Prophylaxis and treatment strategies for optimizing chemotherapy relative dose intensity

ABSTRACT

Introduction

A decrease in relative-dose intensity (RDI) of chemotherapy has been shown to be associated with poor patient outcomes in solid tumors and non-Hodgkin’s lymphoma. The actual delivered chemotherapy dose received by patients can be influenced by dose reductions and treatment delays, often due to toxicities, most commonly chemotherapy-induced neutropenia (CIN).

Areas covered

We review seminal evidence and more recent studies that have shown an association between higher RDI and improved patient survival. A smaller number of studies has shown no association between RDI and outcomes. These differences may be due to study limitations, including low power, differences in patient and disease characteristics, or the chemotherapeutic regimen. We describe guidelines recommendations to prevent and treat CIN with granulocyte-colony stimulating factor (G-CSF) and describe novel approaches to prevent neutropenia that are being developed that may provide greater value and be associated with fewer adverse events than standard G-CSF options.

Expert opinion

Maintaining RDI is important to ensure optimal patient outcomes. This can be achieved through the proper administration of G-CSF prophylaxis and treatment. Newer agents in development to treat and/or prevent CIN are entering regulatory review and may potentially change the treatment landscape for CIN in the future.

KEYWORDS:

• Chemotherapy-induced neutropenia
• G-CSF
• patient outcomes
• relative dose intensity
• dose intensity

1. Introduction

The relative dose intensity (RDI) of chemotherapy has been shown to impact outcomes of patients with early stage solid tumors and lymphoma, with low RDI associated with shorter survival. RDI is defined as the ratio of the delivered dose intensity to the reference dose intensity for the specific chemotherapy regimen [1–3]. The reported RDI threshold to achieve optimal patient outcomes varies by cancer type and is suggested to be 85% for early stage breast cancer and ~70% for non-Hodgkin’s lymphoma (NHL) [4,5]. Deviations in optimal RDI are often due to dose reductions, treatment delays, or withdrawal from therapy due to adverse events experienced throughout chemotherapy [2,6,7]. Chemotherapy-induced neutropenia (CIN) is the most common adverse event leading to reductions in RDI, thereby negatively impacting clinical outcomes. Accordingly, healthcare costs are also increased due to hospitalizations for patients with febrile neutropenia and related complications [7–11].

The incidence of CIN or febrile neutropenia varies across tumor types and chemotherapy regimens [8,9,12–15], with rates of 0‒48% reported for breast cancer, 3‒57% for small cell lung cancer, 0‒54% for non-small cell lung cancer (NSCLC), and 10‒78% for NHL [12]. Across all tumor types, neutropenia is more common during the first cycle of treatment when patients typically receive the full dose(s) of chemotherapy and decreases with subsequent cycles of treatment, irrespective of disease stage, patient age, and line of therapy [8]. The incidence of neutropenia tends to decrease from cycle 2 onward as physicians try to manage it with preventative strategies [8,14].

Severe neutropenia (grade 3 or 4) is a significant complication that can lead to increased morbidity and mortality, which also varies according to tumor type [2,9,13–15]. In a retrospective analysis of 5,990 patients with solid tumors or NHL compared to propensity score–matched controls, the incidence of early and overall mortality was higher in patients who developed febrile neutropenia compared to those who did not (HR 1.15 and 1.35, respectively). Patients with lung cancer had the greatest risk of early mortality, while the risk was lowest for patients with breast cancer [13]. In general, mortality rates for patients hospitalized for febrile neutropenia are approximately 10% and even higher for patients with multiple or severe comorbidities (approximately 20%) [2,14,16].

Patients who develop CIN may also require hospitalization [9,13,14], with mean length of hospital stay ranging from 4.1 to 7.9 days [9]. This increase in hospitalization and patient management has a large economic impact [9,15]. A retrospective analysis of patients treated between 2006 and 2009 reported total costs for NHL, lung or breast cancer patients who experienced febrile neutropenia as 37,555, USD 32,964, USD and 20,462, USD respectively (in 2013 USD) [9]. Similarly, according to an analysis of the 2012 National Inpatient Sample and Kids’ Inpatient Database, the total cost for 108,419 patients hospitalized for cancer-related neutropenia in 2012 was 2.7 USD billion (in 2012 USD) [17].

To manage CIN, physicians often dose-reduce or delay chemotherapy to allow for neutrophil recovery. Although this approach reduces the negative impact of chemotherapy, it also results in lower RDI and poorer clinical outcomes because patients are not receiving the optimal dose and frequency of chemotherapy to most effectively treat their disease [2,6,7]. Administration of granulocyte-colony stimulating factor (G-CSF) therapy is commonly used and recommended by guidelines for patients who have a high risk of neutropenia to prevent the development of CIN, which allows maintenance of optimal RDI and improved patient outcomes [12,18–23]. However, because the currently available G-CSF therapies are associated with adverse events, such as bone pain, headache, and myalgias, there is interest in treatments that are effective in preventing CIN while reducing adverse events and health care costs [22,24]. Furthermore, some patients receiving G-CSF will still experience febrile neutropenia; therefore, there is a need for continued investigations of drugs other than G-CSF to further reduce the risk of febrile neutropenia [25].

