Japanese Journal of Clinical Oncology 31:482-487 (2001)
© 2001 Foundation for Promotion of Cancer Research
A Dose Escalation Study of Paclitaxel and Carboplatin in Untreated Japanese Patients with Advanced Non-small Cell Lung Cancer
Division of Thoracic Oncology, Department of Internal Medicine, National Cancer Center Hospital, Tokyo, Japan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Background: The combination of paclitaxel (225 mg/m2, 3-h infusion) and carboplatin (area under the curve 6) is widely used for non-small cell lung cancer in the USA. In Japan, however, the recommended dose for single-use paclitaxel in 3-h infusion is 210 mg/m2 and the optimal dose of this agent in combination with carboplatin has not been established. This dose escalation study was designed to determine the maximum tolerated dose of paclitaxel in 3-h infusion plus carboplatin at a fixed dose of area under the curve 6 for Japanese patients with advanced, untreated non-small cell lung cancer.
Methods: Between October 1999 and May 2000, 19 patients were enrolled and 18 of these patients were evaluable for toxicity. Chemotherapy consisted of carboplatin area under the curve 6 and an escalated dose of paclitaxel on day 1 every 3–4 weeks. The initial dose of paclitaxel was 175 mg/m2 and was increased by 25 mg/m2 at each dose level.
Results: Neutropenia was the major toxicity observed, but was not dose related. Febrile neutropenia was not observed. No grade 3 or more peripheral neuropathy, myalgia or arthralgia was reported. The maximum tolerated dose was not determined even at the highest paclitaxel dose level (225 mg/m2) in this study. Partial responses were observed in six of the 19 patients (31.6%).
Conclusion: We conclude that paclitaxel at 225 mg/m2 in 3-h infusion and carboplatin area under the curve 6 can safely be given to Japanese patients with non-small cell lung cancer.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Lung cancer is currently the most common cause of cancer deaths in many countries, including Japan. Although meta-analyses have proved that cisplatin-based chemotherapy improves survival over best supportive care, the benefits have been modest (1–3). During the past few years, several new chemotherapeutic drugs with novel mechanisms of action, including paclitaxel, have demonstrated the promising activity in patients with advanced non-small cell lung cancer (NSCLC).
Paclitaxel, an antimicrotubule agent, interferes with mitosis during cell division (4–8). It binds preferentially, promotes assembly and stabilizes microtubules. In the USA, the combination of paclitaxel and carboplatin has been a more widely used regimen for NSCLC because of the low toxicity profile and efficacy of this combination for NSCLC (7,9,10). Moreover, in contrast to cisplatin, carboplatin does not affect the pharmacokinetics of paclitaxel owing to the sequence of these two drugs (11).
The Southwest Oncology Group (SWOG) reported a phase III trial of the paclitaxel (225 mg/m2, 3-h infusion) plus carboplatin [area under the concentration–time curve (AUC) 6] combination versus the SWOG standard vinorelbine plus cisplatin regimen (12). There was no significant difference in response rate, median survival time (MST) or 1-year survival rate between the two regimens, but neutropenia and nausea were higher in the vinorelbine plus cisplatin arm whereas peripheral neuropathy was increased in the paclitaxel plus carboplatin arm. It was concluded that both regimens are effective, but the paclitaxel plus carboplatin regimen was preferred for future studies owing to its favorable toxicity profile and better tolerability and compliance.
The Eastern Cooperative Oncology Group (ECOG) 1594 trial had four arms, including 24-h infusion of paclitaxel plus cisplatin, 3-h infusion of paclitaxel plus carboplatin, docetaxel plus cisplatin and gemcitabine plus cisplatin (13). The MST and 1-year survival rates did not differ among the four arms. The fewest patients with grade 3 or 4 toxicity were in the paclitaxel (225 mg/m2, 3-h infusion) plus carboplatin (AUC 6) arm and this arm also had significantly less nausea, vomiting and febrile neutropenia. However, the SWOG and ECOG trials revealed that the combination of paclitaxel and carboplatin was useful, making it a standard regimen because of its lower toxicity profile and ease of administration.
