ABSTRACT
Background
Patients with non‐small cell lung cancer (NSCLC) receiving docetaxel (DTX) and ramucirumab (RAM) regimen frequently experience febrile neutropenia (FN). We aimed to clarify the incidence rate and predictive factors of FN under prophylactic pegfilgrastim.
Methods
Fifty‐four patients with NSCLC received DTX + RAM from 2018 to 2023 in our hospital. Age, gender, performance status (PS), treatment line, prior thoracic irradiation, body mass index (BMI), neutrophil count at baseline (BNC) and the lowest neutrophil count (LNC), serum albumin, and incidence of FN were recorded. The correlation between BNC and LNC was analyzed. We evaluated the association between BNC and FN using logistic regression analysis. The baseline characteristics of two groups stratified by the cutoff BNC using the ROC curve were compared.
Results
All the patients received prophylactic pegfilgrastim. Three (5.5%) patients experienced FN. There was a significant correlation between BNC and LNC (r s = 0.43, p = 0.0003). BNC and cardiovascular disease were significantly associated with FN (odds ratio 0.998, p = 0.0151 and odds ratio 28.64, p = 0.034). The receiver operating characteristic curve showed the cutoff value of BNC was 3000/μL (AUC 0.88). There was no significant difference in other baseline characteristics between the patients with BNC of 3000/μL or more and those with BNC less than 3000/μL.
Conclusion
Our data showed the incidence rate of FN receiving DTX + RAM with prophylactic pegfilgrastim was 5.5%. Despite prophylactic pegfilgrastim, BNC was correlated with LNC and might be predictive of FN. We should be careful of BNC even if it meets the criteria for starting DTX + RAM treatment.
Keywords: baseline neutrophil count, docetaxel, febrile neutropenia, pegfilgrastim, ramucirumab
In our study, 5.5% of the patients who received the first dose of docetaxel and ramucirumab with prophylactic pegfilgrastim developed febrile neutropenia (FN). The baseline neutrophil count of less than 3000 is a risk factor for FN.
1. Introduction
Docetaxel (DTX) and ramucirumab (RAM) regimen has been approved as a standard second‐line treatment for non‐small cell lung cancer (NSCLC). REVEL study demonstrated that DTX + RAM significantly extended overall survival (OS) as well as progression‐free survival (PFS) compared to DTX alone. Considering safety, DTX dose was reduced in East Asia from 75 to 60 mg/m2. Although use of granulocyte colony stimulating factor (G‐CSF) was allowed, 16% of DTX + RAM group resulted in febrile neutropenia (FN), while 10% of DTX group resulted in FN [1]. In Japan, randomized double‐blind Phase 2 study (JVCG trial), comparing DTX + RAM and DTX, was conducted as well [2]. They reported that the survival benefit was not significant (PFS: hazard ratio (HR) 0.83, 95% CI: 0.59–1.16. OS: HR 0.86, 95% CI: 0.56–1.32). In addition, FN was seen in 34.2% of DTX + RAM group and in 19.8% of DTX group [2]. As such, there is room for considering the use of prophylactic pegfilgrastim when introducing the DTX + RAM regimen. In the present study, we aimed to evaluate the incidence rate of FN in those receiving the regimen with prophylactic pegfilgrastim and to identify the risk factor for FN.
2. Patients and Methods
2.1. Study Design
This is a single institution retrospective observational study. The study protocol was approved by the Ethics Committee of Hirosaki University Graduate School of Medicine (approval number; 2024‐055). We reviewed the medical records of patients with NSCLC who received DTX + RAM from January 2018 to December 2023. We collected data regarding age, gender, performance status (PS), treatment line, prior thoracic irradiation, body mass index (BMI), baseline neutrophil count, and the lowest neutrophil count between Cycle 1 Day 1 and Cycle 2 Day 1, renal function, history of cardiovascular diseases, serum albumin level, and the incidence of FN. Renal dysfunction was described according to common terminology criteria for adverse events version 5. We also reviewed the dose of DTX and timing of administration of pegfilgrastim. In Japan, G‐Lasta Subcutaneous Injection 3.6 mg BodyPod, which is an automated injection device, has also been approved. In our institution, only conventional pegfilgrastim was utilized. Because this is a retrospective study, informed consent was waived. Opt out was carried out on the website of Hirosaki University Hospital.
