Japanese Journal of Clinical Oncology Advance Access originally published online on February 2, 2006
Japanese Journal of Clinical Oncology 2006 36(2):80-84; doi:10.1093/jjco/hyi230
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© 2006 Foundation for Promotion of Cancer Research
Weekly Short Infusion of Taxotere at a 4 Week Cycle in Chinese Patients with Advanced NSCLC Who Have Failed or Relapsed after the Frontline Platinum-based Non-Taxane Chemotherapy—A Phase II Trial
1 Department of Internal Medicine, Buddhist Tzu Chi General Hospital, 2 Division of Pulmonary and Critical Care Medicine and 3 Division of Hematology-Oncology, Chang Gung Memorial Hospital, Taipei, Taiwan
For reprints and all correspondence: Thomas Chang Yao Tsao, Department of Internal Medicine, Buddhist Tzu Chi General Hospital, Taipei, Taiwan, 10 Lane 43, Fuxing Road, Xindian, Taipei County 231, Taiwan. E-mail: tcyt{at}tzuchi.com.tw
Received December 22, 2004; accepted December 12, 2005
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Abstract |
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Background: This Phase II study was conducted to evaluate the efficacy and toxicity of weekly docetaxel at a 4 week cycle in second-line therapy for patients with advanced non-small cell lung cancer (NSCLC) who failed to respond or relapsed after the frontline platinum-based, non-taxane regimen.
Methods: Patients with histologically confirmed and progressive NSCLC after one platinum-based, non-taxane regimen were eligible for this study. Performance status of 0–2 and adequate organ function were required. Patients were treated with docetaxel 40 mg/m2/week for three consecutive weeks then following 1 week of rest. Cycles were repeated every 4 weeks for a maximum total of six cycles. Docetaxel was administered intravenously for 30 min with dexamethasone premedication.
Results: Fifty-three patients were eligible for this study. Hematologic toxicity was very mild and with the major toxicity of anemia. Non-hematologic toxicities were modest, Grades 3–4 mucositis, diarrhea and peripheral neuropathy occurred in 6–13% of patients and caused dose modifications. Fatigue (48%) was common but not severe with only 6% of Grades 3–4 toxicity. The overall response rate (ORR) was 13% [95% confidence interval (CI), 3.9–23%]. The median survival time (MST) for all patients was 25.0 weeks (95% CI, 12.7–37.3), and the 1 year survival was 31% (95% CI, 17–58%). For patients with PS 0–1, MST was 29.7 weeks and 1 year survival was 36%.
Conclusions: Weekly docetaxel appeared to be well tolerated as second-line therapy for patients with NSCLC. The efficacy for this regimen was comparable with the standard 3 week schedule but hematologic toxicity was markedly reduced. A schedule of three consecutive weeks, with a 1 week break, may diminish the frequency of fatigue and diarrhea when compared with a schedule of six consecutive weeks.
Key Words: weekly docetaxel • second-line therapy • non-small cell lung cancer
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INTRODUCTION |
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Lung cancer is the most common cause of cancer-related death worldwide. In Taiwan lung cancer was the leading cause of cancer death and caused
6000 deaths in 1999. The age-adjusted mortality rate per 100 000 was 38 in male and 16 in female (1). Non-small cell lung cancer (NSCLC) is found in >80% of the patients with lung cancer in Taiwan. The majority of the patients present with locally advanced cancer, either Stage IIIB or Stage IV distal metastasis which cannot be cured using current therapies. Thus, prolongation of life and palliation of symptoms are the aims of treatment. A meta-analysis of randomized studies that compared cisplatin-based combination chemotherapy with the best support care for patients with advanced NSCLC has shown a modest impact on survival (2). Recently, we conducted three Phase II trials with a platinum-based combination regimen with newer agents, including gemcitabine, vinorelbine or paclitaxel. The response rates (RR) and survival data of these newer combinations have been encouraging, with RR of 37, 34 and 46%, respectively, and 1 year survival rates of 61, 58 and 56%, respectively, for gemcitabine, vinorelbine and paclitaxel combined with cisplatin (3–5). However, once a patient has progressed or relapsed after initial platinum-based treatment, the role of the second-line chemotherapy has been less well defined. Most studies have shown RRs of <10% and median survival times (MST) of 4 months or less. However, in recent Phase II trials, docetaxel has been the exception. It has consistently demonstrated survival advantages (1 year survival of 32 and 40%) and improved quality of life (6,7). Nevertheless, hematologic toxicity in these studies was substantial and Grades 3–4 neutropenia was observed in 54 and 76% of patients treated with docetaxel 75 mg/m2. In a Phase I trial, Hainsworth et al. (8) demonstrated that docetaxel could be administered weekly at a maximum tolerated dose of 43 mg/m2/week for six consecutive weeks followed by 2 weeks without treatment. Fatigue and asthenia were the dose-limiting toxicities. Therefore, myelosuppression was decreased markedly compared with the traditional 3 week schedule. There was no episode of Grade 4 neutropenia, and Grade 3 neutropenia was infrequent. On the basis of the benefits associated with docetaxel in second-line chemotherapy for NSCLC and its relatively mild toxicity when used on a weekly schedule, we conducted a Phase II trial to test weekly docetaxel in patients with second-line NSCLC. A high weekly dose (40 mg/m2/week) and a short treatment course were administered for three consecutive weeks followed by 1 week without treatment.
