Clinical Study Chemotherapy 2013;59:346–353 DOI: 10.1159/000362222
Received: November 28, 2013 Accepted after revision: March 13, 2014 Published online: May 9, 2014
A Randomized Phase II Trial of Gemcitabine plus Carboplatin: Biweekly versus Standard Schedules in Patients with Advanced Non-Small Cell Lung Cancer Yukihiro Hasegawa a, c Dai Miura a Chiho Kitamura a Takaya Suzuki b Kazuma Kobayashi b Nobuyuki Sato b Departments of a Respiratory Medicine and b Thoracic Surgery, Aomori Prefectural Central Hospital, and c Department of Cardiology and Respiratory Medicine, Aomori City Hospital, Aomori, Japan
Abstract Objective: Gemcitabine combined with carboplatin (GC) is a widely used regimen for advanced non-small cell lung cancer (NSCLC), but clinical outcome is still hampered by its toxicity. We conducted a randomized phase II study of GC and compared biweekly versus standard schedules in patients with advanced NSCLC with respect to toxicity and outcome. Methods: Forty patients with stage IIIB or IV NSCLC were randomized to receive either a biweekly regimen of GC [gemcitabine (1,000 mg/m2 on days 1 and 14) and carboplatin (area under the concentration-time curve, AUC = 3 on days 1 and 14)] every 28 days or a standard regimen of GC [gemcitabine (1,000 mg/m2 on days 1 and 8) and carboplatin (AUC = 5 on day 1)] every 21 days. These cycles were repeated until disease progression. Results: Response rates were 55% for the biweekly regimen and 40% for the standard regimen. Median overall and progression-free survival times were 19.7 and 6.2 months, respectively, for the biweekly regimen, and 11.8 and 2.8 months, respectively, for the standard GC regimen. Hematologic toxicity was prominent. However,
© 2014 S. Karger AG, Basel 0009–3157/14/0595–0346$39.50/0 E-Mail [email protected] www.karger.com/che
the incidence of grade 1 or 2 thrombocytopenia was significantly lower in the biweekly than in the standard GC regimen (p < 0.05). Nonhematologic toxicity was mild. Conclusion: A biweekly GC regimen was better tolerated than a standard GC regimen in patients with advanced NSCLC. © 2014 S. Karger AG, Basel
Introduction
Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality among both men and women in the United States and Japan. More than one half of new diagnoses and more than two thirds of annual deaths in patients with NSCLC occur in people >65 years, in whom concomitant diseases or a poor performance status (PS) may complicate the ability to tolerate chemotherapy. Therefore, a novel combination chemotherapy in patients with advanced and metastatic NSCLC may improve outcome while minimizing toxicities and improving quality of life. Platinum-based therapy has become a standard treatment approach for patients with advanced and metastatic NSCLC [1]. Chemotherapy plus best supportive care increased overall survival and reduced the 6-, 12- and 24-month mortality rates of NSCLC Yukihiro Hasegawa, MD Department of Respiratory Medicine Aomori Prefectural Central Hospital 2-1-1 Higashi, Tsukurimichi, Aomori 030-8553 (Japan) E-Mail hasekatuyh @ me.com
Downloaded by: Lund University Libraries 130.235.136.21 - 5/13/2015 12:38:36 PM
Key Words Biweekly chemotherapy · Carboplatin · Gemcitabine · Non-small cell lung cancer
patients [2–4]. Recent results of the Big Lung Trial comparing cisplatin-based therapy and best supportive care in >700 patients with advanced NSCLC showed that treatment benefits were independent of disease stage (III or IV) and extended to patients with a World Health Organization PS of 2 [5]. In the 1990s, there has been a surge of interest in a number of new agents that have displayed activity in advanced NSCLC [6]. Among these, gemcitabine (2′,2′-difluorodeoxycytidine) is one of the most promising. Although structurally similar to cytarabine, gemcitabine has a different spectrum of antitumor activity, probably as a result of the different kinetics of accumulation and elimination. A number of phase II studies of gemcitabine in advanced NSCLC have been performed, and a consistent reproducible response rate of 20–26% has been demonstrated, with mean response duration and median overall survival times of approximately 9 months. In all of these studies, in which gemcitabine was used at weekly doses ranging from 800 to 1,250 mg/m2 for 3 weeks every 28 days, toxicity was considered mild [7–9]. Among the issues in the further development of gemcitabine for treatment of lung cancer, the combined administration with platinum compounds was probably most valid. A combination of gemcitabine with cisplatin (GP) or gemcitabine with carboplatin (GC) has