2. CIN and its impact on relative dose intensity

Use of chemotherapy regimens with myelosuppressive properties, such as cyclophosphamide/methotrexate/fluorouracil (CMF), fluorouracil/doxorubicin/ cyclophosphamide, or docetaxel/cyclophosphamide (TC), in early stage breast cancer can increase the risk of CIN and is associated with an increased risk of low RDI [6]. Among 20,799 early stage breast cancer patients treated with adjuvant chemotherapy from 1997‒2000, dose reductions >15% and treatment delays >7 days occurred in 37% and 25% of patients, respectively. This resulted in 56% of patients receiving an RDI <85%. Interestingly, despite the high rates of dose delays and reductions, G-CSF was only administered in 26% of patients. Furthermore, G-CSF use was predominantly reactive or therapeutic – and not prophylactic – as rates of administration were highest in cycles 3 and 4 [6].

This association between the occurrence of CIN and increased dose delays/reductions and subsequent low RDI has also been observed in other studies in early stage breast cancer, solid tumors, and NHL [7,11,26]. Recent studies have revealed that CIN, dose delays/reductions, and low RDI are still common among early stage breast cancer and NHL patients within the past decade; however, they tend to be lower than what was reported in the early 2000s [8,10,27–30]. This has been attributed to higher rates of G-CSF administration in the past two decades. For example, a comparison of aggressive B-cell NHL patients treated between 2006‒2009 and 1993‒2001 found fewer patients experienced dose reductions (21% vs 35%, respectively) and the percent of patients achieving RDI ≥85% was higher (68% vs 52%, respectively) in more recent years. This was associated with a lower incidence of febrile neutropenia (12% vs 21%) and febrile neutropenia–related hospitalization (10% vs 16%), and higher rates of G-CSF use (75% vs 12%) during the period from 2006–2009 [30]. These combined observations suggest that oncologists may be more aware of recommended strategies to prevent and treat CIN than they were in the past [10,30].

While low RDI due to CIN is common across solid tumor types and lymphomas, its risk varies among patients. The most important risk factor for the development of CIN is the type and intensity of myelosuppressive chemotherapy used. Additional factors found to be associated with increased risk of CIN include age >65 years, poor performance status, comorbidities, advanced disease, history of prior febrile neutropenia, and no prophylactic antibiotic or G-CSF use [2,12]. Of note, these factors are also reported to be associated with low RDI in breast cancer and NHL patients [6,7,26].

3. The association between RDI and outcomes in solid tumors and lymphomas

3.1. The importance of dose intensity

Evidence demonstrates that dose intensity of adjuvant chemotherapy is an important predictor of clinical outcomes. This has primarily been noted in studies of early stage breast cancer and other solid tumors [31,32], with high or moderate dose intensity chemotherapy associated with longer survival [33]. A recent meta-analysis of 26 trials of 37,298 patients with breast cancer found that increasing the dose density of adjuvant chemotherapy by shortening the interval between treatment cycles reduces the 10-year risk of recurrence and death, without increasing mortality from other causes [32]. Improved outcomes have also been observed in bladder cancer patients receiving higher dose intensity chemotherapy [34–36]. It is important to note that these dose-dense treatment strategies cannot be effectively delivered without the use of G-CSF [31].

Several hypotheses have been proposed to explain the benefit of higher dose intensity regimens. Among these, the Norton–Simon hypothesis suggests that more frequent administration of chemotherapy can minimize residual tumor burden. According to Gompertzian kinetics models, chemotherapy that reduces tumor volume will result in an inherent increase in tumor regrowth between cycles. Therefore, to enhance cytoreductive activity, chemotherapy should be delivered in the shortest interval possible. Furthermore, the Goldie–Coldman hypothesis suggests administration of high intensity dose regimens prevents the accumulation of mutations that could lead to drug-resistant clones and subsequently reduce chemotherapy effect [31].

3.2. High RDI is associated with improved outcomes

In addition to dose intensity, high RDI has been shown to be associated with improved patient outcomes across many tumor types. This association has been extensively studied in early stage breast cancer and NHL, with similar observations found in other tumor types [2]. This relationship between high RDI and improved outcomes is particularly strong in patients with early stage disease treated with regimens delivered with curative intent [2]; however, this association is less clear in advanced/metastatic disease [37], which is beyond the scope of this review. Furthermore, there is limited evidence that dosing above the recommended RDI (>100%) improves outcomes, likely due to added toxicities with higher doses [38,39].

The importance of RDI in regard to patient outcomes was shown in a seminal study that enrolled early stage breast cancer patients from 1973‒1975 treated with CMF. After a median follow-up of 20 and 30 years, patients who received a higher RDI (≥85%) had improved relapse-free survival (RFS) and overall survival (OS) [4,40]. More recent prospective and retrospective analyses in early stage breast cancer have confirmed these historical findings, with higher RDI associated with longer OS and a lower risk of death [41–43]. Higher RDI has also been reported to be associated with improved survival in other solid tumors, including colon [44,45], ovarian [38,39], and pancreatic ductal adenocarcinoma [46]. Data from these studies are summarized in Table 1.