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MATERIALS AND METHODS |
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PATIENT ELIGIBILITY
To be eligible for this trial, patients were required to have histologically confirmed NSCLC that had progressed after one platinum-based regimen. To understand the efficacy of docetaxel in second-line chemotherapy for patients without previous treatment with taxanes, patients who had received taxanes-containing regimens were excluded. Before entry in this study, a minimum of 21 days must have elapsed since any prior chemotherapy. Patients should have at least a bidimensionally-measured lesion. Eastern Cooperative Oncology Group performance status of 0–2 was required. In addition, the patients must have adequate bone marrow (absolute granulocyte count of
2.0 x 10 cells/l and platelet count of 100 x 10 cells/l), hepatic (total bilirubin levels were within reference ranges, alkaline phosphatase level 
5 times the upper limit of normal and serum transaminase 1.5 times the upper limit of normal), and renal (serum creatinine level 2.0 mg/dl or creatinine clearance 60 ml/min) function. Patients who had received prior radiation therapy for the only measurable site were excluded. Patients treated for brain metastases by radiation were eligible provided they were neurologically stable. The protocol was reviewed and approved by the Institutional Review Boards (IRBs) of the Chang Gung Memorial Hospital. Written informed consent was obtained from all patients before initiating treatment.
TREATMENT REGIMENS
A total of 40 mg/m2 docetaxel was given on Day 1, every week, in 5% dextrose water or normal saline 125 cm3, administered intravenously for 30 min. Docetaxel was given for three consecutive weeks then followed by 1 week of rest. Cycles were repeated every 4 weeks for a maximum total of six cycles. Premedication consisted of four doses of 4 mg dexamethasone, given orally 13 h and 1 h before chemotherapy administration, respectively, and 12 h and 24 h after chemotherapy, respectively. Further antiemetics were used at the physician's discretion. The use of filgrastim was not allowed. Concomitant radiation therapy was not permitted. Chemotherapy was discontinued for patients with progressive disease (PD) or unacceptable toxicity.
Dose modifications based on hematologic toxicity were made as follows: at the start of each cycle, the leukocyte count must be 2000/mm3 and platelet 75 000/mm3. If on any day of a scheduled treatment the leukocyte count was <2000/mm3 or platelet <75 000/mm3, treatment was withheld that week, and the blood count was reevaluated the following week. Treatment proceeded as scheduled if the blood cell count had risen to leukocytes 2000/mm3 and platelet 75 000/mm3. The missed doses were not ‘made up’. A 25% dose reduction was required if patients developed the following: Grade 4 neutropenia lasting more than 5 days; febrile neutropenia; or Grade 4 thrombocytopenia.
Dose adjustments also were made for patients with non-hematologic toxicities. When any non-hematological Grade 3 or 4 toxicity developed, with the exception of alopecia or nausea/vomiting, the dose of docetaxel was omitted until the toxicity had resolved to less than Grade 2. Docetaxel was then reinstituted at a 75% dose. Diuretics were given to patients with water retention. If edema was Grade 3 or 4 and persistent after diuretic therapy, the dose of docetaxel was omitted until the edema resolved to less than Grade 2. For hepatic dysfunction, doses were adjusted according to bilirubin, alkaline phosphatase and aspartate aminotransferase levels. For neurologic toxicity of Grades 3–4, patients were removed from the study; for Grade 2, patients were retreated on recovery to a less than Grade 1 toxicity with a dose reduction of 25%. The patient was withdrawn from the study when the delay of treatment was for more than one cycle, i.e. 4 weeks.