proven to be among the most palliative treatments for advanced NSCLC. Attempts to reduce the toxicity associated with the GP regimen have included replacing cisplatin with carboplatin, which possesses similar efficacy and hematologic effect, but lacks the nonhematologic toxicities commonly experienced with cisplatin. A randomized phase II study of GC versus GP showed no differences in activity between the two regimens, although there was less emesis, neuropathy and renal toxicity with GC [10]. The same results were confirmed in a phase III study of GC versus GP conducted by Zatloukal et al. [11]. Moreover, the GC regimen reportedly prolonged survival significantly compared with single-agent carboplatin in a randomized phase III study [12]. In fact, the GC regimen has proven to be one of the best regimens for advanced NSCLC with definite anticancer efficacy [13]. However, severe thrombocytopenia was frequently observed with the triweekly regimen of GC [14]. Previously, we reported that a biweekly regimen of GC had a manageable toxicity profile without thrombocytopenia [15, 16]. In a phase I study, we determined that the recommended dose of gemcitabine and carboplatin in a biweekly regimen of GC was 1,000 mg/m2 and the area under the concentration-time curve (AUC) 3, respective-
ly. In the phase II study, we found that the biweekly regimen of GC was well tolerated and active in NSCLC while thrombocytopenia was mild. Therefore, we conducted a randomized phase II trial of a biweekly regimen versus a standard schedule for GC in patients with advanced NSCLC to compare efficacy, feasibility and toxicity profiles of the two schedules. The primary endpoint was the toxicity profiles including thrombocytopenia. The secondary endpoints were the response rate, 1-year survival, progression-free and overall survival.
Biweekly versus Standard GC Therapy for NSCLC
Chemotherapy 2013;59:346–353 DOI: 10.1159/000362222
Patients and Methods
Randomization and Treatment Plan At study entry, patients were assigned randomly to arm A or B. In arm A (biweekly regimen), patients received gemcitabine 1,000 mg/m2 i.v. over 30 min on days 1 and 14. Carboplatin was administered at a dose targeting an AUC of 3 over 60 min on days 1 and 14. This cycle was repeated every 4 weeks until disease progression. In arm B (standard regimen), patients received gemcitabine 1,000 mg/m2 i.v. over 30 min on days 1 and 8. Carboplatin was administered at a dose targeting an AUC of 5 over 60 min on day 1. This cycle was repeated every 3 weeks until disease progression. Prophylactic antiemetics for carboplatin were granisetron 8 mg i.v. and dexamethasone 8 mg i.v. Chemotherapy beyond the second cycle continued if the following criteria were met: neutrophils ≥1,500/μl, platelet counts ≥100,000/μl, serum creatinine ≤1.2 mg/ dl, and if aspartate and alanine aminotransferase levels were ≤2.5 times the upper limit of normal.
347
Downloaded by: Lund University Libraries 130.235.136.21 - 5/13/2015 12:38:36 PM
Patient Selection The patients who were enrolled in this trial had histologically or cytologically confirmed stage IIIB and IV NSCLC. Patients with stage IIIB disease who were not candidates for thoracic radiation and patients with stage IV disease were eligible if they had not received previous chemotherapy, had measurable disease and life expectancy was ≥3 months. Patients who had received previous radiotherapy were included if they had assessable disease outside of the radiation field. Additional entry criteria were age ≥20 years, PS of 0 or 1 on the Eastern Cooperative Oncology Group scale and adequate bone marrow function (leukocyte count ≥3,500/μl, neutrophil count ≥2,000/μl, hemoglobin concentration ≥10.0 g/dl and platelet count ≥100,000/μl), renal function (creatinine ≤1.2 mg/dl), liver function (aspartate and alanine aminotransferase levels ≤2.5 times the upper limit of normal, and total bilirubin ≤1.5 mg/dl) and arterial oxygen saturation (SpO2) on room air ≥93%. Patients were excluded if they had any active concomitant malignancies, symptomatic brain metastases, interstitial pneumonia identified by chest X-ray, cirrhosis, superior vena cava syndrome or other serious complications, such as uncontrolled angina pectoris, myocardial infarction within 3 months, heart failure, uncontrolled diabetes mellitus or hypertension, and uncontrolled massive pleural effusion or ascites. The Ethical Committees for the Research of the Aomori Prefectural Central Hospital and Aomori City Hospital approved this study protocol. All patients signed written informed consent forms before enrollment.