Table 1. Summary of studies of RDI and patient outcomes in solid tumors and NHL

Study (reference)	Type of study	Tumor type	Dates patients treated; median follow-up	N	CT regimens	RDI-related findings
Bonadonna 1995 [4]	Prospective RCT	Node-positive breast cancer, pre- and post-menopausal	1 June 1973–11 September 1975; median follow-up: 19.4 years	207 vs 179	Adjuvant CMF vs no treatment	RDI ≥85% associated with improved RFS and OS
Abdel-Rahman 2019 [41]	Prospective RCT; secondary analysis of control arm of phase 3 BCIRG005 trial	Stage I‒IV node-positive, HER2-negative operable breast cancer	August 2000–February 2003; median follow-up 126 months (range 7–155)	1,326	AC → docetaxel	AC-docetaxel regimen: RDI ≥90% associated with improved OS (P = .006) Docetaxel only: RDI ≥90% no impact on OS (P = .628) AC portion: RDI ≥90% moderate impact on OS (P = .051)
Cespedes Feliciano 2020 [42]	Retrospective analysis of patients treated at Kaiser Permanente Northern CA	Stage II/III breast cancer	1 January 2005–31 December 2013; median follow-up 7.3 years (max, 12)	1,395	Anthracycline and taxane-based chemotherapy	RDI ≥85% associated with improved OS (P = .01) and lower incidence of breast cancer death (P = .02)
Zhang 2018 [43]	Retrospective analysis of Louisiana Tumor Registry	Stage I–III ER+/PR+, HER2− breast cancer, or TNBC	2011; average follow-up ER+/PR+, HER2 − 5.12 years (range 0.73–6.02), TNBC: 4.70 years (range 0.44–6.06)	494 ER+/PR+, HER2− and 180 TNBC	Standard regimens, including AC-T → paclitaxel or docetaxel; TC, TAC, and AC	ER+/PR+, HER2−: RDI ≥85% associated with improved OS (P = .02) TNBC: RDI ≥75% associated with improved OS (P = .04)
Aspinall 2015 [44]	Retrospective analysis of patients treated at 19 VA medical centers	Stage III colon cancer	2003‒2008; patients followed until June 2011	367	Standard regimens, including 5-FU//LV, oxaliplatin + 5-FU/LV, oxaliplatin + capecitabine, capecitabine monotherapy	RDI >70% associated with improved 5-year OS (P < .001) and 3-year DFS (P = .009)
Van Eeghen 2015 [45]	Analysis of consecutively treated patients at Zaans Medisch Centrum, Netherlands	Stage II/III colon cancer	2002–2008; median follow-up 5.84 years (IQR 3.00–7.84)	243	FOLFOX/CAPOX, oxaliplatin, 5-FU	Patients treated with FOLFOX/CAPOX above the median RDI had improved RFS (P = .045); no association observed with oxaliplatin or 5-FU
Fauci 2011 [39]	Retrospective analysis at University of Alabama Birmingham	Stage I‒IV epithelial ovarian carcinoma	2001–2008; median follow-up not provided	138	Paclitaxel or docetaxel + carboplatin	RDI 70‒110% associated with improved PFS vs RDI <70% or >110% (P = .046)
Anuradha 2016 [38]	Retrospective analysis in Australia	Stage I‒IV epithelial ovarian carcinoma	2005; survival data analyzed in 2012	351	Carboplatin + paclitaxel after cytoreductive surgery	RDI >70% associated with better survival (P < .05)
Yabusaki 2016 [46]	Analysis of consecutively treated patients at Nagoya University Hospital, Japan	Stage I‒III PDAC	May 2005–January 2015; median follow-up 24.5 months (range 3.8–95.0)	134	S-1 monotherapy, gemcitabine monotherapy, or S-1 + gemcitabine	RDI ≥80% associated with improved OS (P < .001)
Lepage 1993 [5]	Subgroup analysis of prospective LNH87-2 protocol	Stage I‒IV NHL, <55 years	Dates not provided; median follow-up: 20 months	311	ACVB induction	RDI ≥70% associated with improved response rate (P = 0.01) and 2-year OS (P = 0.02)
Hirakawa 2010 [47]	Retrospective analysis of patients treated at Nippon Medical School Hospital	Stage I‒IV DLBCL	January 1996–January 2009; median follow-up 1.5 years (range 0.2–6.2)	152; R-CHOP n = 101; R-THPCOP n = 51	R-CHOP or R-THPCOP	All patients: RDI ≥70% associated with improved 2-year OS (P = .005) and 2-year PFS (P = .003) R-CHOP: RDI ≥70% associated with improved 2-year OS (P = .053) and 2-year PFS (P = .042) R-THPCOP: RDI ≥70% trend toward association with improved 2-year PFS (P = .080), but not in OS (P = .142)
Lee 2020 [48]	Retrospective analysis of 3 institutions in Japan	Stage I‒IV newly diagnosed DLBCL, ≥80 years	2007–2017; median follow-up 15.4 months (range 0.30–107.6)	127	CHOP or THP-CHP, ± R	tARDI >50% associated with better 2-year OS (P = .029) A linear association was observed for tARDI and mortality (P = .049)
Dlugosz-Danecka 2019 [49]	Retrospective analysis	Stage I‒IV treatment-naïve DLBCL	2005–2013; median follow-up 6 years	223	R-CHOP	ARDI >90% associated with improved PFS (P < .00001) and OS (P < .00001)
Yamamoto 2020 [50]	Retrospective review of consecutively diagnosed patients	Stage I‒IV newly diagnosed DLBCL	January 2010–October 2018. Follow-up to October 2018	211	R-CHOP	RDI >70% associated with improved EFS and OS
Gutierrez 2015 [51]	Retrospective review of consecutively treated patients at University Hospital Son Espases	Stage I‒IV DLBCL	January 2001–August 2013; median follow-up: 68 months (range 4–156)	115; R-CHOP21 n = 74; R-CHOP14 n = 41	R-CHOP21 or R-CHOP14	R-CHOP21: reduction in RDI >15% associated with OS (P < .001)) and PFS (P < .001) R-CHOP14: no association for RDI reduction and OS (P = .82) and PFS (P = .12)
Klasa 1991 [52]	Meta-analysis of 60 published studies	Limited and extensive-stage SCLC	Studies published between January 1975–July 1988	60 published studies	CAV, CAE, CAVE, EP	CAV (23 studies) and EP (15 studies): no correlation between RDI and outcomes CAE (9 studies) and CAVE (8 studies) analyzed together: RDI correlated positively with median survival in extensive-stage disease only
Ladwa 2018 [53]	Retrospective analysis in Queensland, Australia	Stage I‒IV breast cancer, ≥65 years	2010–2015; median follow-up: 43 months (range 6–117)	281	AC-weekly paclitaxel, TC, FEC-D/FEC-T, FEC 100, TAC, TCH, weekly paclitaxel	No association found between RDI ≥85% and recurrence (P = .399) or all-cause mortality (P = .951)
Schraa 2017 [54]	Retrospective analysis at St. Antonius Hospital in The Netherlands	Stage I‒III breast cancer, all subtypes	1 January 2008–31 December 2013; median follow-up: 38 months (IQR 32)	605	FEC-D, ACTH, TAC, FE100C, FE90C, TC, TCH	No association between RDI as a continuous or dichotomous variable on DFS (P = .569) in the overall population, or for separate chemotherapy regimens or tumor character.stics A trend existed for low RDI impact on DFS for the FEC-D regimen in TNBC (P = .063)
Smoragiewicz 2014 [55]	Retrospective analysis at British Columbia Cancer Agency	Resected stage II and III colon cancer	1 January 2006–31 December 2007; median follow-up: 5.2 years	114	FOLFOX	No association between RDI as a continuous variable for RFS (5-FU P = .84) and (oxaliplatin P = .99) or OS (5-FU P = .57) and (oxaliplatin P = .78) No association between outcomes and categorical RDI (<70%, 70–90%, >90%)