2.2. Definition of Febrile Neutropenia
In abroad, febrile neutropenia is defined as a rise in axillary temperature to 38.5°C or higher for at least 1 h while having an absolute neutrophil count of less than 0.5 × 109/L [3]. In the present study, we defined it according to Japanese recommendation [4]. To sum up, (i) A single axillary temperature of ≥ 37.5°C or a single oral temperature of ≥ 38°C and (ii) A neutrophil count less than 1000 cells/μL with a predicted decline to < 500 cells/μL.
2.3. Statistical Analysis
The correlation between the baseline neutrophil count and the lowest neutrophil count was calculated with Spearman's correlation analysis. The association between the baseline variables and the incidence of FN was calculated with logistic regression analysis. The cutoff value of the baseline neutrophil count associated with the onset of FN was estimated with receiver operating characteristic (ROC) curve. A comparison of baseline characteristics between two groups stratified with the cutoff value was calculated with Wilcoxon rank sum test or Fisher's exact test. All the p values were considered significant if less than 0.05. Statistical analysis was carried out with JMP pro 14.0 (SAS Institute Inc., Cary, NC).
3. Results
3.1. Patients' Characteristics
From 2018 to 2023, 58 patients received DTX + RAM in our institution (Figure 1). All the patients received prophylactic pegfilgrastim subcutaneously on the following day of chemotherapy. Four patients were excluded from this research due to PS 2. Finally, 54 patients with NSCLC who received DTX + RAM treatment were enrolled (Table 1). All 54 patients received DTX at a dose of 60 mg/m2. The median age was 65.5 years (range 44–75 years). Male accounted for 33 (61.1%). PS of 0 and 1 were observed in 11 (20.4%) and 43 (79.6%) patients, respectively. Fourteen (25.9%) patients received DTX + RAM as the second line treatment and 40 (74.1%) patients as the third or later. Seventeen (31.4%) patients had received thoracic irradiation. The median BMI was 21.9 (range 15.2–29.4). The median neutrophil count was 3965/μL (range 1990–15 210/μL). Those with renal dysfunction of Grade 1 and 2 were seen in 25 (46.2%) and 3 (5.5%) patients, respectively. History of cardiovascular diseases was present in 7 (12.9%) patients. The median serum albumin was 3.8 g/dL (range 2.6–4.6 g/dL).
FIGURE 1.
Consort diagram. Fifty‐eight patients received docetaxel and ramucirumab regimen. Of these, four patients were excluded because of poor performance status. All the patients received prophylactic pegfilgrastim. Finally, 54 patients were recruited. DTX, docetacel; PS: performance status; RAM, ramucirumab.
TABLE 1.
Characteristics of patients with NCSLC receiving DTX + RAM (n = 54).
| Age (years), median (range) | 65.5 (44–75) |
| Gender, male, n (%) | 33 (61.1%) |
| PS, 0/1, n (%) | 11 (20.4)/43 (79.6) |
| Treatment line, second/third or later, n (%) | 14 (25.9)/40 (74.1) |
| Prior thoracic irradiation, n (%) | 17 (31.4) |
| BMI, median (range) | 21.9 (15.2–29.4) |
| Neutrophil count (/μL), median (range) | 3965 (1990‐15 210) |
| Renal dysfunction, Grade 1/Grade 2, n (%) | 25 (46.2)/3 (5.5) |
| Cardiovascular disease, n (%) | 7 (12.9) |
| Serum albumin (g/dL), median (range) | 3.8 (2.6–4.6) |
Abbreviations: BMI, body mass index; DTX, docetaxel; NSCLC, non‐small‐cell lung cancer; PS, performance status; RAM, ramucirumab.
3.2. The Incidence Rate of Febrile Neutropenia and the Association Between the Baseline Neutrophil Count and the Lowest Neutrophil Count
In 14 (25.9%) patients, the lowest neutrophil count after the first dose of DTX + RAM was higher than the baseline neutrophil count. FN was seen in 3 (5.5%) patients even though all the patients received prophylactic pegfilgrastim. We evaluated the association between the baseline neutrophil count and the lowest neutrophil count after the first dose of DTX + RAM (Figure 2). There was a significant correlation between them (r s = 0.43, p = 0.0003).
FIGURE 2.
The correlation between the baseline neutrophil count and the lowest neutrophil count. X‐axis and Y‐axis indicate the baseline neutrophil count (×103/μL) and the lowest neutrophil count, respectively. r s : correlation coefficient.