Treatment Evaluation The pretreatment evaluation included a complete histology and physical examination, ECG, chest X-ray, respiratory tests, fiberoptic bronchoscopy and computed tomography (CT) of the chest and upper abdomen. A bone radionucleotide scan and CT or magnetic resonance imaging of the brain was also performed if necessary to document disease extent. Laboratory investigation included a complete blood cell count with differential white blood cell and platelet counts, a full chemistry profile and urinalysis. Physical examination and routine laboratory tests were performed every week for a minimum of 8 weeks after treatment. Toxicity was scored every month during treatment according to National Cancer Institute Common Toxicity Criteria (version 3.0). Response was evaluated every 4 weeks during treatment, and every 6 months until disease progression thereafter, using Response Evaluation Criteria in Solid Tumors [17]. Statistical Methods The primary endpoint of this study was the toxicity profiles including thrombocytopenia. If the threshold thrombocytopenia and the expected thrombocytopenia were to be 30 and 50%, respectively, the study has 90% confidence using Simon’s selection design when 20 patients were included in each arm. We compared Kaplan-Meier curves for overall and progression-free survival using the standard log-rank test. Overall survival was defined as the interval from the date of random treatment assignment to the date of death or the last follow-up information for patients who remained alive. Progression-free survival was defined as the interval from the date of random treatment assignment to the date of progression or death, whichever occurred first, or the last follow-up information for patients who remained alive and for patients whose disease did not progress. Except for age, response rates, dose reduction rate in each cycle and toxicity incidence, patient characteristics were compared using Pearson’s χ2 contingency table analysis. Age and the number of treatment cycles were compared using the unpaired t test with Welch’s correction.
348
Chemotherapy 2013;59:346–353 DOI: 10.1159/000362222
Table 1. Patient characteristics
Age, years Mean Range Gender Male Female Performance status 0 1 Histology Adenocarcinoma Squamous cell carcinoma Clinical stage IIIB IV
Arm A (n = 20)
Arm B (n = 20)
67.9 54 – 80
68.8 57 – 87
13 7
16 4
13 7
10 10
15 5
16 4
2 18
0 20
Results
Patient Characteristics From February 2006 to November 2012, 40 patients were assigned to arm A (n = 20 patients) or arm B (n = 20 patients). All patients enrolled were eligible. Baseline patient characteristics according to treatment arm are shown in table 1. Essentially, patients were divided equally between the two treatment arms in terms of gender, age, PS, disease stage and histologic subtypes. Treatment Delivery The median number of cycles administered to arm A was 4 (95% CI, 3.055–6.945; range, 1–20) and to arm B it was 3 (95% CI, 2.57–7.43; range, 1–24). The difference between the two arms in the number of chemotherapy courses administered was not statistically significant (p = 0.34). However, as shown in table 2, patients who required dose reductions were more frequent in arm B (n = 10 patients, 50%) than in arm A (n = 4 patients, 20%; p = 0.096). Treatment Response and Survival In arm A, there were 0 complete and 11 partial responses, with an overall response rate of 55% (table 3). In addition, 5 patients (25%) had stable disease and 4 patients (20%) had progressive disease. In arm B, there were 0 complete and 8 partial responses, with an overall response rate of 40%. There were 7 patients (35%) with stable disease and 5 patients (25%) with disease progression. Hasegawa /Miura /Kitamura /Suzuki / Kobayashi /Sato
Downloaded by: Lund University Libraries 130.235.136.21 - 5/13/2015 12:38:36 PM
Drugs were administered on an in- or outpatient basis according to institutional and/or patient preference. Patients received the treatment unless one of the following occurred: disease progression, unacceptable toxicity, withdrawal of consent by the patient and physician’s discretion. Therapy continuation after study termination was permitted at the discretion of the investigator. The treatment dose was modified in the subsequent cycle in both arms if, during the previous course, grade 4 leukopenia, chemotherapyinduced neutropenic fever >38 ° C, thrombocytopenia (
Received: November 28, 2013 Accepted after revision: March 13, 2014 Published online: May 9, 2014