5-FU, 5-fluorouracil; AC, doxorubicin, cyclophosphamide; AC-T, doxorubicin, cyclophosphamide, paclitaxel; ACTH, doxorubicin, cyclophosphamide, paclitaxel, trastuzumab; ACVB, doxorubicin, cyclophosphamide, vindesine, bleomycin, prednisone; CAE, cyclophosphamide, doxorubicin, etoposide; CAPOX, capecitabine, oxaliplatin; CAV, cyclophosphamide, doxorubicin, vincristine; CAVE, cyclophosphamide, doxorubicin, vincristine, etoposide; CMF, cyclophosphamide, methotrexate, fluorouracil; DFS, disease-free survival; EP, etoposide, cisplatin; ER, estrogen receptor; FE100C, fluorouracil, epirubicin (100), cyclophosphamide; FE90C, fluorouracil, epirubicin (90), cyclophosphamide; FEC-D, 5-fluorouracil, epirubicin, cyclophosphamide, docetaxel; FEC-D, 5-fluorouracil, epirubicin, cyclophosphamide, paclitaxel; FOLFOX, folinic acid, fluorouracil, oxaliplatin; HER2, human epidermal growth factor receptor 2; IQR, interquartile range; LV, leucovorin; OS, overall survival; PDAC, pancreatic ductal adenocarcinoma; PR, progesterone receptor; R, rituximab; R-CHOP (14/21), rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (14 days/21 days); RDI, relative dose intensity; TAC, docetaxel, doxorubicin, cyclophosphamide; tARDI, total average relative dose intensity; TC, docetaxel, cyclophosphamide; TCH, docetaxel, cyclophosphamide, trastuzumab; THP-CHP, pirarubicin, cyclophosphamide, vincristine, prednisone; TNBC, triple-negative breast cancer.

Similar associations between RDI and outcomes have also been reported in NHL (Table 1). Early studies in NHL patients treated with an anthracycline-containing induction regimen showed that 28% of patients had an RDI <70%, which was associated with a decreased response rate and shorter overall 2-year survival [5]. Similar findings have been reported in more recent studies with the rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) regimen, noting poor survival associated with RDI of less than 50‒90% (Table 1) [47–50].

3.3. Optimal RDI cutoff values

In general, an RDI cutoff of 85% has been suggested to be optimal for early stage breast cancer patients [4]; however, optimal RDI values may differ according to subtype. An analysis of 494 ER+/PR+, HER2‒ and 180 triple-negative breast cancer (TNBC) patients treated with standard chemotherapy in 2011 found that RDI <85% was associated with poor outcomes in ER+/PR+ HER2‒ patients and <75% in TNBC patients [43]. This study was the first to show differences in RDI cutoff values among breast cancer subtypes, and it is unclear as to the reason for these differences; therefore, additional studies are needed to confirm these findings.

