Abstract
Pemetrexed plus carboplatin therapy is widely administered to patients with non-squamous non-small cell lung cancer. Although severe neutropenia is often observed during this combination therapy, its predictive factors are unknown. Therefore, we investigated the predictive factors for severe neutropenia in 77 patients treated with this combination therapy at the Department of Respiratory Medicine, Kyushu University Hospital, between September 2009 and September 2013. All data were retrospectively collected from the electronic medical record system, and univariate and multivariate logistic regression analyses were performed to identify risk factors for grade 3 or 4 neutropenia. Among the 77 patients, 34 (44%) developed grade 3 or 4 neutropenia. Multivariate analysis revealed that lower baseline hemoglobin values (odds ratio [OR], 1.97 per 1 g/dL decrease; 95% confidence interval [CI], 1.39–2.99, p<0.01) and lower baseline neutrophil counts (OR, 1.71 per 1000/mm3 decrease; 95% CI, 1.14–2.71, p=0.01) were significantly associated with grade 3 or 4 neutropenia. During 4 courses of pemetrexed plus carboplatin therapy, the incidence of grade 3 or 4 neutropenia in patients with baseline hemoglobin values of <11.6 g/dL was significantly higher than that in patients with values of ≥11.6 g/dL [84% (16/19) vs. 31% (18/58), p<0.001]. In conclusion, patients with lower baseline neutrophil counts or lower baseline hemoglobin values, especially those with baseline hemoglobin values of <11.6 g/dL, should be monitored more carefully during pemetrexed plus carboplatin therapy.
Lung cancer is one of the most common types of cancer and is the leading cause of cancer deaths worldwide and in Japan.1,2) Approximately 85% of all patients with lung cancer are diagnosed as having non-small cell lung cancer (NSCLC). Pemetrexed is a multi-targeted folate-based antimetabolite. In patients with non-squamous NSCLC, pemetrexed in combination with a platinum agent was recently shown to have a better therapeutic effect and to prolong overall survival compared to other anti-cancer drugs in combination with a platinum agent.3–5)
Therefore, in the current clinical practice guidelines, pemetrexed plus cisplatin therapy is recommended as one of the standard first-line therapies for chemotherapy-naïve patients with non-squamous NSCLC who have a good performance status (PS).6,7) Cisplatin is associated with more unpleasant adverse effects, including neurotoxicity, emesis, and acute kidney injury, and its administration requires prolonged hydration and hospitalization. On the other hand, carboplatin does not require prolonged hydration.8) Pemetrexed plus carboplatin therapy is widely administered due to its lower toxicity and more convenient administration.9)
The major toxicity observed after pemetrexed monotherapy is severe neutropenia.10) The incidence of grade 3 or 4 neutropenia according to the Common Terminology Criteria for Adverse Events (CTC AE) was 29–54% among patients with non-squamous NSCLC receiving pemetrexed plus carboplatin therapy in Japanese clinical trials.11–14) Severe neutropenia often induces fatal infection. In addition, neutropenic complications require antimicrobial treatment and result in high health care costs.15,16) Therefore, it is important to clarify the risk factors for severe neutropenia in patients receiving pemetrexed plus carboplatin therapy. Recently, Sakata et al.17) reported that a baseline creatinine clearance rate (Ccr) of <45 mL/min was a risk factor for severe adverse drug events in 82 Japanese patients with advanced NSCLC receiving pemetrexed monotherapy. However, the predictive factors for severe neutropenia in patients receiving pemetrexed plus carboplatin therapy are unknown. Therefore, we investigated the predictive factors for severe neutropenia in patients with non-squamous NSCLC receiving this combination therapy.
MATERIALS AND METHODS
Study Design, Setting, and Patient PopulationThe present study was conducted in accordance with the Declaration of Helsinki and the Ethical Guidelines for Epidemiological Research by the Ministry of Education, Culture, Sports, Science and Technology, and the Ministry of Health, Labour and Welfare of Japan. The protocol was approved by the Ethics Committee of Kyushu University Graduate School and Faculty of Medicine (approval no. 25–291). The need for informed consent was waived for this retrospective study. Patients were eligible for the study if they were 20 years of age or older, diagnosed with advanced or recurrent NSCLC, and received pemetrexed plus carboplatin therapy at the Department of Respiratory Medicine, Kyushu University Hospital, between September 1, 2009 and September 31, 2013.
