© 2004 Foundation for Promotion of Cancer Research
Weekly Paclitaxel and Nedaplatin With Concurrent Radiotherapy for Locally Advanced Non-small-cell Lung Cancer: a Phase I/II Study
1 The Second Department of Internal Medicine, 2 Department of Radiology and 3 Department of Clinical Pharmacology, Hirosaki University School of Medicine, Hirosaki, Aomori, Japan
For reprints and all correspondence: Yukihiro Hasegawa, Second Department of Internal Medicine, Hirosaki University School of Medicine, 5 Zaifu-cho, Hirosaki 036-8562, Japan. E-mail: yukihase{at}cc.hirosaki-u.ac.jp
Received June 19, 2004; accepted September 3, 2004
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Abstract |
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 TOP Abstract INTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONReferences |
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Objective: The purpose of this study was to determine the safety and efficacy of nedaplatin and paclitaxel when given concurrently with radiation therapy (RT) for locally advanced non-small-cell lung cancer (NSCLC).
Methods: Nedaplatin was administered at a fixed dose of 20 mg/m2, and paclitaxel was administered at a starting dose of 30 mg/m2 with an incremental increase of 5 mg/m2 until dose-limiting toxicity (DLT) occurred in more than one-third of the patients. The chemotherapy was administered once a week for 6 weeks. The RT was given at a single daily dose of 2 Gy for 5 days per week. The pharmacokinetics of nedaplatin and paclitaxel were investigated.
Results: Overall, 20 patients were recruited and assigned to three different treatment groups: group 1 (paclitaxel 30 mg/m2), group 2 (paclitaxel 35 mg/m2) and group 3 (paclitaxel 40 mg/m2). Pulmonary toxicity was the main toxicity which occurred in 16 of 20 patients. In group 3, grades 3 and 4 pulmonary toxicity occurred in two of six patients and grade 3 esophagitis in one patient. The maximum tolerated dose of paclitaxel in this study was 40 mg/m2 and the recommended dose of paclitaxel was therefore 35 mg/m2. Four complete and 11 partial responses were observed, resulting in a 75% overall response rate. The area under the concentration–time curve of paclitaxel in group 3 was significantly higher than that in group 1.
Conclusion: Nedaplatin 20 mg/m2 and paclitaxel 35 mg/m2 could be safely administered for NSCLC with concurrent thoracic RT, and this regimen was effective. The most important DLT was pulmonary toxicity.
Key Words: non-small cell lung cancer • paclitaxel • nedaplatin • radiotherapy • pulmonary toxicity • pharmacokinetics
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INTRODUCTION |
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TOPAbstractINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONReferences |
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Non-small-cell lung cancer (NSCLC) accounts for
80% of all lung cancers, with 1.2 million new cases worldwide each year (1,2). NSCLC caused more than 1 million deaths worldwide in 2001 (1) and is the leading cause of cancer-related mortality in both men and women (31 and 25%, respectively) (3). Only a small percentage of patients present disease susceptible to surgical resection. In fact, 30–40% of patients with NSCLC present with locally or regionally advanced unresectable tumors (4). Thoracic irradiation with modern megavoltage equipment plays a critical role in the treatment of these patients, because it ensures good local control of the tumor in most patients. However, the appearance of distant metastases also affects their prognosis. In an attempt to reduce the risk of distant metastases, addition of chemotherapy to radiation therapy (RT) has been advocated. Several randomized trials have shown a significant survival advantage for patients who received chemotherapy and RT combinations as compared with RT alone (5–7). A meta-analysis of all randomized trials that compared RT alone with the combined approach showed an unequivocal, although modest, survival advantage when cisplatin-based chemotherapy was added to RT (8). However, the best regimen and schedule to be combined with RT is still undefined.
Paclitaxel is a potent radiosensitizer, as demonstrated in preclinical studies (9–11). Recently, regimens combining paclitaxel and platinum compounds in chemoradiotherapy have been demonstrated to be effective and tolerable in the treatment for stage III NSCLC. Frasci et al. conducted a phase I study of weekly paclitaxel and cisplatin (CDDP) with concurrent RT in locally advanced NSCLC and recommended the dose of CDDP 35 mg/m2 and paclitaxel 45 mg/m2 for phase II study (12). Phase II trials of paclitaxel and carboplatin with radiation for unresectable stage III NSCLC were conducted and high response rates with acceptable toxicity and survival were demonstrated (13,14).