3.3. The Association Between the Baseline Neutrophil Count and the Incidence of FN
We evaluated the association between baseline variables and the incidence of FN using logistic regression analysis (Table 2). In univariate analysis, the baseline neutrophil count was modestly associated with the incidence of FN (odds ratio 0.998, 95% CI: 0.996–1.000, p = 0.0159). Cardiovascular disease was also significant (odds ratio 18.33, 95% CI: 1.41–240.83, p = 0.02). In multivariate analysis, these two factors were both significant (baseline neutrophil count: odds ratio 0.998, 95% CI: 0.996–1.000, p = 0.0151, history of cardiovascular disease: odds ratio 28.64, 95% CI: 1.28–637.78, p = 0.034). ROC curve estimated the cutoff value of baseline neutrophil count associated with FN to be 3000 (AUC 0.88, 95% CI: 0.73–1.00, p = 0.015) (Figure 3). We also evaluated the relationship between baseline neutrophil count and FN when baseline neutrophil count was treated as a categorical variable (i.e., ≥ 3000 vs. < 3000) (Table S1). The baseline neutrophil count as a categorical variable was not significant (odds ratio 0.09, 95% CI: 0.004–1.07, p = 0.057).
TABLE 2.
The association between baseline variables and incidence of FN.
| Univariate | Multivariate | |||
|---|---|---|---|---|
| Odds ratio (95% CI) | p | Odds ratio (95% CI) | p | |
| Age, ≧ 65 versus < 65 years | 1.400 (0.12–16.45) | 0.78 | ||
| Treatment line, second vs. third or late | 1.461 (0.12–17.48) | 0.76 | ||
| Prior thoracic irradiation, yes versus no | 4.799 (0.40–57.02) | 0.21 | ||
| BMI | 1.239 (0.88–1.74) | 0.19 | ||
| Baseline neutrophil count (/μL) | 0.998 (0.996–1.000) | 0.0159 | 0.998 (0.996–1.000) | 0.0151 |
| Renal dysfunction, Grade 0–1 versus 2 | 0.081 (0.01–1.32) | 0.07 | ||
| Cardiovascular disease, yes versus no | 18.33 (1.41–240.83) | 0.02 | 28.64 (1.28–637.78) | 0.034 |
| Serum albumin (g/dL) | 1.421 (0.13–15.31) | 0.77 | ||
Note: Bold denotes p < 0.05.
Abbreviations: BMI, body mass index; CI, confidence interval; FN, febrile neutropenia; SE, standard error.
FIGURE 3.
Receiver operating characteristic curve of the baseline neutrophil count associated with the onset of febrile neutropenia. X‐axis and Y‐axis indicate 1‐specificity and sensitivity, respectively. AUC, area under curve; CI, confidence interval. Solid circle indicates the point at which the AUC is highest.
To evaluate confounding factors, we compared the baseline characteristics between groups stratified with the cutoff value (Table 3). The median age of the patients with the baseline neutrophil count less than 3000/μL (relatively neutropenic group) and those with a baseline neutrophil count of 3000/μL or more (non‐neutropenic group) was 69 and 65 years, respectively (p = 0.19). Males in the relatively neutropenic and the non‐neutropenic groups accounted for 7 (70%) and 26 (59.1%) patients, respectively (p = 0.72). PS 0 and 1 were seen in 2 (20.0%) and 8 (80%) patients in the relatively neutropenic group, while 9 (20.5%) and 35 (79.5%) patients were in the non‐neutropenic group (p = 1.0). Four (40%) and 6 (60%) patients received the DTX + RAM regimen as a second line and a third or later in the relatively neutropenic group, while 10 (22.7%) and 34 (77.3%) patients were in the non‐neutropenic group (p = 0.42). Previous thoracic irradiation was conducted in 5 (50%) and 12 (27.3%) patients in the relatively neutropenic and the non‐neutropenic groups, respectively (p = 0.25). The median BMI was 22.7 and 21.4 in the relatively neutropenic and non‐neutropenic groups (p = 0.77). Renal dysfunction of Grade 1 and 2 was observed in 4 (40.0%) and 2 (20.0%) patients in the relatively neutropenic and 21 (47.7%) and 1 (2.2%) patients in the non‐neutropenic group, respectively (p = 0.15). A history of cardiovascular diseases was present in 2 (20.0%) and 5 (11.3%) patients in the relatively neutropenic and the non‐neutropenic groups, respectively (p = 0.60). The median serum albumin was 4.0 and 3.7 g/dL in the relatively neutropenic and non‐neutropenic groups (p = 0.057).