The phase III study reported by Kosmidis et al. (14) evaluating the dose of paclitaxel combined with carboplatin reported that the median time to progression was significantly more prolonged in the higher dose of paclitaxel arm (225 mg/m2) than the lower dose (175 mg/m2) arm and that the better response rate, overall survival and 1-year survival rate observed with the higher dose of paclitaxel were not statistically significant.
In Japan, a phase I study of paclitaxel infused over 3 h demonstrated the maximum tolerated dose (MTD) to be 240 mg/m2 and that the recommended dose for the phase II study should be 210 mg/m2 (15). The phase II study of paclitaxel at 210 mg/m2 revealed that 38% of patients achieved a partial response, MST was 11.2 months and the 1-year survival rate was 48% (16). Although the recommended dose of paclitaxel was 225 mg/m2 when combined with carboplatin in the USA, the single-use recommended dose of paclitaxel in Japan was 210 mg/m2, i.e. lower than the standard dose in other countries.
The optimal dose of paclitaxel has not yet been defined for Japanese patients when paclitaxel and carboplatin are combined. We therefore conducted a combination dose escalation study with 3-h infusion of paclitaxel plus the fixed dose of carboplatin (AUC 6) in Japanese patients with advanced, untreated NSCLC. The primary objective was to determine the MTD and recommended dose of paclitaxel, including assessment of the safety of 225 mg/m2 paclitaxel treatment (the standard dose in the USA) for Japanese patients. The secondary objective was to evaluate the toxicity and response to this combination.
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PATIENTS AND METHODS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Eligibility
Patients with histologically or cytologically confirmed stage IIIB (with malignant effusion) or stage IV NSCLC were eligible for this study. Eligibility criteria included: (1) age 20–74 years; (2) ECOG performance status 0–1; (3) measurable lesion; (4) adequate bone marrow function (WBCs 4000–12 000/µl, neutrophil
2000/µl, hemoglobin 9.5 g/dl, platelets 100 000/µl), renal function (creatinine 
1.5 mg/dl) and liver function (transaminase 2x upper normal limit, total bilirubin 1.5 mg/dl); (5) stable sinus rhythm with no clinical heart disease; and (6) absence of moderate or severe peripheral neuropathy. Patients with brain metastases were also eligible if they were asymptomatic and did not require steroids or radiotherapy. Patients with a past history of malignancy were excluded. Patients who had received prior chemotherapy and/or radiotherapy were also excluded, but previous surgery was allowed. All patients were required to provide written informed consent. This study was approved by the Institutional Review Board at the National Cancer Center.
Pretreatment and Follow-up Evaluations
Before enrollment, detailed medical histories were obtained and all patients underwent physical examinations and performance status assessments. Blood samples were obtained for complete blood counts (CBCs), electrolytes and renal and liver functions. For creatinine clearance measurement 24-h urine samples were collected at least twice and the average creatinine clearance was calculated. This calculation of creatinine clearance was used as an estimate of the glomerular filtration rate for the purposes of inclusion in Calvert’s dosing equation for carboplatin (17). An electrocardiogram was mandatory. Required radiographs included baseline chest X-ray, computed tomography (CT) scan of the chest and CT and/or ultrasound of the abdomen. A CT scan and/or magnetic resonance imaging (MRI) scan of the brain and a bone scan were also required.
After initiating chemotherapy, physical examinations were performed daily. CBCs were repeated two or three times per week. Routine serum chemistry studies, including total protein, albumin, total cholesterol, electrolytes, blood urea nitrogen, creatinine, total bilirubin, AST, ALT, LDH, alkaline phosphatase and urinalysis, were performed weekly. Chest radiographs for tumor measurement were required once per week and CT scans after two courses of treatment.