TreatmentChemotherapy consisted of pemetrexed (500 mg/m2) through a 10-min intravenous infusion, carboplatin at an area under the concentration–time curve (AUC) of 5 or 6 mg/mL·min over 30 min, and/or bevacizumab (15 mg/kg) on day 1 every 3 weeks. Dose reduction was performed in some patients based on the judgment of the physicians. The dose of carboplatin was calculated using the Calvert formula with the calculated Ccr derived using the Cockcroft–Gault equation. All patients received folic acid (0.5 mg) orally every day and a vitamin B12 (1 mg) injection intramuscularly every 9 weeks, beginning at least 1 week before the first dose and continuing until 3 weeks after the last dose of pemetrexed. The use of granulocyte-colony stimulating factor (G-CSF) was permitted as a therapeutic intervention for neutropenia but not for prophylaxis. Other medications for underlying diseases, complications, and pain control were allowed.
Data Collection and AssessmentAll data were collected from the electronic medical record system. We evaluated information regarding patients’ sex, age, body weight, smoking history, histology, Eastern Cooperative Oncology Group (ECOG) PS, clinical stage, prior chemotherapy, dose of pemetrexed and carboplatin, concomitant medications, serum albumin, Ccr, aspartate aminotransferase (AST), alanine aminotransferase (ALT), bilirubin, and blood cell counts. These variables were monitored between the beginning of the first course of therapy and 21 d after the fourth course. In the present study, the frequency of laboratory tests was determined at the physician’s discretion. We also evaluated the severity of diarrhea, nausea and vomiting.
The severity of toxicities were classified according to the CTC AE v.4.0. The nadir neutrophil count in each patient was determined as the lowest value during any course of pemetrexed plus carboplatin therapy. Neutropenic events were defined as febrile neutropenia, infections, G-CSF treatment or blood transfusion.
Tumor responses were classified according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria version 1.1. The response was evaluated from the findings of computed tomography (CT) scans of the chest and the upper abdomen.
The primary objective was to detect the risk factors associated with grade 3 or 4 neutropenia.
Statistical AnalysesTo compare categorical data, the Chi-square test or Fisher’s exact test was used as appropriate. For continuous data, normally distributed values are presented as mean±standard deviation (S.D.). Values that were not normally distributed are presented as the median and range. Student’s t-test was used to compare normally distributed variables between groups. Mann–Whitney’s U test was used to compare non-normally distributed variables between groups. The correlation between continuous data was determined using the Pearson’s correlation coefficient test.
To identify the factors associated with grade 3 or 4 neutropenia, univariate logistic regression analyses were performed using patients’ sex, age, body weight, ECOG PS, prior therapy, dose of carboplatin, concomitant medications, albumin, Ccr, and neutrophil, hemoglobin, and platelet counts as independent variables. Factors with a p value of <0.10 in univariate analyses were evaluated as potential covariates in multivariate stepwise logistic regression analysis with backward selection.
The correlations between baseline hemoglobin values and other laboratory data were determined using the Pearson’s correlation coefficient test. Data were analyzed using JMP 9.0.2 (SAS Institute Inc., Cary, NC, U.S.A.). p values of <0.05 were considered statistically significant.
RESULTS
Patient CharacteristicsBetween September 2009 and September 2013, 78 patients were treated with pemetrexed plus carboplatin therapy for NSCLC at the Department of Respiratory Medicine, Kyushu University Hospital. Among them, one patient with leukocyte counts >10000/mm3 at the beginning of pemetrexed plus carboplatin therapy for inflammation after pleurodesis with OK-432 (Picibanil) was excluded. The baseline characteristics of the remaining 77 patients are summarized in Table 1. Sixty-three patients had a good PS (0 or 1), and 16 patients had previously received one or more chemotherapy regimens. Twenty-four patients received carboplatin at a target AUC of ≤5 mg/mL·min, and 2 patients received pemetrexed at a dose of 400 mg/m2. Thirty-six patients received non-steroidal anti-inflammatory drugs (NSAIDs) concomitantly (loxoprofen, n=23; diclofenac, n=8; celecoxib, n=4; meloxicam, n=1). Mean neutrophil counts (4.0±1.4 vs. 4.8±1.3×103/mm3, p=0.006), albumin levels (3.6±0.4 vs. 3.9±0.4 g/dL, p=0.006), and hemoglobin values (11.7±1.8 vs. 13.3±1.3 g/dL, p<0.001) at baseline were significantly lower in patients who developed grade 3 or 4 neutropenia (n=34) than in those with grade 2 or less neutropenia (n=26) or without neutropenia (n=17). The numbers of patients who received 1, 2, 3, and 4 courses of pemetrexed plus carboplatin therapy were 12, 12, 15, and 42, respectively.