RESPONSE AND TOXICITY EVALUATION
The treatment response was recorded according to World Health Organization (WHO) criteria for the assessment of chemotherapy efficacy. A complete response (CR) was defined as the complete disappearance of all evidence of tumor. Partial response (PR) was defined as a 50% reduction in the sum of the products of the largest perpendicular diameters of all measured lesions for at least 4 weeks. Stable disease was defined as a decrease of <50% or an increase of <25% in well-outlined lesions for at least 4 weeks. PD was defined as an increase >25% in the cross-sectional area of one or more lesions, or the occurrence of new lesions. Toxicity was evaluated using the WHO toxicity grading scale. To evaluate and confirm the efficacy, all patients received chest X-ray examinations before each cycle of chemotherapy. Chest computed tomography (CT) scans were performed 2 weeks after the second, fourth and sixth courses of chemotherapy. The chest X-ray films were independently reviewed by one pulmonary physician and one radiologist who agreed on the diagnoses and response evaluation. Tumor responses were assessed radiologically every two cycles. Those patients with stable or responsive conditions received further treatment until disease progression and a maximum total of six cycles were given. After completion of six cycles of treatment complete physical examination, chest X-ray examinations were performed each month and chest CT scan was performed if there was any change in chest X-ray films. Brain CT scans or bone scans were performed when patients had symptoms of brain or bone metastasis.
STATISTICAL ANALYSIS
The primary purposes of this Phase II trial were to evaluate the efficacy and the toxicity of weekly docetaxel in patients with recurrent or refractory NSCLC. Patients who received at least two cycles of treatment were evaluable for responses, and patients who received at least one cycle of treatment were evaluable for toxicity. Time to disease progression was calculated from the study entries until evidence of PD. According to Simon two-stage optimal design, a total of 53 assessable patients were needed to guarantee 80% power under a 
-level of 5%. The study had an 80% power, with a level of significance of 0.05, to test the hypothesis that H0: P-value <5% versus P-value >0.15, where P denotes the RR as defined above.
The overall survival was analyzed using the Kaplan–Meier estimation method. Survival was defined as the time between initiation of treatment and death. If death had not occurred, survival time was considered censored at time of last follow-up.
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RESULTS |
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PATIENT CHARACTERISTICS
From August 1999 to December 2001, 53 patients were entered into this Phase II trial at Chang Gung Memorial Hospital in Linkou, Taiwan. Their characteristics are listed in Table 1. There were 37 males and 16 females with a median age of 61 years (range: 35–75 years). Most of our patients had been previously treated with the regimen of cisplatin combined with gemcitabine (35/53, 66%), and with cisplatin combined with vinorelbine (17/53, 32%). The remaining patient underwent concurrent chemoradiotherapy with the chemotherapy regimen including vinorelbine and cisplatin. Responses to first-line chemotherapy are shown in Table 1. Thirty-four patients had a PS of 0–1 (64%) and 19 had PS of 2 (36%).
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RESPONSE
Of the 53 eligible patients, seven achieved a PR. The overall response rate (ORR) was 13% [95% confidence interval (CI), 3.9–23%]. Ten had SD (19%), and 32 had PD after the first two cycles (60%) (Table 2). Four patients did not complete the first two cycles of therapy and were not considered evaluable for response: three patients withdrew consent and requested to be transferred to another hospital and one moved out of the city and could not be observed. First-line therapy for the seven patients who responded consisted of gemcitabine plus cisplatin in five and vinorelbine plus cisplatin in two. Performance status was not a predictor of response: three responders with PS 2. Prior response to chemotherapy was not predictive of response. In contrast, all of the 11 patients who responded to previous regimens failed to respond to single docetaxel. The median time to disease progression for all patients was 12.0 weeks (95% CI, 9.4–14.6). At a median follow-up of 6.9 months, the MST for all patients was 25.0 weeks (95% CI, 12.7–37.3). The patients with PS = 0–1 had longer MST [29.7 weeks (95% CI, 11.8–47.6)] than the patients with PS = 2 had [18.1 weeks (95% CI, 4.1–32.1)], but the difference was not statistically significant. The overall survival curve and survival stratified by performance status are shown in Fig. 1. The 1 year survival was 31% (95% CI, 17–58%). For patients with PS of 0–1 and PS of 2, the 1 year survival were 36 and 21%, respectively.
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TOXICITY
Table 3 shows the hematologic and non-hematologic toxicities of the treatment. All 53 eligible patients who received a total of 239 treatment doses were evaluable for toxicity. The median number of cycles per patient was one (range: 1–6). Hematologic toxicity was very mild and with the major toxicity of anemia. Eight patients (15%) developed Grades 3–4 anemia. There were no episodes of Grades 3–4 neutropenia or thrombocytopenia.
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Mucositis, nausea/vomiting and peripheral neuropathy were the most common non-hematologic toxicities. Grades 3–4 mucositis, diarrhea and peripheral neuropathy occurred in seven (13%), three (6%) and five (10%) patients, respectively, and required dose modifications in all of them. Fatigue was common (48% in all) but not severe [3/53 (6%), with Grades 3–4 episodes], and occurred mostly at the end of the 6 week cycle. Diarrhea was also common but not severe [13/53 (25%) with Grades 1–2 episodes and 3/53 (6%) with Grades 3–4 episodes]. One patient had one episode of Grades 3–4 peripheral edema and the symptom was controlled with diuretics. Nail changes, lacrimation and alopecia were mild, but persistent. Hepatic and renal impairment was mild.