Treatment Plan
The patients received chemotherapy according to the dose escalation of paclitaxel and the fixed dose of carboplatin (AUC 6 mg/ml/min ) shown in Table 1. The scheduled number of patients entering each level was six. Intrapatient dose escalation was not allowed. Paclitaxel was administered as a 3-h intravenous infusion followed by 1-h infusion of carboplatin. The total dose of paclitaxel was diluted in 500 ml of saline. Polyethylene-lined nitroglycerine tubing and in-line filtration with a 0.22 µm filter were used for all infusions. To prevent hypersensitivity reactions (HSRs), all patients received premedication with (1) dexamethasone (20 mg) intravenously, 1 h before paclitaxel; (2) ranitidine (50 mg) intravenously, 1 h before paclitaxel; and (3) diphenhydramine (50 mg) orally, 30 min before paclitaxel infusion, as previously reported (18,19). Continuous electrocardiographic telemetry and estimation of blood pressure every 30 min were performed during the infusion of paclitaxel. The carboplatin dose was calculated as the target AUC 6 mg/ml/min , using the Calvert equation (17). The total carboplatin dose was diluted in 250 ml of saline. Antiemetic regimens were devised by individual attending physicians. Chemotherapies were repeated every 3–4 weeks for a minimum total of two courses, unless a patient had progressive disease or intolerable toxicity. The doses of carboplatin and paclitaxel were determined for every course of chemotherapy using the recent creatinine clearance and body weight. Granulocyte colony-stimulating factor (G-CSF) was allowed for patients who developed grade 4 leukopenia and/or neutropenia. Both paclitaxel and carboplatin were reduced by 25% if febrile neutropenia occurred or the platelet count fell below 20 000/µl. If a patient did not recover to WBC count 4000/µl, neutrocyte count 2000/µl and platelet count 100 000/µl during the 6 weeks from the start of chemotherapy, the study protocol was discontinued. Toxicities were graded according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 2.0.
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MTD was defined as the dose level at which three or more out of six patients experienced dose limiting toxicity (DLT) in the first course. DLTs were defined as (1) grade 4 neutropenia exceeding 5 days, (2) fever with grade 4 neutropenia, (3) platelet count of
20 000/µl and (4) grade 3 non-hematological toxicity except for nausea, vomiting and appetite loss. The final determination of further dose escalation and MTD was made by a monitoring committee consisting of three independent members.
Patients with measurable lesions were assessable for the response to therapy. Responses were evaluated using the criteria of the Japan Lung Cancer Society, based on the WHO criteria. A complete response (CR) was defined as the disappearance of all measurable and evaluable disease without evidence of new lesions for at least 4 weeks. A partial response (PR) required a 50% decrease in the sum of the products of perpendicular diameters of all measurable lesions under the baseline without progression of evaluable disease or evidence of new disease for a minimum of 4 weeks. Stable disease (SD) was <50% regression or <25% increase in the sum of the diameters of measurable lesions without evidence of new lesions for a minimum of 4 weeks. Progressive disease (PD) was reported if there was a 25% increase in the sum of the products of measurable lesions over the smallest sum observed or if there was clear worsening of evaluable disease, the appearance of any lesion or failure to return for evaluation owing to deterioration. Patients considered not evaluable (NE) for response included those with treatment discontinuation before tumor re-evaluation in the absence of PD.
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RESULTS |
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Patient’s Characteristics
Nineteen patients were enrolled in this study between October 1999 and May 2000. Seven patients were entered at level 1 and six patients each at levels 2 and 3. All patients were eligible and received chemotherapy. The characteristics for the 19 patients are presented in Table 1. All patients had good performance status. The patients were between 35 and 73 years old, with a median age of 63 years (range, 50–73 years) at level 1, 58 years (range, 53–70 years) at level 2 and 51 years (range, 35–60 years) at level 3; 58% (11 patients) were male and 42% (eight patients) were female. The majority of patients had stage IV disease. Adenocarcinoma was the most frequent histology. The median number of chemotherapy courses in a patient was two (range, 1–4) and a total of 48 courses were delivered. No dose reduction was required.