Differences in optimal RDI cutoff values have also been noted among NHL studies. Early observations suggested that RDI <70% was associated with poor outcomes [5]; however, among recent studies assessing RDI in patients treated with R-CHOP21, optimal RDI values were reported as 70%, 85%, and 90% [47,49–51]. These variations may be due to differences in patient- or disease-specific characteristics among the cohorts, length of follow-up, or RDI calculation methods.

3.4. Studies showing no association between RDI and outcomes

Although many studies have shown improved survival with high RDI, some have reported no association between RDI and patient outcomes (Table 1) [52–55]. Explanations for these differing conclusions may include length of follow-up period, sample size, RDI calculation method, or disease- or patient-specific characteristics. Alternatively, the type of chemotherapy regimen could differentially impact potential associations between RDI and outcomes. The myelosuppressive effect of chemotherapy agents can differ, even among the same class of agents, as exemplified by taxanes. The incidence of neutropenia following docetaxel given every 3 weeks is much higher than weekly or every-3-weekly infusions of paclitaxel (46% vs ≤4%) [56]. Thus, higher rates of dose delays/reductions and lower RDI levels are observed in docetaxel-treated patients [41]. Furthermore, the impact of RDI may vary according to individual agents within a regimen or the duration of treatment [41,45,51,52]. Among HER2-negative breast cancer patients treated with docetaxel/doxorubicin/cyclophosphamide (TAC), an RDI ≥90% was associated with improved OS; however, an RDI ≥90% for the docetaxel-only portion of the regimen had no impact on OS, while RDI ≥90% for the doxorubicin/cyclophosphamide (AC) portion moderately impacted survival [41]. Similarly, in NHL, reductions in RDI >15% were significantly associated with poor OS and progression-free survival (PFS) in patients treated with R-CHOP21; however, no associations were found between reductions in RDI and outcomes with the R-CHOP14 regimen [51] (Table 1).

3.5. RDI in special populations

Elderly patients have an increased risk of toxicity and mortality during treatment with curative chemotherapy, and advanced age is considered the most important patient-specific risk factor for the development of febrile neutropenia [2,22]. As a result, elderly patients tend to receive more dose reductions and delays than do younger patients. Delays due to treatment-related toxicities result in lower RDI [2]. Among 976 patients with solid tumors or lymphoma in a prospective analysis, 51% of patients age 70‒74 years received RDI ≤85%; this rate increased to 60% for patients age ≥80 years due to higher rates of dose delays and reductions. In the 50% of patients who received RDI ≥85%, there was no difference in the rates of severe or febrile neutropenia by age, suggesting advanced age alone does not increase the risk of hematologic toxicity [57]. Similar observations have been reported in other studies; nevertheless, advanced age (≥65 years) remains a common variable associated with reduced chemotherapy RDI [6,7,26,53,58].

Despite the risk of chemotherapy-induced toxicities, elderly patients benefit from chemotherapy to the same extent as younger patients; consequently, current guidelines do not recommend dose modification in the first cycle simply based on patient age [2]. Several studies have confirmed that elderly patients are able to maintain RDI ≥85%, and appropriate patient assessment and prophylactic use of G-CSF agents could support optimal dosing [53,58]. A recent retrospective analysis of Medicare data of patients 66 years of age and older with breast cancer, lung cancer, or NHL who received myelosuppressive chemotherapy between 1995 and 2015 reported the use of prophylactic G-CSF increased after 2002 and was associated with an annual decrease in the incidence of neutropenia-related hospitalizations up to 2010, which then remained stable until 2015. These observations demonstrate that G-CSF administration is feasible and provides benefits in an elderly population [59]. These benefits of G-CSF in elderly patients are reflected in guideline recommendations. Current National Comprehensive Cancer Network (NCCN) Guidelines consider growth factor support the best strategy to improve treatment in elderly patients and recommend G-CSF administration in this population when dose intensity is required for response or cure [60].

In addition to advanced age, body surface area ≥2 m² or high body mass index (BMI) is also associated with lower RDI [6,26,61]. In a retrospective analysis of breast cancer patients, most of the difference in dose intensity in obese patients was in the intended dose, with no reductions due to toxicity. This suggests physicians routinely underdose overweight or obese patients [6]. It has been reported that up to 40% of obese patients receive limited chemotherapy based on reduced intended dose [62]. These reductions are initiated due to concerns regarding toxicities in this population; however, these concerns are unfounded, as numerous studies have shown no association between increased BMI and toxicities [63–67]. Moreover, some studies have reported that the incidence of febrile neutropenia, reduced leukocyte count, and grade 3/4 toxicities are lower in obese patients receiving full-dose chemotherapy [63,64,67]. Given these observations, American Society of Clinical Oncology (ASCO) guidelines recommend full weight-based chemotherapy dosing in obese patients, particularly in the curative setting, to maintain RDI and chemotherapy efficacy [62].