Table 1. Patient Characteristics
| Characteristics | Grade 2 or less (n=43) | Grade 3 or 4 (n=34) | p-Value |
|---|
| Sex, n |
| Male/Female | 21/22 | 19/15 | 0.539 |
| Age (years), median (range) | 67 (29–76) | 63 (43–76) | 0.180 |
| Weight (kg), mean±S.D. | 55.0±8.7 | 54.5±10.0 | 0.823 |
| Smoking history |
| Yes | 24 (55.8%) | 20 (58.8%) | 0.791 |
| No | 19 (44.2%) | 14 (41.2%) | |
| Histology |
| Adenocarcinoma | 43 (100%) | 33 (97.1%) | 0.442 |
| Adenocarcinoma+small cell carcinoma | 0 (0%) | 1 (2.9%) | |
| ECOG PS |
| 0 | 7 (16.3%) | 7 (20.6%) | 0.888 |
| 1 | 28 (65.1%) | 21 (61.8%) | |
| 2 | 8 (18.6%) | 6 (17.7%) | |
| Clinical stage |
| IIIB | 1 (2.3%) | 2 (5.9%) | — |
| IV | 39 (90.7%) | 32 (94.1%) | |
| Recurrence | 3 (7.0%) | 0 (0%) | |
| Prior chemotherapy |
| None | 37 (86.1%) | 24 (70.6%) | — |
| 1 | 5 (11.6%) | 8 (23.5%) | |
| 2–4 | 1 (2.3%) | 2 (5.8%) | |
| Carboplatin dose (AUC), n (%) |
| ≤5 | 16 (37.2%) | 8 (23.5%) | 0.198 |
| 6 | 27 (51.2%) | 26 (76.5%) | |
| Pemetrexed dose (mg/m2) |
| 500 | 42 (97.7%) | 33 (97.1%) | 1.000 |
| 400 | 1 (2.9%) | 1 (2.9%) | |
| Concomitant use of bevacizumab, n (%) | 20 (46.5%) | 9 (26.5%) | 0.075 |
| Concomitant use of NSAIDs, n (%) | 23 (53.5%) | 13 (38.2%) | 0.183 |
| Albumin (g/dL), mean±S.D. | 3.9±0.4 | 3.6±0.4 | 0.006 |
| Ccr (mL/min), mean±S.D. | 83.1±25.3 | 78.6±28.9 | 0.467 |
| AST (U/L), median (range) | 18 (13–35) | 20 (9–66) | 0.632 |
| ALT (U/L), median (range) | 16 (7–47) | 12 (5–48) | 0.118 |
| Bilirubin (U/L), median (range) | 0.6 (0.2–1.0) | 0.6 (0.2–0.9) | 0.716 |
| Neutrophil count (×103/mm3), mean±S.D. | 4.8±1.3 | 4.0±1.4 | 0.006 |
| Hemoglobin (g/dL), mean±S.D. | 13.3±1.3 | 11.7±1.8 | <0.001 |
| Platelet count (×104/mm3), median (range) | 24.4 (14.2–45.8) | 21.0 (13.6–48.1) | 0.412 |
ECOG, Eastern Cooperative Oncology Group; PS, performance status; AUC, area under the curve; NSAIDs, non-steroidal anti-inflammatory drugs; Ccr, creatinine clearance rate; AST, aspartate transaminase; ALT, alanine transaminase.
The incidences of all grade neutropenia and grade 3 or 4 neutropenia during the pemetrexed plus carboplatin therapy were 78% (60/77) and 44% (34/77), respectively. The incidence of febrile neutropenia (p=0.034) was significantly higher in patients who developed grade 3 or 4 neutropenia (Table 2). The percentages of patients who received G-CSF treatment (p=0.001) and patients with dose reductions of pemetrexed/carboplatin in the subsequent course due to myelosuppression (p=0.028) were also significantly higher in patients who developed grade 3 or 4 neutropenia (Table 2).