One of the 19 patients was not assessable for toxicity. The sixth patient entering at level 1 died of hemoptysis during the first course. He had squamous cell lung cancer with a peripheral primary site in the right middle lobe and had stage IV disease with pleural effusion and pulmonary metastasis. On day 12 in the early morning, he suddenly developed dyspnea and died at home owing to a large quantity of hemoptysis. This patient was autopsied. The size of the primary site was 4.5 x 3.8 cm, the inside was necrotic and the cavity was filled with blood. Primary tumor invasion and lymph node metastasis to vessels were not observed. From the results of the autopsy, the cause of death was judged to be respiratory failure caused by bleeding from the primary lesion. We could not rule out the possibility, however, that this death was treatment-related. Nevertheless, hematological toxicity was not observed on day 11. We judged this death neither to be specific for this protocol study nor to be related to the dosages of the two drugs. For these reasons, this episode was judged to be an unpredictable, unforeseen event and we concluded that his death was not related to the toxicity of the drugs. Toxicity was therefore not evaluable in this case. The monitoring committee reached the same conclusion. Accordingly, one additional patient was entered at level 1 and we continued the study. For this reason, seven patients were entered at level 1, but toxicity and response were evaluated only in six.
Hematological Toxicity
Hematological toxicities in the first course and all courses of treatment are summarized in Tables 2 and 3, respectively. There was no grade 4 leukopenia. Grade 4 neutropenia was observed in six of 18 patients (33.3%) in the first course and in 17 of all 46 courses (37.0%). In the first course, the nadir of neutropenia occurred between days 11 and 17. The median duration of grade 4 neutropenia was 2 days and did not exceed 5 days in the first course, except in one patient. Febrile neutropenia was not observed. No patients required antibiotics or developed sepsis. G-CSF was administered in five of 18 patients in the first course and in 15 of all 46 courses.
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Anemia and thrombocytopenia were mild. Grade 1 and 2 anemia occurred in two and one patient, respectively. None of the patients had grade 2 or greater thrombocytopenia in the first course. Transfusions of packed red blood cells and platelets were not required in any of the courses. The dose-limiting hematological toxicity in the first course was grade 4 neutropenia for 6 days (level 2).
Non-hematological Toxicity
Non-hematological toxicities in the first course and all courses were mild, as shown in Tables 2 and 3. Clinically significant HSRs were not observed. There was no clinically significant nausea or vomiting. Alopecia was common. One level 2 patient developed a grade 3 symptomatic supraventricular arrhythmia on day 19 of her second course. With medication, she reverted to a normal sinus rhythm within 24 h. There were no other cardiac toxicities related to paclitaxel, such as hypotension, bradycardia or conduction disturbance. No more than grade 3 peripheral neuropathy was reported, but only one patient (level 3) experienced grade 2 peripheral neuropathy during his third course of treatment. The number of patients in whom peripheral neuropathy developed during the first course was one at level 1, three at level 2 and all six at level 3 and all patients were scored grade 1. Myalgia and arthralgia were observed in 17 of 18 patients (94%) but were scored grade 2 or less in this study. Grade 3 elevation of total bilirubin was observed in one patient at level 3. This toxicity manifested for 5 days after drug administration and then resolved within a few days. This patient’s transaminase levels were normal even while total bilirubin was elevated.
Non-hematological toxicities in the first course considered to be dose limiting were as follows: grade 3 hyponatremia (level 1) and mild liver toxicity including grade 3 total bilirubin elevation (level 3). There was no MTD even at the highest dose level.
Response
Responses are shown in Table 4. Six, nine, three and one patient had PR, SD, PD and NE, respectively. The overall response rate in 19 patients was 31.6% (95% CI: 12.6–56.6%).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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This combination dose escalation study has shown that the combination of paclitaxel (225 mg/m2 infused over 3 h) and carboplatin (AUC 6) can be given to Japanese patients with advanced NSCLC with acceptable toxicity. It would be useful to know the recommended dose of paclitaxel in combination with carboplatin (AUC 6) for phase II or III studies in Japan. The most frequent toxicities produced by short-infusion of the paclitaxel plus carboplatin regimen were leukopenia and neutropenia (20,21). Also in this study, neutropenia was the major toxicity but it was clinically mild. Neither febrile neutropenia nor antibiotic use was observed. No patient died from any toxicity related to neutropenia. Other studies have reported peripheral neuropathy, arthralgia and myalgia to be DLTs when paclitaxel was combined with either cisplatin or carboplatin (21,22). In our study, the frequencies of these toxicities were lower and they were not dose limiting up to a paclitaxel dose of 225 mg/m2. Moreover, these toxicities were reversible. However, it is not possible to discuss these cumulative toxicities adequately because the number of courses in our study was smaller than in other studies.