Nedaplatin is a second-generation platinum complex that was developed by Shionogi Phamaceutical Co. (Osaka, Japan). Clinical studies have demonstrated that nedaplatin has a high activity against rodent solid tumors and has a lower renal toxicity and higher aqueous solubility than CDDP (15,16). A phase I study demonstrated that nedaplatin had therapeutic effects in nasopharyngeal carcinoma, adenocarcinoma of the cervix, and lung and gastric cancers (17). A phase II study has demonstrated that nedaplatin was well tolerated and had the same activity as CDDP in NSCLC (18). Recent studies have reported that combination therapy with nedaplatin and RT is effective in the treatment of patients with oral cancer and esophageal cancer (19,20).
Based on these previous clinical considerations, we designed this phase I/II study to determine the safety and efficacy of nedaplatin and paclitaxel when given weekly with concomitant thoracic RT. Furthermore, plasma concentrations of these compounds were determined to demonstrate the relationship between clinical effects or toxicities and amount of dosage exposure to these compounds.
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SUBJECTS AND METHODS |
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TOPAbstractINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONReferences |
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ELIGIBILITY CRITERIA
Patients with histologically or cytologically documented locally advanced NSCLC were enrolled into this study. Other eligibility criteria included the following: (i) age <75 years; (ii) Eastern Cooperative Oncology Group (ECOG) performance status <2; (iii) measurable or assessable tumor; (iv) adequate bone marrow function (granulocytes
2000/ml, hemoglobin level >10 g/dl, platelet count 100 000/ml), renal function (creatinine clearance >60 ml/min) and pulmonary function (arterial oxygen partial pressure PaO2 >65 Torr); (v) acceptable cardiac function as determined by electrocardiogram and echocardiogram; (vi) absence of central nervous system metastases, polyneuropathy and active infection; (vii) life expectancy >8 weeks; (viii) absence of previous chemotherapy or thoracic RT; and (ix) no serious medical or psychiatric illness that would preclude informed consent. All patients gave written informed consent before enrollment. This protocol was approved by the Ethical Committee for Research at Hirosaki University.
DIAGNOSTIC EVALUATION
Diagnosis was made by a biopsy performed during fiberoptic bronchoscopy or by a transthoracic fine-needle aspiration biopsy in cases of peripheral mass. At entry, a complete medical history was obtained, clinical and physical examination (including assessment of weight loss in the last 6 months and of performance status) was performed, and the following laboratory tests were carried out: white blood cell (WBC) count (total and differential), red blood cell and platelet count, hemoglobin level, levels of glutamic oxaloacetic transaminase and glutamic pyruvic transaminase, alkaline phosphatase, 
-glutamyl transferase, lactate dehydrogenase, bilirubin, glucose, blood urea nitrogen (BUN), uric acid, creatinine, total protein and albumin, carcinoembryonic antigen tissue polypeptide antigen, neuron-specific enolase, Cyfra21.1, serum sodium, potassium, calcium, phosphorus and creatinine clearance. The extent of disease was evaluated by means of the following instrumental tests: chest X-ray, computed tomography (CT) scan of thorax and upper abdomen, and bone scintigraphy. A contrast-enhanced CT scan or magnetic resonance imaging (MRI) of the brain was performed to rule out cases with cerebral metastases. Bone X-ray was limited to suspicious areas found by radionuclide scan. Baseline neurological evaluation that included assessment of muscle strength, sensory perception and deep tendon reflexes was also made.
WBC count (total and differential), serum electrolytes and chemistry profiles were determined once a week during the treatment. Within 30 days from the end of treatment, a chest CT scan was repeated to evaluate the response. Fiberoptic bronchoscopy was mandatory to confirm the achievement of complete response in cases of complete disappearance of the lesions in CT. After completion of the treatment, physical examination, routine laboratory tests and chest X-ray were performed at 3 month intervals. Chest and upper abdomen CT scans were repeated every 6 months.
Toxicity was measured using common toxicity criteria (CTC) of the National Cancer Institute (NCI-CTC Version 2.0, April 30, 1999) including the European Organization for Research and Treatment of Cancer (EORTC) late radiation morbidity scoring scheme.
TREATMENT
Chemotherapy. Increasing doses of paclitaxel (Bristol-Myers K.K., Tokyo, Japan) and a fixed dose (20 mg/m2) of nedaplatin (Shionogi Pharmaceutical Co, Osaka, Japan) were administered once a week for 6 weeks, starting on the first day of local RT. Paclitaxel was administered over 1 h, followed by nedaplatin, which was given over 1 h. Antiemetic prophylaxis was not given. All patients received pre-treatment medications to prevent hypersensitivity reactions: dexamethasone [20 mg, intravenously (i.v.)], diphenhydramine (50 mg, orally) and ranitidine (50 mg, i.v.) were administered 30 min before chemotherapy.