A Randomized Phase II Trial of Gemcitabine plus Carboplatin: Biweekly versus Standard Schedules in Patients with Advanced Non-Small Cell Lung Cancer Yukihiro Hasegawa a, c Dai Miura a Chiho Kitamura a Takaya Suzuki b Kazuma Kobayashi b Nobuyuki Sato b Departments of a Respiratory Medicine and b Thoracic Surgery, Aomori Prefectural Central Hospital, and c Department of Cardiology and Respiratory Medicine, Aomori City Hospital, Aomori, Japan
Abstract Objective: Gemcitabine combined with carboplatin (GC) is a widely used regimen for advanced non-small cell lung cancer (NSCLC), but clinical outcome is still hampered by its toxicity. We conducted a randomized phase II study of GC and compared biweekly versus standard schedules in patients with advanced NSCLC with respect to toxicity and outcome. Methods: Forty patients with stage IIIB or IV NSCLC were randomized to receive either a biweekly regimen of GC [gemcitabine (1,000 mg/m2 on days 1 and 14) and carboplatin (area under the concentration-time curve, AUC = 3 on days 1 and 14)] every 28 days or a standard regimen of GC [gemcitabine (1,000 mg/m2 on days 1 and 8) and carboplatin (AUC = 5 on day 1)] every 21 days. These cycles were repeated until disease progression. Results: Response rates were 55% for the biweekly regimen and 40% for the standard regimen. Median overall and progression-free survival times were 19.7 and 6.2 months, respectively, for the biweekly regimen, and 11.8 and 2.8 months, respectively, for the standard GC regimen. Hematologic toxicity was prominent. However,
© 2014 S. Karger AG, Basel 0009–3157/14/0595–0346$39.50/0 E-Mail [email protected] www.karger.com/che
the incidence of grade 1 or 2 thrombocytopenia was significantly lower in the biweekly than in the standard GC regimen (p < 0.05). Nonhematologic toxicity was mild. Conclusion: A biweekly GC regimen was better tolerated than a standard GC regimen in patients with advanced NSCLC. © 2014 S. Karger AG, Basel
Introduction
Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality among both men and women in the United States and Japan. More than one half of new diagnoses and more than two thirds of annual deaths in patients with NSCLC occur in people >65 years, in whom concomitant diseases or a poor performance status (PS) may complicate the ability to tolerate chemotherapy. Therefore, a novel combination chemotherapy in patients with advanced and metastatic NSCLC may improve outcome while minimizing toxicities and improving quality of life. Platinum-based therapy has become a standard treatment approach for patients with advanced and metastatic NSCLC [1]. Chemotherapy plus best supportive care increased overall survival and reduced the 6-, 12- and 24-month mortality rates of NSCLC Yukihiro Hasegawa, MD Department of Respiratory Medicine Aomori Prefectural Central Hospital 2-1-1 Higashi, Tsukurimichi, Aomori 030-8553 (Japan) E-Mail hasekatuyh @ me.com
Downloaded by: Lund University Libraries 130.235.136.21 - 5/13/2015 12:38:36 PM
Key Words Biweekly chemotherapy · Carboplatin · Gemcitabine · Non-small cell lung cancer
patients [2–4]. Recent results of the Big Lung Trial comparing cisplatin-based therapy and best supportive care in >700 patients with advanced NSCLC showed that treatment benefits were independent of disease stage (III or IV) and extended to patients with a World Health Organization PS of 2 [5]. In the 1990s, there has been a surge of interest in a number of new agents that have displayed activity in advanced NSCLC [6]. Among these, gemcitabine (2′,2′-difluorodeoxycytidine) is one of the most promising. Although structurally similar to cytarabine, gemcitabine has a different spectrum of antitumor activity, probably as a result of the different kinetics of accumulation and elimination. A number of phase II studies of gemcitabine in advanced NSCLC have been performed, and a consistent reproducible response rate of 20–26% has been demonstrated, with mean response duration and median overall survival times of approximately 9 months. In all of these studies, in which gemcitabine was used at weekly doses ranging from 800 to 1,250 mg/m2 for 3 weeks every 28 days, toxicity was considered mild [7–9]. Among the issues in the further development of gemcitabine for treatment of lung cancer, the combined administration with platinum compounds was probably most valid. A combination of gemcitabine with cisplatin (GP) or gemcitabine with carboplatin (GC) has proven to be among the most palliative treatments for advanced NSCLC. Attempts to