For the calculation of creatinine clearance, the equation of Cockcroft and Gault (Cockcroft method) is also generally used in clinical practice and trials, in addition to using 24-h urine samples (24-h urine method). The Cockcroft equation is
creatinine clearance = {[140 – age (years)] x weight (kg)} (x 0.85 if female)/{72 x [serum creatinine (mg/dl)]}
The median 24-h creatinine clearance was 102.0 (range 55.9–185) ml/min and the median dose of carboplatin was 762.0 (range 485.0–1260) mg/body in this study. When the Cockcroft equation was used in this study’s patients, the median creatinine clearance and carboplatin dose were 83.6 (range 57.3–173.4) ml/min and 651.6 (range 493.8–1190.4) mg/body, respectively. From these results, creatinine clearance and carboplatin dose calculated with the Cockcroft method were lower than those for the 24-h urine method, but there was no statistically significant difference between these values (p = 0.37, paired t-test). It is not possible to discuss adequately the differences of creatinine clearance and carboplatin dose between this study and other studies including the SWOG and ECOG trials because the number of patients in this study was too small.
In several studies, investigators have noted that thrombocytopenia was much milder than anticipated from that with carboplatin alone and suggested that paclitaxel appeared to offer some protective effect against carboplatin-induced thrombocytopenia (20,21,23,24). Studies evaluating the pharmacokinetics of these two drugs identified no drug interactions (25–27). Although the underlying mechanism explaining this effect is not clear, it has been postulated that paclitaxel stimulates the production of interleukin (IL) 1 from macrophages and of IL 6 and thrombopoietin (TPO), which then stimulate megakaryocyte and platelet production (20,28). Moreover, some reports have suggested that this platelet-sparing effect is attributable to the paclitaxel-induced release of hematopoietic growth factors and megakaryocyte colony-forming units in the bone marrow (27,29,30). In this study, thrombocytopenia was not severe, which is consistent with the results of previous studies. To clarify the reasons for this mild thrombocytopenia, we measured IL 6 and TPO levels on days 1, 2 and 5 in the first course. However, there were no clear or significant relationships among platelet counts, the rate of platelet decrease or the values of IL 6 and TPO (data not shown).
In addition to thrombocytopenia, our combination chemotherapy with paclitaxel and carboplatin was less likely to cause serious toxicity when compared with phase I and II studies of single-use paclitaxel (3-h infusion) in Japan (15,16). Grade 3 and 4 hypotension and grade 3 peripheral neuropathy were DLTs in the phase I study (15), whereas grade 4 neutropenia, neutropenic fever and neuromuscular toxicity were common in the phase II study (16). Of these toxicities, no hypotension, severe neuropathy or neutropenic fever were seen in our study. Toxicity might be decreased in our study, but our response rate was slightly lower than in the paclitaxel-alone phase II study. The numbers of patients entered at each level of the study were too small to allow comparison of the response rates. We could not rule out the possibility that the combination of paclitaxel and carboplatin reduces not only toxicity but also efficacy. However, only a large randomized study can answer this question.
In conclusion, combination chemotherapy with paclitaxel (225 mg/m2 infused over 3 h) and carboplatin (AUC 6) was well tolerated by untreated Japanese patients with advanced NSCLC.
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FOOTNOTES |
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+ For reprints and correspondence: Yoshiko Akiyama, Department of Internal Medicine, National Cancer Center Hospital,1–1 Tsukiji 5-chome, Chuo-ku, Tokyo, 104-0045, Japan
Abbreviations: NSCLC, non-small cell lung cancer; SWOG, Southwest Oncology Group; ECOG, Eastern Cooperative Oncology Group; AUC, area under the concentration–time curve; MST, median survival time; MTD, maximum tolerated dose; CBC, complete blood count; CT, computed tomography; MRI, magnetic resonance imaging; HSR, hypersensitivity reaction; G-CSF, granulocyte colony-stimulating factor; NCI-CTC, National Cancer Institute Common Toxicity Criteria; DLT, dose limiting toxicity; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; NE, not evaluable
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Received April 9, 2001; accepted July 17, 2001.
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