Radiotherapy. External-beam RT was given concurrently with chemotherapy. The RT volumes and fields were individualized for each patient and were thus highly variable. Generally, the radiation fields encompassed the area of gross disease including both primary lesion and metastatic lymph nodes with a 1 cm margin. The total dose aim for was 64 ± 4 Gy and the final total dose was determined by irradiated volume, clinical response and status of the patient. RT was administered with a linear accelerator. A single daily dose of 2 Gy was given five times a week.
PHARMACOKINETICS
Pharmacokinetic sampling. Plasma samples for pharmacokinetic evaluation of paclitaxel and nedaplatin were collected from 19 of 20 patients in their first course of therapy. Blood samples were obtained through an indwelling catheter placed in an antecubital vein of each subject at the end of paclitaxel infusion (before nedaplatin infusion) and at 1 h (the end of nedaplatin infusion), 2 h (1 h), 3 h (2 h), 4 h (3 h), 6 h (5 h), 8 h (7 h) and 19 h (18 h) after the paclitaxel (nedaplatin) administration. Sampling was done with care taken to avoid contamination with paclitaxel in the i.v. line. Plasma was separated immediately and its unbound fraction was obtained by an ultrafiltration method. These samples were kept at –20°C until analysis. Plasma concentrations of paclitaxel were determined by the HPLC method (21), and plasma concentrations of unbound platinum were measured by an atomic absorption spectrometry assay method (22). The limit of quantification was 0.01 and 0.2 µg/ml for paclitaxel and nedaplatin, respectively. The area under the concentraion–time curve (AUC) from zero to the last time at which quantifiable concentrations were obtained was calculated with use of the trapezoidal rule. This procedure was made at the Department of Clinical Pharmacology at Hirosaki University School of Medicine.
STUDY DESIGN
This phase I/II study was designed to define the maximum tolerated dose (MTD) of paclitaxel when combined with a fixed dose (20 mg/m2) of nedaplatin and thoracic RT. The first dose level of paclitaxel was set at 30 mg/m2/week. The paclitaxel dose was to be escalated in 5 mg/m2 increments until dose-limiting toxicity (DLT) occurred in more than one-third of the patients enrolled in each group. DLT was defined as CTC grade 3 or 4 non-hematological toxicity, excluding nausea or vomiting and alopecia, CTC grade 4 neutropenia, CTC grade 3 or 4 thrombocytopenia, and Radiation Therapy Oncology Group (RTOG) grade 3 or 4 esophagitis or pneumonitis. If one instance of DLT was observed among three patients, three additional patients were to be treated at the same dose level. The dose increase was continued if DLT was observed in only one or two of six patients. The dose level at which DLT was observed in three of six patients was defined as the MTD.
RESPONSE EVALUATION AND SURVIVAL ANALYSIS
Complete response was defined as the total disappearance of all clinically detectable lesions for at least 4 weeks. Partial response required a reduction of 30% in the sum of the longest perpendicular diameters of the lesions lasting at least 4 weeks. Stable disease was defined as a <30% reduction or a 20% increase in the sum of the product of the longest perpendicular diameters of the lesions, whereas progressive disease was defined as an increase of 20% or >20% in the sum of the longest perpendicular diameters of the lesions or the appearance of new lesions (23).
Overall survival was defined as the time from the date of initiation of therapy to death, while progression-free survival was defined as the time from the date of initiation of therapy to documented disease progression or death. The survival curve was estimated by the Kaplan–Meier method (24). The relationship between dose and the AUC of either nedaplatin or paclitaxel was examined by one-way analysis of variance (ANOVA). The relationship between clinical effect or toxicity and the AUC of paclitaxel or nedaplatin level was examined by one-way ANOVA. A P-value <0.05 was considered statistically significant.
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RESULTS |
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TOPAbstractINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONReferences |
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Between September 2001 and May 2003, a total of 20 consecutive chemotherapy-naive NSCLC patients were enrolled onto this phase I/II study. Patient characteristics are listed in Table 1. The stage of the disease was IIIA in five patients and IIIB stage in 15 patients. Eleven patients had squamous cell carcinoma, eight had adenocarcinoma and one had large cell carcinoma. Seven patients were in group 1, seven in group 2 and six in group 3. Twenty assessable patients received the intended RT dose of 44–73 Gy, with a median dose of 64 Gy. Mean dose of RT in each group was 66 Gy (range 44–73) in group 1, 64 Gy (range 60–71) in group 2, and 59.3 Gy (range 46–66) in group 3. In group 1, one patient received 44 Gy but could not resume the additional RT because of the large radiation field. Therefore, one patient was added in group 1. In group 3, one patient received 48 Gy due to the early appearance of pulmonary toxicity and another patient required 58 Gy due to tumor progression. There was no significant difference of radiation dose among the three treatment groups. Fifteen of 20 enrolled patients received the total planned chemotherapy. In group 1, three patients did not receive 1–3 doses of chemotherapy because of leukopenia. In group 2, one patient did not receive one dose because of leukemia. In group 3, one patient did not receive one dose because of pulmonary toxicity.