TABLE 3.
Comparison of characteristics between groups stratified with cutoff value of baseline neutrophil count.
| Variables | BNC < 3000/μL (n = 10) | BNC ≥ 3000/μL (n = 44) | p |
|---|---|---|---|
| Age (years), median (range) | 69 (57–75) | 65 (44–74) | 0.19 |
| Gender, male, n (%) | 7 (70) | 26 (59.1) | 0.72 |
| PS 0/1, n (%) | 2 (20)/8 (80) | 9 (20.5)/35 (79.5) | 1.0 |
| Treatment line, second/third or later, n (%) | 4 (40)/6 (60) | 10 (22.7)/34 (77.3) | 0.42 |
| Prior thoracic irradiation, n (%) | 5 (50) | 12 (27.3) | 0.25 |
| BMI, median (range) | 22.7 (17.3–29.3) | 21.4 (15.1–28.9) | 0.77 |
| Renal dysfunction, Grade 1/2, n (%) | 4 (40.0)/2 (20.0) | 21 (47.7)/1 (2.2) | 0.15 |
| Cardiovascular disease, n (%) | 2 (20.0) | 5 (11.3) | 0.60 |
| Serum albumin (g/dL), median, range | 4.0 (3.3–4.6) | 3.7 (2.6–4.6) | 0.057 |
Abbreviations: BMI, body mass index; BNC, baseline neutrophil count; PS, performance status.
4. Discussion
Chemotherapy‐induced FN is one of the oncological emergencies, possibly leading to severe infection or sepsis [5]. As such, various guidelines recommend routine use of primary G‐CSF prophylaxis for the regimen of FN risk > 20% [6, 7, 8, 9]. The JVCG trial showed a much higher incidence rate of FN compared to the present study (34.2% vs. 5.5%), although the baseline characteristics were not so different between the two studies. As a difference, our patients all received pegfilgrastim, while it was not mandatory in the JVCG trial, suggesting primary prophylactic pegfilgrastim might prevent FN. Saito et al. conducted a retrospective study including 155 patients and showed that prophylactic G‐CSF administration in combination with the first dose of DTX + RAM was associated with the reduction of FN events even after adjusting for other covariates (odds ratio 0.18, 95% CI: 0.08–0.42, p < 0.0001) [10]. So far, there have been only two reports demonstrating the incidence rate of FN in those receiving DTX + RAM with prophylactic pegfilgrastim. One is a prospective Phase 2 study, which recruited 20 patients previously treated, and demonstrated that one (5%) patient developed FN [11]. The other is a retrospective study, in which 223 patients receiving DTX + RAM with prophylactic pegfilgrastim after chemoimmunotherapy in the second‐line setting were recruited. It demonstrated that 25 (10.1%) patients developed FN [12]. Given these data including ours, as much as 5%–10% of patients receiving DTX + RAM are expected to have FN despite prophylactic pegfilgrastim.
We expect pegfilgrastim to boost up the level of the lowest neutrophil count and prevent FN. However, our data showed that the baseline neutrophil count was significantly correlated with the lowest neutrophil count, indicating that pegfilgrastim might not prevent neutropenia if the baseline neutrophil count is low. As such, we should not let our guard down even after administration of prophylactic pegfilgrastim, especially when the baseline neutrophil count is low. On the other hand, several factors such as steroid use, the recent infection, prior treatment, and duration of treatment can affect the baseline neutrophil count. In fact, in our study, nine patients had received steroids for various reasons, including immune‐related adverse events and cerebral edema due to brain metastases. All nine patients had baseline neutrophil > 3000/μL and fortunately did not develop FN. Therefore, we should recognize that the baseline neutrophil count is only one of multiple risk factors.
Several factors associated with FN are already known, such as (i) age > 65 years, (ii) previous radiation therapy, (iii) poor PS or nutrition status, (iv) poor renal function, (v) cardiovascular disease, and (vi) preexisting neutropenia [13]. However, whether these factors are significant even after receiving a primary prophylactic pegfilgrastim is unknown. Our study showed that the baseline neutrophil count and the history of cardiovascular diseases were risk factors for FN. With respect to cardiovascular diseases, the odds ratio showed a wide range (1.28–637.78). Of the three patients who developed FN, two (66.7%) had a history of cardiovascular disease, whereas five patients (9.8%) without FN had such a history. This disproportion and wide confidence interval may have occurred by chance due to the limited sample size. Accordingly, the significance should be interpreted with caution. To the best of our knowledge, this is the first report evaluating the risk factor for FN in patients receiving DTX + RAM with primary prophylactic pegfilgrastim.