Table 2. Relationship between Grade 3 or 4 Neutropenia and Neutropenic Events or Dose Reductions of Chemotherapy
| Events | Grade 2 or less (n=43), n (%) | Grade 3 or 4 (n=34), n (%) | p-Value |
|---|
| G-CSF treatment | 3 (7.0%) | 13 (38.2%) | 0.001 |
| Febrile neutropenia | 0 (0%) | 4 (11.8%) | 0.034 |
| Infection | 7 (16.3%) | 4 (11.8%) | 0.746 |
| Blood transfusions | 3 (7.0%) | 5 (14.7%) | 0.454 |
| Dose reduction of pemetrexed or carboplatin | 10 (23.3%) | 16 (47.1%) | 0.028 |
G-CSF, granulocyte-colony stimulating factor.
Among the patients in this study, 16 of 77 were administered G-CSF. However, the incidence of infection (p=0.746) and frequency of patients who received blood transfusions (p=0.454) were not significantly different between these two groups.
Association between Pemetrexed Plus Carboplatin Therapy-Induced Neutropenia and Efficacy or Adverse Drug ReactionsOut of 77 patients, 72 patients were evaluable for efficacy analysis. In patients who developed grade 2 or less neutropenia, the number of patients who achieved a complete response (CR), a partial response (PR) and a stable disease (SD) were 0, 11 and 20, respectively. In patients who developed grade 3 or 4 neutropenia, the number of patients who achieved CR, PR and SD were 0, 6 and 16, respectively. The response rates were similar between both groups (26.8% vs. 19.4%, p=0.460).
The incidences of nausea (62.8% vs. 64.7%, p=0.862), vomiting (14.0% vs. 14.7%, p=0.925) and diarrhea (11.6% vs. 11.8%, p=0.985) were similar between patients who developed grade 2 or less neutropenia and patients who developed grade 3 or 4 neutropenia (Table 3).
Table 3. Relationship between Grade 3 or 4 Neutropenia and Other Adverse Drug Events
| Adverse drug events | Grade 2 or less neutropenia (n=43), n (%) | Grade 3 or 4 neutropenia (n=34), n (%) | p-Value |
|---|
| All | Grade 1 | Grade 2 | Grade 3 | All | Grade 1 | Grade 2 | Grade 3 |
|---|
| Nausea | 27 (62.8%) | 16 | 10 | 1 | 22 (64.7%) | 5 | 14 | 3 | 0.862 |
| Vomiting | 6 (14.0%) | 5 | 1 | 0 | 5 (14.7%) | 5 | 0 | 0 | 0.925 |
| Diarrhea | 5 (11.6%) | 5 | 0 | 0 | 4 (11.8%) | 1 | 2 | 1 | 0.985 |
Univariate analyses revealed that baseline albumin values (odds ratio [OR], 0.22; 95% confidence interval [CI], 0.07–0.65; p=0.005), baseline neutrophil counts (OR, 0.61; 95% CI, 0.41–0.87; p=0.006), and baseline hemoglobin values (OR, 0.52; 95% CI, 0.35–0.72; p<0.001) were significantly associated with grade 3 or 4 neutropenia after pemetrexed plus carboplatin therapy (Table 4). Baseline neutrophil counts were not correlated with baseline hemoglobin values (r=0.137; p=0.235). On the other hand, a weak but significant positive correlation was observed between baseline hemoglobin values and baseline albumin values (r=0.428; p<0.001) and between baseline hemoglobin values and the lowest nadir neutrophil counts after pemetrexed plus carboplatin therapy (r=0.372; p=0.001).
Table 4. Univariate Analysis for Grade 3 or 4 Neutropenia
| Variables | Odds ratio | 95% CI | p-Value |
|---|
| Male sex | 1.33 | 0.54–3.31 | 0.539 |
| Age (years) | 0.98 | 0.94–1.03 | 0.480 |
| Weight (kg) | 0.99 | 0.95–1.04 | 0.821 |
| ECOG PS 2 | 0.94 | 0.28–3.01 | 0.914 |
| Prior chemotherapy | 2.57 | 0.84–8.43 | 0.097 |
| Carboplatin AUC=6 | 1.93 | 0.72–5.47 | 0.195 |
| Concomitant use of bevacizumab | 0.44 | 0.16–1.11 | 0.082 |
| Concomitant use of NSAIDs | 0.54 | 0.21–1.33 | 0.182 |
| Albumin (g/dL) | 0.22 | 0.07–0.65 | 0.005 |
| Ccr (mL/min) | 0.99 | 0.98–1.01 | 0.458 |
| Neutrophil count (×103/mm3) | 0.61 | 0.41–0.87 | 0.006 |
| Hemoglobin (g/dL) | 0.52 | 0.35–0.72 | <0.001 |
| Platelet count (×104/mm3) | 0.99 | 0.93–1.06 | 0.906 |
CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; PS, performance status; NSAIDs, non-steroidal anti-inflammatory drugs; Ccr, creatinine clearance rate.