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TOXICITY
All patients were fully assessable for toxicity. Toxicity was evaluated on the first day of every week during the treatment. No hematological DLT was observed. Maximal hematological toxicity grades for each dose level are listed in Table 2. Neutropenia was the most relevant hemotological toxicity. Each treatment group had grade 3 neutropenia, but did not have grade 4. In group 2, one patient had grade 3 anemia but he had a gastric ulcer. Thrombocytopenia was uncommon and mild (grade 1). Non-hematological toxicities observed in this study are listed in Table 3. Pulmonary toxicity was the principal DLT in this study. It occurred in 16 of 20 enrolled patients and, in three patients, it was of grade 3 or 4, which caused a temporary suspension of the treatment in three patients. Esophagitis of grade 3 occurred in one patient. The patient was administered partial parenteral nutrition. Hypersensitivity reactions did not occur. Alopecia was uncommon and mild (grade 1). Emesis occurred in five patients but was never greater than grade 3. These patients were administered antiemetic agents.
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DOSE RECOMMENDATION
Dose increment was stopped in group 3 because of DLT in more than one-third of patients (Table 3). The MTD of paclitaxel in this study was determined as 40 mg/m2. Therefore, the recommended paclitaxel dose was 35 mg/m2 when combined with 20 mg/m2 of nedaplatin and thoracic RT, and a total of seven patients were enrolled at this level to assess further the tolerability and efficacy of this treatment.
RESPONSES
The responses to the treatment are listed in Table 4. Among 20 patients, four CRs and 11 PRs were confirmed, and two patients had stable disease after treatment. Three patients had PD. One of the patients had simultaneous disease progression outside of the radiation field. Overall tumor response rate was 75% (51–91%). Median follow-up time for all patients was 46 weeks (27–64 weeks). Median time to progression was 24 weeks (4–43 weeks) and 15 patients had developed progressive disease (Fig. 1A). At July 2004, 13 of 20 patients had died: seven patients as a result of progression of NSCLC; five patients as a result of pneumonia; and one patient as a sudden death. Three patients with grade 3 or 4 pulmonary toxicity developed pneumonia. Median survival time was 46 weeks (28–64 weeks), with a 1-year survival of 40% and 2-year survival of 33% (Fig. 1B).
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PHARMACOKINETIC STUDIES
The plasma concentrations of both nedaplatin and paclitaxel in the three treatment groups were measured in 19 of 20 patients. The mean AUC in six patients treated with 30 mg/m2 of paclitaxel (group 1), in seven patients with 35 mg/m2 (group 2) and in six patients with 40 mg/m2 (group 3) was 755 ± 218 (SD)µg/ml/min, 860 ± 126, and 1148 ± 105, respectively. The AUC of paclitaxel in group 3 was significantly higher than that in group 1 (P < 0.05). The AUC of paclitaxel was not related to either the greatest toxicity experienced or response rates (data not shown). The AUC of nedaplatin in 19 patients ranged from 728 to 2663 µg/ml/min (mean ± SD; 1940 ± 550). The AUC of nedaplatin was not related to either the greatest toxicity experienced or the response rate in each group.
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DISCUSSION |
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TOPAbstractINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONReferences |
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Over the past decade, the data have clearly emerged in locally advanced NSCLC demonstrating the benefits of chemotherapy combined with local measures, in particular radical RT. Three separate studies have demonstrated a survival benefit for induction chemotherapy followed by definitive radiation compared with radiation alone, with improvements primarily in systemic control (6,7,25). In addition, three other studies have demonstrated a radiosensitizing benefit to concurrent chemotherapy and radiation versus radiation alone, with improved local control and enhanced survival rates (5,26,27). A Japanese study has demonstrated the superiority of concurrent chemoradiation over sequential chemotherapy followed by radiation (28). Another question still unanswered concerns the best chemotherapy regimen to be combined with RT. Although there is universal agreement that platinum compounds are irreplaceable in the therapeutic strategy of NSCLC, it is still unclear whether the addition of other drugs may result in a substantial therapeutic advantage.
