metastatic Sites 1
2 (6)
2
15 (46)
3
16 (49)
Number of Comorbidities 0
5 (15)
1
12 (36)
2
7 (21)
3
9 (27)
*Other histologies included large-cell carcinoma and undifferentiated NSCLC.
were set at 5% and 20%, respectively. The drug combination was considered of interest if ≥ 3 responses were observed out of 29 evaluable patients. Time to progression was calculated from the date of registration to the date of clinical and/or radiologic evidence of progression or death, whichever occurred first. Survival was calculated from registration to death or last follow-up. Survival and TTP were estimated using the KaplanMeier method.7 Data were analysed using SPSS/PC version 11.5 statistics software.
Results Patient Characteristics From July 2002 to February 2005, a total of 33 patients entered the study. Twenty-nine patients (88%) were men, and 4 (12%) were women; median age was 74 years (range, 70-83 years). Three patients (9%) had PS 0, 22 patients (67%) had PS 1, and 8 patients (24%) had PS 2. Squamous cell carcinoma was the most frequent histology (n = 15); 10 patients had adeno-
Abbreviations: CI = confidence interval; OS = overall survival
carcinoma, 4 patients had large-cell carcinoma, and 4 patients had undifferentiated NSCLC. All patients had stage IV disease. Patient characteristics are summarized in Table 1. Dose Administration Thirty-three patients received a total of 132 cycles. The median number of courses was 4 (range, 1-6 courses). The delivered dose intensity was 20.6 mg/m2 per week, and the relative dose intensity was 82.4%. Twenty treatment delays (15% of the courses) were reported. The reasons for the delays were 4 episodes of grade 2 mucositis, 1 episode of grade 3 diarrhea, 2 episodes of grade 2 diarrhea, 2 episodes of grade 2 skin toxicity, and 7 other reasons not related to toxicity. Only 2 patients discontinued treatment because of grade 3 diarrhea and allergic reaction to docetaxel. The docetaxel dose was reduced by 25% in 20 administrations and by 50% in 2 administrations. Response and Survival Twenty-nine patients were evaluable for response. Four patients were not evaluable for the following reasons: 1 patient refused to continue chemotherapy after the first cycle, 1 patient reported herpes zoster syndrome and discontinued treatment before the first evaluation, 1 patient experienced an allergic reaction after the second administration of docetaxel and discontinued treatment. We observed 1 early death during the first month of chemotherapy that was not correlated to toxicity but presumably to tumor progression. Overall response rate according to the intent-to-treat analysis was 21.2% (7 of 33 patients; 95% confidence interval, 8.98%38.91%); 12 patients (36.3%) had stable disease, and 14 patients (42.5%) had progressive disease. Among the patients with PS 2, we observed 3 with partial response, 1 with stable disease, and 4 with progressive disease. Median TTP was 4 months (range, 1-24 months), and median duration of survival was 6 months (range, 1-24 months). The 1-year survival rate was 22.2% (Figure 1).
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Modified Schedule of Docetaxel in Advanced-Stage NSCLC Table 2
Hematologic and Nonhematologic Toxicity Per Patient Grade 1
Grade 2
Grade 3
Neutropenia
Toxicity
6
3
9
Thrombocytopenia
3
0
0
Anemia
27
18
3
Nausea/Vomiting
36
3
6
Diarrhea
36
21
6
Mucositis
42
24
0
Asthenia
45
21
6
Nail Toxicity
15
0
3
Skin Toxicity
3
3
0
Table 3 Hematologic Toxicity in Trials with Weekly and Every-3-Week Docetaxel Grade 3/4 Toxicity (%) Study Tibaldi
Gridelli et al13
Camps et al14
Values are percentages. There were no grade 4 toxicities. Patients were graded according to the NCI-CTC.
Toxicity All patients were evaluable for toxicity. Observed toxicities were mild with good compliance to treatment. No grade 4 hematologic toxicity was observed, and grade 3 neutropenia and anemia were reported in 9% and 3% of patients, respectively. No patients developed febrile neutropenia or hemorrhages. Nonhematologic toxicity consisted mainly of grade 3 nausea/ vomiting, grade 3 diarrhea, grade 3 asthenia occurring in 6% of patients, and grade 3 nail toxicity occurring in 3% of patients. No treatment-related deaths occurred. Patients with PS 2 had comparable grade 3/4 toxicity (1 episode of grade 3 diarrhea and 1 episode of grade 3 anemia). Hematologic and nonhematologic toxicities are summarized in Table 2.