4. Current strategies to prevent and Treat CIN, and improve RDI

Identification of patients at increased risk of developing CIN and appropriate prophylactic use of G-CSF to decrease risk of CIN is crucial to achieve optimal RDI levels, maintain chemotherapeutic activity, and prevent CIN-associated morbidity and mortality [2,12,22,23]. According to expert guidelines, maintenance of dose intensity with G-CSF should be standard of care for any treatment with a curative intent [68]. G-CSF agents have been the standard of care in the prevention and management of CIN since the approval of the recombinant human G-CSF (rhG-CSF) drug filgrastim in 1991 [69]. CIN supportive care improved in 2002 with the introduction of the first long-acting recombinant G-CSF, pegylated filgrastim, which allowed once-per-cycle therapy [70]. Current treatment options for CIN have not changed substantially since that time, with common agents limited to rhG-CSF (filgrastim, tbo-filgrastim), long-acting pegylated rhG-CSF (pegfilgrastim), and their biosimilars (filgrastim-sndz, filgrastim-aafi, pegfilgrastim-jmdb, pegfilgrastim-dbqv, pegfilgrastim-bmez, pegfilgrastim-apgf) [12,22,23]. While biosimilar products are highly similar to their reference product, they are not currently considered interchangeable and cannot be substituted without intervention of the prescriber [71]. Furthermore, it is important to note that tbo-filgrastim was approved in Europe as a biosimilar in 2008; however, in the United States, it was approved in 2012 as a biologic product because it was filed under a Biologics License Application since the biosimilars pathways was not established at the time of FDA submission [72].

Short-acting rhG-CSF agents (ie, filgrastim, tbo-filgrastim) are recommended to be administered daily 24 hours after cytotoxic chemotherapy for up to 2 weeks or until neutrophil recovery [73,74]. Alternatively, long-acting pegylated rhG-CSF agents (ie, pegfilgrastim) are administered once per cycle 24 hours post-chemotherapy [70]. Both formulations can also be administered up to 3‒4 days after completion of myelosuppressive chemotherapy [22]. Delayed administration of G-CSF ≥24 hours post-chemotherapy is recommended because G-CSF agents can induce the proliferation of myeloid progenitor cells. These cells can be negatively impacted by cytotoxic therapies, thereby further increasing the risk of febrile neutropenia. In fact, patients who receive G-CSF off schedule have an increased risk of developing febrile neutropenia [75,76].

Numerous studies, including meta-analyses, have shown that G-CSF agents reduce the incidence and duration of severe neutropenia and increase chemotherapy completion and RDI; however, effects on overall mortality and infection-related mortality are not as clear [12]. A recent exploratory analysis of the phase 3 PANTHER study of 5-fluorouracil/epirubicin/cyclophosphamide plus docetaxel (FEC/D) versus EC/D adjuvant chemotherapy in breast cancer patients demonstrated the value of G-CSF therapy. Patients administered G-CSF had a lower incidence of neutropenic events and dose delays [77]. The benefit of G-CSF agents has also been shown in meta-analyses of randomized, controlled trials. In all analyses, G-CSF agents reduced the risk of febrile neutropenia [18,19,21,78]. G-CSF was also shown to reduce hospitalization time and improve neutrophil recovery [18,21]; however, its impact on infection-related mortality and overall mortality varied among studies [18–21].

Despite the benefits of G-CSF agents, they are also associated with several limitations, including potential adverse events and additional unplanned costs. Bone pain is the primary adverse event associated with G-CSF use, which has been reported in 25‒83% of patients across different tumor types and chemotherapeutic regimens. Additional common adverse events of G-CSF agents and their respective incidence rates include headache (15‒83%), myalgias (13‒68%), fatigue (9‒59%), nausea and/or vomiting (3‒18%), fever/chills/sweats (0‒27%), and skin reaction (1‒3%) [22,24]. Furthermore, rare serious adverse events may also occur during G-CSF administration, and all G-CSF agents include a warnings and precautions statement for these events, including fatal splenic rupture, acute respiratory distress syndrome, serious allergic reactions, sickle cell crisis in patients with sickle cell disease, glomerulonephritis, and capillary leak syndrome [24,73,74,79]. While these events are rare, physicians need to be aware of them and act accordingly to reduce the risk of their occurrence. In addition to these potential adverse events, the need for regular clinical visits to receive G-CSF may be challenging for some patients; however, on-body injectors or self-administration could eliminate this burden [80].

G-CSF agents also pose an additional financial burden to cancer patients beyond their direct cancer care. Biologics (filgrastim, pegfilgrastim, epoetin alfa) in particular tend to be more expensive, and this has limited their accessibility for many patients [22,81]. For example, based on the use of 60 doses per year, the annual effective plan per-patient drug cost is estimated to be approximately 19,000 USD for filgrastim 300-mcg syringes, based on wholesale acquisition drug costs from 2016 [82]. The approval of G-CSF biosimilars, which tend to be less expensive, may alleviate these issues for some patients [81]. In both the US and European G5 countries, cost-efficiency analyses have revealed that biosimilar filgrastim provides significant cost savings relative to originator filgrastim and pegfilgrastim [83–85]. According to modeling of US data, the savings afforded by administration of biosimilar filgrastim could expand access to additional therapeutic or supportive prophylactic care on a budget-neutral basis, thereby increasing access to cancer care to more patients at no additional costs [85].