Multivariate stepwise logistic regression analysis with backward selection revealed that lower baseline hemoglobin values (OR, 1.97 per 1 g/dL decrease; 95% CI, 1.39–2.99, p<0.001) and lower baseline neutrophil counts (OR, 1.71 per 1000/mm3 decrease; 95% CI, 1.14–2.71, p=0.009) were significant predictors of grade 3 or 4 neutropenia (Table 5).
Table 5. Multivariate Analysis for Grade 3 or 4 Neutropenia
| Variables | Odds ratio | 95% CI | p-Value |
|---|
| Lower baseline hemoglobin values | 1.97 (per 1 g/dL decrease) | 1.39–2.99 | <0.001 |
| Lower baseline neutrophil counts | 1.71 (per 103/mm3 decrease) | 1.14–2.71 | 0.009 |
Figure 1 shows the relationships between baseline neutrophil or hemoglobin values and the incidence of neutropenia during the first course (Figs. 1A, C) and during all courses of pemetrexed plus carboplatin therapy (Figs. 1B, D). The baseline neutrophil count and hemoglobin values were grouped into four quartiles. According to the baseline neutrophil counts, the lower quartile (Q1) included the 25% of patients with the lowest counts (<3174/mm3); Q2 (3174–4565/mm3) and Q3 (4566–5410/mm3) extended 25% below and above the median neutrophil count, respectively; Q4 included the 25% of patients with the highest count (>5410/mm3). After all courses, the incidence of grade 3 or 4 neutropenia among patients with a baseline neutrophil count of Q1 and Q2 was significantly higher than that in patients with baseline neutrophil counts of Q3 and Q4 [59.0% (23/39) vs. 28.9% (11/38), p=0.012] (Fig. 1B). After the first course of pemetrexed plus carboplatin therapy, the incidence of grade 3 or 4 neutropenia in patients with a baseline hemoglobin value in Q1 (<11.6 g/dL) was significantly higher than that in Q2 (11.6–12.7 g/dL) to Q4 (>13.8 g/dL) [63.2% (12/19) vs. 17.2% (10/58), p<0.001] (Fig. 1C). Similarly, after all courses, the incidence of grade 3 or 4 neutropenia in patients with a baseline hemoglobin value in Q1 was significantly higher than that in Q2–Q4 [84.2% (16/19) vs. 31.0% (18/58), p<0.001] (Fig. 1D).
DISCUSSION
This is the first study to evaluate the risk factors associated with severe neutropenia in patients with non-squamous NSCLC receiving pemetrexed plus carboplatin therapy. Severe neutropenia requires dose reduction or delay in treatment, leading to chemotherapy discontinuation.15,18) Despite the fact that pemetrexed plus carboplatin therapy has become widely used,9) the risk factors for severe neutropenia in patients receiving this therapy have not been reported. In fact, the incidence of febrile neutropenia and percentage of patients with dose reduction were significantly higher in patients who developed grade 3 or 4 neutropenia (Table 2). Multivariate logistic regression analysis in the present study revealed that lower baseline hemoglobin values and lower baseline neutrophil counts were significant risk factors for grade 3 or 4 neutropenia in patients receiving pemetrexed plus carboplatin therapy (Table 5). The incidences of severe neutropenia were higher in patients with lower baseline neutrophil counts and lower baseline hemoglobin values (Fig. 1).