There are a few reports evaluating the impact of pegfilgrastim on overall survival in other cancers [13]. In breast cancer, a Phase 3 double‐blind, randomized trial for patients receiving DTX with or without pegfilgrastim was reported [14]. The patients receiving prophylactic pegfilgrastim showed tendency for less OS events than those with placebo (hazard ratio 0.40, 95% CI: 0.14–1.17, p = 0.09). Similarly, in colorectal cancer, a Phase 2 double‐blind, randomized trial, which included the patients receiving FOLFOX4, FOLFIRI, or FOIL with or without pegfilgrastim, was reported [15]. The patients with prophylactic pegfilgrastim showed a tendency for less OS events than those with placebo (hazard ratio 0.81, 95% CI: 0.54–1.20, p = 0.292). With respect to patients with NSCLC receiving DTX + RAM, Miura et al. reported that those with pegfilgrastim had longer OS than those without (12.8 vs. 8.1 months, p = 0.004), although there were some differences in patients' background between the groups [12]. Until today, it remains controversial whether prophylactic pegfilgrastim should be routinely used. In those with less baseline neutrophil count, DTX dose reduction or RAM omission might also be options, and these issues need to be further investigated.
There are some limitations in our study. First, our study is a small‐sized, single‐institutional, and retrospective study. We did not expect that such a small number of patients experienced FN when receiving prophylactic pegfilgrastim. To improve statistical power, more patients should have been recruited. Accordingly, our result should be interpreted with caution. Second, because the incidence rate of FN was low, there is a possibility that the impact of already known factors affecting FN, such as age and nutrition status (i.e., albumin and BMI), might not have been appropriately evaluated. Third, the impact of prophylactic pegfilgrastim on the prognoses was not evaluated because our study did not include those without pegfilgrastim.
5. Conclusion
Lower baseline neutrophil count could be a risk factor for febrile neutropenia in patients with NSCLC treated with DTX plus RAM regardless of prophylactic pegfilgrastim. In patients with low baseline neutrophil count, attention should be paid to the occurrence of FN even with prophylactic administration of pegfilgrastim.
Author Contributions
Conceptualization: Tomonori Makiguchi. Investigation: Haruka Odagiri, Tomonori Makiguchi, Hisashi Tanaka, Kageaki Taima, and Sadatomo Tasaka. Formal analysis: Tomonori Makiguchi. Resources: Haruka Odagiri. Writing – original draft: Tomonori Makiguchi. Writing – review and editing: Tomonori Makiguchi. Visualization: Hisashi Tanaka and Kageaki Taima. Supervision, review and editing: Sadatomo Tasaka. All authors had full access to the data in the study and took responsibility for the integrity of the data and the accuracy of the data analysis.
Ethics Statement
This study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). This study was approved by the Ethics Committee of Hirosaki University Graduate School of Medicine (approval number; 2024‐055).
Conflicts of Interest
The authors declare no conflicts of interest.
Supporting information
Data S1. Supporting Information.
Acknowledgments
We thank all the patients.
Funding: The authors received no specific funding for this work.
Data Availability Statement
Data will be available upon reasonable request to the corresponding author.