Given the inherently greater benefit-risk ratio of G-CSF administration, patients who are at a higher risk of developing CIN need to be identified prior to chemotherapy initiation and should receive G-CSF prophylactically. The European Organization for Research and Treatment of Cancer (EORTC), ASCO, and NCCN guidelines, as well as expert guidelines, recommend that patients who have an approximately 20% or higher risk for febrile neutropenia should be administered primary prophylaxis with a G-CSF agent starting with the first cycle of chemotherapy and continuing treatment through subsequent cycles of chemotherapy (Figure 1). Initial assessment is based on the frequency of febrile neutropenia associated with a patient’s therapeutic regimen. Additional patient- and disease-specific factors are also considered when assessing the potential risk of CIN development (Figure 1). Patients should be reevaluated for the risk of neutropenia before each subsequent cycle of chemotherapy [12,22,23,68]. This dynamic assessment is supported by results from the MONITOR-GSCF study that evaluated treatment patterns and outcomes of patients treated with chemotherapy and biosimilar filgrastim across 140 global cancer centers and including 1447 patients [86,87]. Physicians can reassess patients based on specific cycle-level risk factors associated with the development of CIN in later cycles, such as the development of CIN in a prior cycle, concomitant antibiotic prophylaxis, impaired performance status, and under-prophylaxis [86]. Accordingly, guidelines recommend that G-CSF should be administered as secondary prophylaxis for patients who did not receive G-CSF but developed febrile neutropenia or a dose-limiting neutropenic event during a prior cycle of chemotherapy [12,22,23,68].

Figure 1. Patient assessment algorithm to determine G-CSF use based on ASCO, EORTC, and NCCN guidelines [12,21,22]. Initial assessment is based on disease and type of chemotherapy regimen. Further refinement of intermediate febrile neutropenia risk is based on patient-specific factors. If indicated, administer G-CSF in the first cycle 24 hours or 3-4 days after completion of myelosuppressive chemotherapy until neutrophil recovery. Patients should be reevaluated prior to second and subsequent chemotherapy cycles. G-CSF should be used as secondary prophylaxis in patients who develop febrile neutropenia or a dose-limiting neutropenic event. In patients who had prior G-CSF, consider chemotherapy dose reduction or change in treatment regimen

a In general, dose-dense regimens require G-CSF support to maintain dose intensity and schedule. b Included in ASCO guidelines. cIncluded in EORTC guidelines. d Included in NCCN Guidelines.ASCO, American Society of Clinical Oncology; EORTC, European Organization for Research and Treatment of Cancer; FN, febrile neutropenia; G-CSF, granulocyte-colony stimulating factor; HIV, human immunodeficiency virus; NCCN, National Comprehensive Cancer Network.

Despite these recommendations, these guidelines are often not followed and G-CSF agents are commonly misused. A prospective analysis of 3,638 solid tumor and lymphoma patients from 2002‒2006 reported that prophylactic G-CSF use more than doubled from cycle 1 to cycle 4, while the majority of neutropenic and infection events occurred in cycle 1, suggesting that G-CSF was being used in response to first-cycle neutropenic events rather than as a prophylactic agent in combination with high-risk chemotherapy regimens [8]. A more recent retrospective analysis of 22,868 solid tumor and lymphoma patients also reported under- and mistimed use of G-CSF agents. Of patients with a high risk of developing febrile neutropenia, 76% received prophylactic G-CSF, while only 28% of intermediate-risk patients received G-CSF prophylaxis. Importantly, there was no difference among G-CSF use in intermediate-risk patients who did or did not have ≥1 risk factor for febrile neutropenia, suggesting a lack of awareness of guideline recommendations. Additionally, a concerning proportion of patients (9%) received G-CSF prophylaxis on the same day as completion of chemotherapy rather than the day after chemotherapy as recommended [80]. While data exist that both support and oppose same-day dosing of pegfilgrastim, NCCN guidelines continue to recommend FDA approved dosing schedules of 24 hours or up to 3–4 days post-chemotherapy [22,88,89]. Several studies have also revealed that patients often do not receive the recommended number of doses of filgrastim prophylaxis likely due to perceived patient inconvenience with potential lack of adherence. This practice could result in compromised efficacy [68,90–93]. As a result, expert guidelines state that if there is a risk that filgrastim may not be continued for 11 days, pegfilgrastim may be a preferred option over filgrastim [68]. In summary, these combined observations suggest the importance of continued physician education and awareness of recommended guidelines for G-CSF administration.

5. Emerging agents for prevention and treatment of CIN

Although G-CSF agents have been the standard of care for prevention and treatment of CIN for approximately 30 years, emerging novel agents in various phases of development and approval may help address some of the challenges associated with G-CSF therapy and may change the treatment landscape for CIN (Table 2) [25].

Table 2. Emerging agents in development to prevent or treat neutropenia

Drug type	Name	Mechanisms of action	Company	Latest development phase	Reference
Long-acting recombinant hematopoietic growth factor	Eflapegrastim	rhG-CSF analog conjugated via PEG linker human IgG Fc domain	Spectrum Pharmaceuticals	3	[94]
	Mecapegfilgrastim	Pegfilgrastim biosimilar	Jiangsu Hengrui Medicine Co., Ltd.	3+	[99,100]
	Pegteograstim	Novel formulation of pegylated rhG-CSF	Green Cross	3	[102]
	Efbemalenograstim alpha (F-627)	rhG-CSF conjugated to the human IgG2 Fc domain	Evive Biotech	3	[105]
Small molecule	Plinabulin	β-tubulin destabilizer	BeyondSpring, Inc.	3	[107]
	Trilaciclib	CDK4/6 inhibitor	G1 Therapeutics, Inc	3	[116]
	Myelo001	Protects hematopoietic bone marrow cells	Myelo Therapeutics, Inc.	2	[124]
	EC-18	Lipid-based small molecule; attenuates neutrophil extravasation	Enzychem Lifesciences Corporation	2	[127]
Human allogeneic myeloid progenitor cell	Romyelocel-L (CTL-008)	Produces effector cells to prevent chemotherapy damage	Cellerant Therapeutics, Inc.	2	[130]

CDK4/6, cyclin-dependent kinase 4/6; IgG2, immunoglobulin 2; rhG-CSF, PEG, polyethylene glycol; recombinant human granulocyte-colony stimulating factor.