reduce the toxicity associated with the GP regimen have included replacing cisplatin with carboplatin, which possesses similar efficacy and hematologic effect, but lacks the nonhematologic toxicities commonly experienced with cisplatin. A randomized phase II study of GC versus GP showed no differences in activity between the two regimens, although there was less emesis, neuropathy and renal toxicity with GC [10]. The same results were confirmed in a phase III study of GC versus GP conducted by Zatloukal et al. [11]. Moreover, the GC regimen reportedly prolonged survival significantly compared with single-agent carboplatin in a randomized phase III study [12]. In fact, the GC regimen has proven to be one of the best regimens for advanced NSCLC with definite anticancer efficacy [13]. However, severe thrombocytopenia was frequently observed with the triweekly regimen of GC [14]. Previously, we reported that a biweekly regimen of GC had a manageable toxicity profile without thrombocytopenia [15, 16]. In a phase I study, we determined that the recommended dose of gemcitabine and carboplatin in a biweekly regimen of GC was 1,000 mg/m2 and the area under the concentration-time curve (AUC) 3, respective-
ly. In the phase II study, we found that the biweekly regimen of GC was well tolerated and active in NSCLC while thrombocytopenia was mild. Therefore, we conducted a randomized phase II trial of a biweekly regimen versus a standard schedule for GC in patients with advanced NSCLC to compare efficacy, feasibility and toxicity profiles of the two schedules. The primary endpoint was the toxicity profiles including thrombocytopenia. The secondary endpoints were the response rate, 1-year survival, progression-free and overall survival.
Biweekly versus Standard GC Therapy for NSCLC
Chemotherapy 2013;59:346–353 DOI: 10.1159/000362222
Patients and Methods
Randomization and Treatment Plan At study entry, patients were assigned randomly to arm A or B. In arm A (biweekly regimen), patients received gemcitabine 1,000 mg/m2 i.v. over 30 min on days 1 and 14. Carboplatin was administered at a dose targeting an AUC of 3 over 60 min on days 1 and 14. This cycle was repeated every 4 weeks until disease progression. In arm B (standard regimen), patients received gemcitabine 1,000 mg/m2 i.v. over 30 min on days 1 and 8. Carboplatin was administered at a dose targeting an AUC of 5 over 60 min on day 1. This cycle was repeated every 3 weeks until disease progression. Prophylactic antiemetics for carboplatin were granisetron 8 mg i.v. and dexamethasone 8 mg i.v. Chemotherapy beyond the second cycle continued if the following criteria were met: neutrophils ≥1,500/μl, platelet counts ≥100,000/μl, serum creatinine ≤1.2 mg/ dl, and if aspartate and alanine aminotransferase levels were ≤2.5 times the upper limit of normal.
347
Downloaded by: Lund University Libraries 130.235.136.21 - 5/13/2015 12:38:36 PM
Patient Selection The patients who were enrolled in this trial had histologically or cytologically confirmed stage IIIB and IV NSCLC. Patients with stage IIIB disease who were not candidates for thoracic radiation and patients with stage IV disease were eligible if they had not received previous chemotherapy, had measurable disease and life expectancy was ≥3 months. Patients who had received previous radiotherapy were included if they had assessable disease outside of the radiation field. Additional entry criteria were age ≥20 years, PS of 0 or 1 on the Eastern Cooperative Oncology Group scale and adequate bone marrow function (leukocyte count ≥3,500/μl, neutrophil count ≥2,000/μl, hemoglobin concentration ≥10.0 g/dl and platelet count ≥100,000/μl), renal function (creatinine ≤1.2 mg/dl), liver function (aspartate and alanine aminotransferase levels ≤2.5 times the upper limit of normal, and total bilirubin ≤1.5 mg/dl) and arterial oxygen saturation (SpO2) on room air ≥93%. Patients were excluded if they had any active concomitant malignancies, symptomatic brain metastases, interstitial pneumonia identified by chest X-ray, cirrhosis, superior vena cava syndrome or other serious complications, such as uncontrolled angina pectoris, myocardial infarction within 3 months, heart failure, uncontrolled diabetes mellitus or hypertension, and uncontrolled massive pleural effusion or ascites. The Ethical Committees for the Research of the Aomori Prefectural Central Hospital and Aomori City Hospital approved this study protocol. All patients signed written informed consent forms before enrollment.