Discussion Docetaxel 75 mg/m2 once every 3 weeks is considered the standard of care in second-line treatment of advanced-stage NSCLC8; however, severe myelosuppression is common and a concern. Because of myelosuppression, there is a subset of patients who are not expected to tolerate the full-dose every3-week regimen. In general, these patients have a poor PS, comorbidities, and poor hematologic reserve, similar to many elderly patients. Futhermore, tolerability data of docetaxel at a full-dose every-3-week regimen in elderly patients with NSCLC are inconsistent or lacking. In our study, a modified schedule of docetaxel proved to be active and showed an interesting response rate of 21.2% (95% confidence interval, 8.98%-38.91%) that was in line with the activity data of the initial phase II studies carried out with docetaxel at 75-100 mg/m2 once every 3 weeks.9-12 Although the planned dose intensity of our regimen was the same as in the original every-3-week regimen (25 mg/m2 per week), the observed hematologic toxicities were mild and acceptable with grade 3 neutropenia and anemia occurring in only 9% and 3% of patients, respectively. Nonhematologic toxicities consisted of grade 3 nausea/vomiting, diarrhea, and asthenia in 6% of patients and grade 3 nail toxicity in 3% of patients. The favorable toxicity profile of our schedule produced good compliance to the treatment and, consequently, an optimal relative
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Schuette et al15
Gervais et al17
Regimen 37.5 mg/m2 for 2
Neutropenia Thrombocytopenia Anemia 9
0
3
33.3 mg/m2 for 6 weeks every 8 weeks
2
1
0
75 mg/m2 every 3 weeks
19
1
3
36 mg/m2 for 6 weeks every 8 weeks
4
1
6
75 mg/m2 every 3 weeks
12
0
3
35 mg/m2 for 3 weeks every 4 weeks
5
0
1
75 mg/m2 every 3 weeks
21
0
6
40 mg/m2 for 6 weeks every 8 weeks
16
NR
13
75 mg/m2 every 3 weeks
48
NR
10
weeks every 3 weeks
Abbreviation: NR = not reported Patients were graded according to the NCI-CTC.
dose intensity of docetaxel equal to 82.4%. It is noteworthy that these tolerability data were observed in an unselected patient population, 24% of whom had poor general conditions (PS 2). Our tolerability data are consistent with those reported in recent randomized phase III trials that compared docetaxel 75 mg/m2 every 3 weeks with a weekly schedule in second-line advanced-stage NSCLC. In the first trial, reported by Gridelli et al, 220 patients with advanced-stage NSCLC, aged < 75 years (median age, 63 years), were randomized to receive docetaxel 75 mg/m2 on day 1 every 3 weeks for 6 cycles or docetaxel 33.3 mg/m2 for 6 weeks followed by 2 weeks of rest for 2 cycles. The primary endpoint of the study was quality of life (QOL). Quality of life patterns generally favored the weekly arm; the every-3-week docetaxel regimen caused more leukopenia, neutropenia, febrile neutropenia, and hair loss.13 The second trial, carried out by the Spanish Lung Cancer Group, randomized 246 patients (median age, 62.3 years) to docetaxel 75 mg/m2 once every 3 weeks or docetaxel 36 mg/m2 for 6 weeks in an 8-week course; median survival, the primary endpoint of the study, was equivalent in both arms. Grade 3/4 leukopenia and neutropenia were more frequent in the every-3-week arm than in the weekly arm (11% vs. 4.5% and 8.8% vs. 2.3%, respectively).14 Overall survival was also the primary endpoint of the third trial, which compared docetaxel 75 mg/m2 once every 3 weeks with docetaxel 35 mg/m2 for 3 weeks, followed by 1 week without therapy, in 215 patients (median age, 63 years).15 These data also indicated that there was similar efficacy with weekly docetaxel but significantly less severe toxicity in terms of leukopenia, neutropenia, and anemia. Severe fatigue was the most common complaint after weekly treatment and occurred mainly at the end of the 6 consecutive treatment weeks and
Carmelo Tibaldi et al partly regressed during the 2-week rest interval.16 However, it is not clear whether the incidence of fatigue is actually increased by the weekly schedule. Indeed, studies from Gridelli et al and Camps et al observed no difference in the incidence of asthenia between the 2 schedules.13,14 In contrast, Gervais et al reported that severe asthenia was more common with the weekly regimen (11.1% vs. 4.8%; Table 3).17 In a phase II study carried out with weekly docetaxel as first-line chemotherapy in elderly patients with advanced-stage NSCLC, severe asthenia was reported in 50% of patients.18 In our study we observed severe asthenia (grade 3) in only 6% of patients. Our toxicity data are comparable with those observed in a randomized phase II study carried out in elderly patients and/or patients with poor PS NSCLC who are chemotherapynaive treated with docetaxel weekly or every 3 weeks.19 Another important aspect of our regimen is that, with respect to the 8-week schedule, the number of admissions to the hospital is lower, and this is remarkable especially in the elderly population; likewise, the incidence of corticosteroid-related complications caused by premedication (eg, hyperglycaemia or peptic/duodenal ulcers) was reduced. Recently, in a large phase III study involving 571 patients, a new drug, pemetrexed, was found equivalent to every-3-week docetaxel as second-line treatment for advanced-stage NSCLC.20 In this study by Hanna et al, survival, response rate, and QOL results were similar, but pemetrexed was less toxic. Severe myelosuppresion was significantly lower in the pemetrexed arm than in the docetaxel arm, so this drug could be of interest for treatment of elderly patients. Notably, patients receiving pemetrexed required regular folic acid and vitamin B12 supplements to reduce hematologic and nonhematologic toxicity.
Conclusion Our modified schedule of docetaxel is an active and well-tolerated treatment regimen in elderly patients with advanced-stage NSCLC who are candidates for second-line chemotherapy, and could represent a valuable choice. Future trials should better define the best strategy in terms of efficacy, toxicity, QOL, and economic analysis in this subset of elderly patients with NSCLC.
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