Our result, that the baseline neutrophil count was significantly associated with the risk of severe neutropenia, was supported by the findings of previous studies.19,20) Another risk factor in this study was lower baseline hemoglobin values. This result is consistent with that of other studies.21–23) Among 704 patients with malignant lymphoma who were treated with chemotherapy, a baseline hemoglobin value of <12 g/dL was a significant risk factor for febrile neutropenia.23) This may reflect the inflammatory status in each patient. Maccio et al.24) reported a significant negative correlation between the hemoglobin value and the serum interleukin-6 (IL-6) concentration in patients with advanced epithelial ovarian cancer. Similarly, Kuroda et al.25) reported that serum IL-6 levels were negatively correlated with hemoglobin and albumin values in patients with prostate cancer. The univariate analysis in our study also showed that, in addition to the baseline hemoglobin values, the baseline albumin values were significantly associated with the risk of grade 3 or 4 neutropenia after pemetrexed plus carboplatin therapy (Table 4). Although the serum concentrations of proinflammatory cytokines, including IL-6, were not evaluated, the inflammatory status may be involved in the severity of neutropenia in patients receiving pemetrexed plus carboplatin therapy in association with the albumin and hemoglobin values. For other regimens with carboplatin and anticancer drugs for patients with NSCLC, no study showed an association between baseline hemoglobin values and risk of severe neutropenia. Considering a triple combination therapy with paclitaxel, carboplatin, and bevacizumab for patients with advanced NSCLC, the incidence of grade 3 or worse neutropenia was significantly higher in patients aged 70 years or older.26) Taken together, the lower baseline hemoglobin values were suggested to be a specific risk factor for severe neutropenia in patients receiving pemetrexed plus carboplatin therapy.
In a Japanese clinical trial that prospectively evaluated the efficacy and safety of pemetrexed plus carboplatin therapy followed by maintenance pemetrexed in chemo-naïve patients with advanced non-squamous NSCLC, the eligibility criteria for bone marrow was hemoglobin level ≥9.0 g/dL, white blood cell count ≥3000/mm3, neutrophil count ≥1500/mm3, and platelet count ≥100000/mm3.11) Usually, patients with high baseline neutrophil counts are considered to be at low risk for neutropenia. However, the lower baseline hemoglobin values were one of the independent risk factors for grade 3 or 4 neutropenia. The incidence of grade 3 or 4 neutropenia in patients with baseline hemoglobin values of <11.6 g/dL was significantly higher than that in patients with ≥11.6 g/dL in the first and all courses of carboplatin plus pemetrexed therapy (Fig. 1). Therefore, we selected the cut off level of 11.6 g/dL of baseline hemoglobin value. The results of this study showed that patient with baseline hemoglobin values of <11.6 g/dL should be monitored carefully, even if they have high baseline neutrophil counts.
Sweeney et al.27) found that concomitant use of ibuprofen elevated the AUC of pemetrexed by 20%, with no increase in pemetrexed-related toxicity in patients with advanced cancer. Thus, it is recommended to avoid taking NSAIDs for several days before and after the day of administration of pemetrexed.28) However, as summarized in Table 1, the incidence of grade 3 or 4 neutropenia in patients who received NSAIDs concomitantly was 36.1% (13/36 patients), which was relatively low compared with the incidence in patients who did not receive NSAIDs (51.2%, 21/41 patients). In the present study, the most frequent NSAID concomitantly administered with pemetrexed was loxoprofen (63.9%, 23/36 patients). A recent in vitro study demonstrated that ibuprofen at a clinical dose could increase the pemetrexed AUC by direct inhibition of pemetrexed tubular excretion via human organic anion transporter 3 (hOAT3).29) On the other hand, the IC50 value of loxoprofen determined in that study was considerably higher than its therapeutic concentration, suggesting that drug–drug interaction between pemetrexed and loxoprofen via hOAT3 was unlikely. Our data support these results.
In conclusion, our data indicate that lower baseline neutrophil counts or hemoglobin values are significant risk factors for grade 3 or 4 neutropenia in patients with non-squamous NSCLC receiving pemetrexed plus carboplatin therapy. Therefore, patients with these risk factors, especially those with baseline hemoglobin values of <11.6 g/dL, should be monitored more carefully. However, the limitation of this study is the retrospective, uncontrolled design of the study. In addition, the previous treatment of the patients is various and heterogeneous. Therefore, future investigations will be required including the prospective evaluation of proinflammatory cytokine such as IL-6 as well as the baseline neutrophil counts and hemoglobin values.
Acknowledgments
This study was supported in part by a Grant-in-Aid for Scientific Research (KAKENHI) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan and a Grant-in-Aid from the Japan Research Foundation for Clinical Pharmacology.
Conflict of Interest
The authors declare no conflict of interest.
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