Treatment Evaluation The pretreatment evaluation included a complete histology and physical examination, ECG, chest X-ray, respiratory tests, fiberoptic bronchoscopy and computed tomography (CT) of the chest and upper abdomen. A bone radionucleotide scan and CT or magnetic resonance imaging of the brain was also performed if necessary to document disease extent. Laboratory investigation included a complete blood cell count with differential white blood cell and platelet counts, a full chemistry profile and urinalysis. Physical examination and routine laboratory tests were performed every week for a minimum of 8 weeks after treatment. Toxicity was scored every month during treatment according to National Cancer Institute Common Toxicity Criteria (version 3.0). Response was evaluated every 4 weeks during treatment, and every 6 months until disease progression thereafter, using Response Evaluation Criteria in Solid Tumors [17]. Statistical Methods The primary endpoint of this study was the toxicity profiles including thrombocytopenia. If the threshold thrombocytopenia and the expected thrombocytopenia were to be 30 and 50%, respectively, the study has 90% confidence using Simon’s selection design when 20 patients were included in each arm. We compared Kaplan-Meier curves for overall and progression-free survival using the standard log-rank test. Overall survival was defined as the interval from the date of random treatment assignment to the date of death or the last follow-up information for patients who remained alive. Progression-free survival was defined as the interval from the date of random treatment assignment to the date of progression or death, whichever occurred first, or the last follow-up information for patients who remained alive and for patients whose disease did not progress. Except for age, response rates, dose reduction rate in each cycle and toxicity incidence, patient characteristics were compared using Pearson’s χ2 contingency table analysis. Age and the number of treatment cycles were compared using the unpaired t test with Welch’s correction.
348
Chemotherapy 2013;59:346–353 DOI: 10.1159/000362222
Table 1. Patient characteristics
Age, years Mean Range Gender Male Female Performance status 0 1 Histology Adenocarcinoma Squamous cell carcinoma Clinical stage IIIB IV
Arm A (n = 20)
Arm B (n = 20)
67.9 54 – 80
68.8 57 – 87
13 7
16 4
13 7
10 10
15 5
16 4
2 18
0 20
Results
Patient Characteristics From February 2006 to November 2012, 40 patients were assigned to arm A (n = 20 patients) or arm B (n = 20 patients). All patients enrolled were eligible. Baseline patient characteristics according to treatment arm are shown in table 1. Essentially, patients were divided equally between the two treatment arms in terms of gender, age, PS, disease stage and histologic subtypes. Treatment Delivery The median number of cycles administered to arm A was 4 (95% CI, 3.055–6.945; range, 1–20) and to arm B it was 3 (95% CI, 2.57–7.43; range, 1–24). The difference between the two arms in the number of chemotherapy courses administered was not statistically significant (p = 0.34). However, as shown in table 2, patients who required dose reductions were more frequent in arm B (n = 10 patients, 50%) than in arm A (n = 4 patients, 20%; p = 0.096). Treatment Response and Survival In arm A, there were 0 complete and 11 partial responses, with an overall response rate of 55% (table 3). In addition, 5 patients (25%) had stable disease and 4 patients (20%) had progressive disease. In arm B, there were 0 complete and 8 partial responses, with an overall response rate of 40%. There were 7 patients (35%) with stable disease and 5 patients (25%) with disease progression. Hasegawa /Miura /Kitamura /Suzuki / Kobayashi /Sato
Downloaded by: Lund University Libraries 130.235.136.21 - 5/13/2015 12:38:36 PM
Drugs were administered on an in- or outpatient basis according to institutional and/or patient preference. Patients received the treatment unless one of the following occurred: disease progression, unacceptable toxicity, withdrawal of consent by the patient and physician’s discretion. Therapy continuation after study termination was permitted at the discretion of the investigator. The treatment dose was modified in the subsequent cycle in both arms if, during the previous course, grade 4 leukopenia, chemotherapyinduced neutropenic fever >38 ° C, thrombocytopenia (