In the present study, we aimed to determine the MDT of weekly paclitaxel with a fixed dose (20 mg/m2) of weekly nedaplatin when given concurrently with thoracic RT. The total dose of nedaplatin during 6 weeks in our study was 120 mg/m2. In a phase II study of nedaplatin in the treatment of NSCLC, when administered as a single i.v. infusion at a dose of 100 mg/m2 every 4 weeks, the drug was well tolerated (18). Recently, two studies have reported that concurrent chemoradiotherapy with nedaplatin at a dose of 80–90 mg/m2 and 5-fluorouracil at a dose of 400–500 mg/m2 for 5 days every 5 weeks was effective against oral cancer (19) and esophageal cancer (20). Therefore, we considered the dose (20 mg/m2) of weekly nedaplatin appropriate in the light of doses used in the previous studies (18–20).
Pulmonary toxicity was the most important and frequent toxicity in the present study. In group 3, two of the three DLTs were pulmonary toxicities, and the other was esophagitis. Therefore, we determined the MTD of paclitaxel at 40 mg/m2 in this study. The early occurrence of an unacceptable degree of pulmonary toxicity in group 3 forced us to stop this incremental increase in the dose of paclitaxel. Severe pulmonary toxicities were observed more frequently in this study than in the studies of Choy et al. (13) and Frasci et al. (12). However, our study was characteristic in that only a few patients developed esophagitis, while the most relevant toxicity in previous studies of concurrent paclitaxel and other platinums (CDDP or carboplatin) with radical thoracic RT in NSCLC was esophagitis (9,12–14,29–32). A recent retrospective cohort study of combination chemotherapy, including paclitaxel plus RT, in breast cancer patients suggested that concomitant paclitaxel and RT resulted in an actuarial risk of radiation pneumonitis (33). The frequent occurrence of radiation pneumonitis in the present study may reflect each different toxicity profile of platinum combined with paclitaxel and RT. The negligible occurrence of other non-hematological toxicities such as neuropathy and alopecia, which were usually related to paclitaxel administration, may be explained by both low peak concentration due to the weekly fractionation and low cumulative dose (180–240 mg/m2) reached. Hematological toxicity was mild. No grade 4 neutropenia was observed and grade 3 neutropenia was observed in six of 20 (30%) patients, while the same results were observed in the previous studies of paclitaxel and the other platinum compounds with thoracic RT (12–14).
The overall response rate observed in the present study suggests that the combinations of paclitaxel and nedaplatin are worth further evaluation, although the small number of patients treated in each cohort prevents us from drawing any conclusion. The 1-year projected survival and median survival were unsatisfactory compared with those shown in the previous studies (12,14), although the 95% confidence intervals were broad because of the small sample size. Thus, in the present study, the median survival and the 1-year projected survival were 46 weeks and 40%, respectively, while previous phase I studies showed that they were 50–80 weeks and 54–62%, respectively (9,12,31,32). The frequent occurrence of pulmonary toxicity may be related to shorter survival of the patients in our study which was similar to the result in the study of Antonia et al. (29). In fact, the patients with severe radiation pneumonia developed pneumonia more frequently. Therefore, we stopped to enroll the patients to be treated at the recommended dose level in the present study.
We measured the AUCs of paclitaxel and nedaplatin in 19 of 20 patients. In group 3, the dose and the AUC of paclitaxel were more than in group 1. Several laboratory studies suggest that the dose–response range for radiosensitization by paclitaxel may be relatively narrow, 10–50 nmol/l, and that the duration of exposure to paclitaxel is more important than the peak concentration for antitumor activity and radiosensitization (34,35). Paclitaxel has an enhancing effect on the toxicity of RT to the lung (33). Our data suggest that the dose of paclitaxel may be correlated with the incidence of toxicity to the lung when both paclitaxel and nedaplatin were administered concomitantly with RT in lung cancer patients.
In conclusion, weekly paclitaxel and nedaplatin is a safe and effective chemotherapy regimen in combination with thoracic radiation, when the administered doses were 35 mg/m2 for paclitaxel and 20 mg/m2 for nedaplatin. The predominant DLT seen with this combination was pulmonary toxicity. Further study to investigate the effect of the combination of paclitaxel and nedaplatin with RT should be directed with attention to pulmonary toxicity as possible results of radiation dose and volumes because pulmonary toxicity was observed more frequently than in several previous studies (10,13,30). More effective approaches should be included in further studies with this regimen to decrease pulmonary toxicity.
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References |
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