References
- 1. Garon E. B., Ciuleanu T.‐E., Arrieta O., et al., “Ramucirumab Plus Docetaxel Versus Placebo Plus Docetaxel for Second‐Line Treatment of Stage IV Non‐Small‐Cell Lung Cancer After Disease Progression on Platinum‐Based Therapy (REVEL): A Multicentre, Double‐Blind, Randomised Phase 3 Trial,” Lancet 384, no. 9944 (2014): 665–673. [DOI] [PubMed] [Google Scholar]
- 2. Yoh K., Hosomi Y., Kasahara K., et al., “A Randomized, Double‐Blind, Phase II Study of Ramucirumab Plus Docetaxel vs Placebo Plus Docetaxel in Japanese Patients With Stage IV Non‐Small Cell Lung Cancer After Disease Progression on Platinum‐Based Therapy,” Lung Cancer 99, no. 99 (2016): 186–193. [DOI] [PubMed] [Google Scholar]
- 3. Crawford J., Caserta C., and Roila F., “Hematopoietic Growth Factors: ESMO Clinical Practice Guidelines for the Applications,” Annals of Oncology 21 (2010): 248–251. [DOI] [PubMed] [Google Scholar]
- 4. Masaoka T., “Evidence‐Based Recommendations for Antimicrobial Use in Febrile Neutropenia in Japan: Executive Summary,” Clinical Infectious Diseases 39, no. Supplement_1 (2004): S49–S52. [DOI] [PubMed] [Google Scholar]
- 5. Klastersky J., “Febrile Neutropenia,” Current Opinion in Oncology 5, no. 4 (1993): 625–632. [DOI] [PubMed] [Google Scholar]
- 6. Crawford J., Becker P. S., Armitage J. O., et al., “Myeloid Growth Factors, Version 2.2017, NCCN Clinical Practice Guidelines in Oncology,” Journal of the National Comprehensive Cancer Network 15, no. 12 (2017): 1520–1541. [DOI] [PubMed] [Google Scholar]
- 7. Smith T. J., Bohlke K., Lyman G. H., et al., “Recommendations for the Use of WBC Growth Factors: American Society of Clinical Oncology Clinical Practice Guideline Update,” Journal of Clinical Oncology 33, no. 28 (2015): 3199–3212. [DOI] [PubMed] [Google Scholar]
- 8. Schnipper L. E., Smith T. J., Raghavan D., et al., “American Society of Clinical Oncology Identifies Five Key Opportunities to Improve Care and Reduce Costs: The Top Five List for Oncology,” Journal of Clinical Oncology 30, no. 14 (2012): 1715–1724. [DOI] [PubMed] [Google Scholar]
- 9. Aapro M. S., Bohlius J., Cameron D. A., et al., “2010 Update of EORTC Guidelines for the Use of Granulocyte‐Colony Stimulating Factor to Reduce the Incidence of Chemotherapy‐Induced Febrile Neutropenia in Adult Patients With Lymphoproliferative Disorders and Solid Tumours,” European Journal of Cancer 47, no. 1 (2011): 8–32. [DOI] [PubMed] [Google Scholar]
- 10. Saito Y., Tamaki S., Hirate D., et al., “Detection of Factors Related to Treatment Reduction in Docetaxel and Ramucirumab for Non‐Small Cell Lung Cancer Treatment,” Scientific Reports 13, no. 1 (2023): 19457. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11. Kasahara N., Sunaga N., Kuwako T., et al., “Administration of Docetaxel Plus Ramucirumab With Primary Prophylactic Pegylated‐Granulocyte Colony‐Stimulating Factor for Pretreated Non‐Small Cell Lung Cancer: A Phase II Study,” Supportive Care in Cancer 28, no. 10 (2020): 4825–4831. [DOI] [PubMed] [Google Scholar]
- 12. Miura K., Yamaguchi O., Mori K., et al., “Prophylactic Pegfilgrastim Reduces Febrile Neutropenia in Ramucirumab Plus Docetaxel After Chemoimmunotherapy in Advanced NSCLC: Post Hoc Analysis From NEJ051,” Scientific Reports 14, no. 1 (2024): 3816. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13. Lyman G. H., Reiner M., Morrow P. K., and Crawford J., “The Effect of Filgrastim or Pegfilgrastim on Survival Outcomes of Patients With Cancer Receiving Myelosuppressive Chemotherapy,” Annals of Oncology 26, no. 7 (2015): 1452–1458. [DOI] [PubMed] [Google Scholar]
- 14. Vogel C. L., Wojtukiewicz M. Z., Carroll R. R., et al., “First and Subsequent Cycle Use of Pegfilgrastim Prevents Febrile Neutropenia in Patients With Breast Cancer: A Multicenter, Double‐Blind, Placebo‐Controlled Phase III Study,” Journal of Clinical Oncology 23, no. 6 (2005): 1178–1184. [DOI] [PubMed] [Google Scholar]
- 15. Hecht J. R., Pillai M., Gollard R., et al., “A Randomized, Placebo‐Controlled Phase II Study Evaluating the Reduction of Neutropenia and Febrile Neutropenia in Patients With Colorectal Cancer Receiving Pegfilgrastim With Every‐2‐Week Chemotherapy,” Clinical Colorectal Cancer 9, no. 2 (2010): 95–101. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data S1. Supporting Information.
Data Availability Statement
Data will be available upon reasonable request to the corresponding author.