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DISCUSSION |
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TOPAbstractINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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This Phase II study was conducted to evaluate the efficacy and toxicity of docetaxel in Chinese patients with advanced NSCL who have failed to respond or relapsed after the frontline platinum-based, non-taxanes chemotherapy. The ORR was 13% with a median survival of 25.0 weeks and 1 year survival of 31%. The toxicity was mild. The results were similar to those from other studies, which were mostly composed of patients with previous treatment with taxanes.
Recently, novel cisplatin-based regimens such as gemcitabine and cisplatin, vinorelbine and cisplatin, or paclitaxel with carboplatin have been conducted in treatment of patients with advanced NSCLC. Because of these regimens, greater proportions of patients are deriving clinical benefits and prolonged survival. However, all patients with advanced disease ultimately develop disease progression after first-line therapy. Before docetaxel, the administration of second-line therapy for these patients was not encouraged due to the lack of demonstrated single-agent efficacy in this setting. Recently, two studies had shown that docetaxel was efficacious in the second-line treatment of NSCLC and provided survival benefits and improved quality of life (6,7). However, when docetaxel was administered on a standard 3 week schedule, the hematologic toxicity was profound and caused treatment limitations.
Similar to the recent report from Lilenbaum et al. (9), our results showed that the weekly administration of docetaxel was a well tolerated and convenient regimen. The major differences between our study and previous studies were, first, none of our patients had been previously treated with taxanes. Second, docetaxel was given at higher doses of 40 mg/m2/week. Third, the patients were treated for three consecutive weeks followed by 1 week of rest and cycles were repeated every 4 weeks. The first two differences might partially account for the slightly higher ORR, 13 versus 10%, in our study. However, when compared with two previous studies which included single weekly docetaxel as second-line therapy for NSCLC (10,11), our ORR was comparatively lower than those reported by Serke et al. and Garcia et al. (17 and 17.3%, respectively).
The effect of previous therapy with paclitaxel on second-line chemotherapy with docetaxel is questionable. Since both paclitaxel and docetaxel are taxanes, cross-resistance might exist. In recent studies, when physicians used the docetaxel as second-line chemotherapy for NSCLC, most of their patients, 33–80%, had been previously treated with paclitaxel-contained regimen (6,9,12,13). To understand this issue, a further two-arm study, one arm with, one arm without previous paclitaxel-therapy, will be conducted and undergone with docetaxel-contained regimen as second-line treatment for NSCLC. In addition, the ORR, although with it may vary, seems to be similar in different dose of weekly docetaxel, ranging from 35 to 43 mg/m2/week. The results were 17% for 35 mg/m2/week (10), 10% for 36 mg/m2/week (9) and 17.4% for 43 mg/m2/week (11), respectively, and in our reports, 10% for 40 mg/m2/week.
In view of hematologic toxicity, the weekly administration of docetaxel seems to be better than the traditional schedule. There was no Grades 3–4 leukopenia or thrombocytopenia in our study. The results were similar to those in previous studies (9–11). Anemia was also uncommon in our study, but 15% of Grades 3–4 anemia was observed in patients who had received two more cycles. Thus, the weekly schedule is particularly suitable for the patients who are at high risk for myelotoxic complications from chemotherapy and which may be common for previously treated and elderly patients.
Diarrhea was neither common nor severe, when docetaxel was given every 3 weeks. However, diarrhea at Grades 3–4 was observed in our study and the study by Lilenbaum et al. (9), at rates of 6 and 14%, respectively. The reasons for this toxicity seem to be schedule-dependent. Based on the above limited data, treatment with three consecutive weeks might have less toxicity in patients when compared with treatment for six consecutive weeks. Cumulative fatigue was also an important part of toxicity and has been well described in patients given docetaxel either every 3 weeks (7) or on a weekly schedule for six consecutive weeks (9). In our study an alternative schedule of three consecutive weeks, with a 1 week break, apparently diminished the frequency of fatigue. The Grades 3–4 fatigue was reduced from 33 to 6% when our results were compared with those from the study by Lilenbaum et al. (9). However, the incidence of paresthesia was relatively higher in our study, and 10% of them were Grades 3–4. The higher weekly dose might be a reason, 40 versus 36 mg/m2/week compared with two studies.
Based on these preliminary reports, the experience for weekly docetaxel as a second-line chemotherapy in NSCLC appears consistent and reproducible. The efficacy for this regimen was comparable with the standard 3 week schedule but hematologic toxicity was minimized. A schedule of three consecutive weeks with a 1 week break may diminish the frequency of fatigue and diarrhea when compared with a schedule of six consecutive weeks.
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References |
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TOPAbstractINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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