5.1. Eflapegrastim: spectrum pharmaceuticals

Eflapegrastim is a long-acting hematopoietic growth factor consisting of a rhG-CSF analog conjugated via a short polyethylene glycol linker to a human immunoglobulin (IgG) Fc fragment, which extends the half-life of the drug [94]. Eflapegrastim differs from other rhG-CSF agents in that the Fc fragment is able to bind to a receptor called FcRn found on endothelial cells and in the bone marrow, which allows the drug to be retained longer in these tissues [95] . In data from two separate phase 3 clinical trials in early stage breast cancer in 237 and 406 patients treated with TC, eflapegrastim demonstrated noninferiority and comparable safety at a lower G-CSF dose than pegfilgrastim. Consistent with approved G-CSF agents, bone pain remained the most common adverse event associated with eflapegrastim in both studies (all grade ~30%). Other common adverse events across the trials were arthralgia, back pain, and myalgia [94,96]. While these studies were not designed to demonstrate superiority, a pooled analysis of the studies revealed that eflapegrastim significantly reduced the risk of severe neutropenia when compared to pegfilgrastim; however, additional trials are needed to confirm these findings [97]. Ongoing studies are further investigating the CIN-preventative properties of eflapegrastim, including same-day dosing as TC in a phase 1 study in breast cancer patients (NCT04187898), and in a phase 2 study in pediatric patients with solid tumors or lymphomas treated with myelosuppressive therapy (NCT04570423) Clinicaltrials.gov; [98] Available from:https://clinicaltrials.gov/.

5.2. Mecapegfilgrastim: Jiangsu Hengrui Medicine Co., Ltd

Mecapegfilgrastim is a long-acting biosimilar of pegfilgrastim that has shown noninferiority versus short-acting G-CSF agents in phase 3 randomized trials of 339 breast cancer patients treated with anthracycline/taxane or AC and 151 NSCLC patients treated with platinum-based chemotherapy. In both trials, no differences in safety signals were observed among the treatment arms. A statistically significant improvement was observed in the incidence of grade 3/4 neutropenia and the duration of grade 4 neutropenia for mecapegfilgrastim in both trials, suggesting that longer-acting G-CSF may provide clinical benefits to patients; however, additional studies are needed to confirm these findings [99,100]. Mecapegfilgrastim has been approved in China to reduce the incidence of infection in patients with non-myeloid malignancies receiving chemotherapy [101]. It is being further investigated in approximately 20 ongoing phase 2‒4 studies in solid tumors and lymphoma in adults and children in China Clinicaltrials.gov; [98].

5.3. Pegteograstim: Green Cross

Pegteograstim is a long-acting, novel formulation of pegylated rhG-CSF, with a higher biological activity than pegfilgrastim [102]. Pegteograstim has shown promising activity as a prophylactic agent for neutropenia in phase 2 and 3 clinical studies [102,103]. In a randomized noninferiority phase 2/3 study in breast cancer patients (n = 60 and n = 117 for the phase 2 and 3 portions, respectively) treated with docetaxel/doxorubicin (DA) or TAC, pegteograstim was as effective as pegfilgrastim at reducing grade 4 neutropenia in chemotherapy cycle 1 and demonstrated a statistically significantly shorter time to neutrophil recovery. The incidence rates and types of adverse events were similar between the treatment arms [103]. Pegteograstim has been approved to treat neutropenia in South Korea [104].

5.4. Efbemalenograstim alpha (F-627): Evive Biotech

Efbemalenograstim alpha is a long-acting recombinant fusion protein of G-CSF and the Fc domain of human IgG2 that allows once-per-cycle administration to prevent neutropenia [105]. Positive results were observed in a phase 3 trial of efbemalenograstim alpha versus placebo in 122 patients with breast cancer treated with DA. Efbemalenograstim alpha significantly reduced the duration of grade 4 neutropenia in cycle 1 and resulted in a lower incidence rate and duration of grade ≥2 neutropenia and febrile neutropenia. Efbemalenograstim alpha was well tolerated, with the most common treatment-emergent adverse events with a frequency ≥2% higher than placebo being leukopenia, anemia, thrombocytopenia, nausea, and alopecia [106]. Furthermore, a recent pivotal phase 3 clinical study in women with stage I‒III breast cancer treated with TC plus efbemalenograstim alpha or pegfilgrastim met its primary and secondary endpoints, demonstrating that efbemalenograstim alpha was able to prevent CIN [105].

5.5. Plinabulin: BeyondSpring, Inc

Plinabulin is a small molecule that binds to β-tubulin and prevents microtubule polymerization. It is being investigated as both an anti-tumor agent and a neutropenia-preventative agent. Plinabulin has demonstrated anti-tumor activity in vitro against several human tumor cell lines through the induction of apoptosis and anti-angiogenic effects [107–110]. Preclinical studies have also revealed that plinabulin prevents the development of CIN in rodents but does not affect the bone marrow or blood G-CSF levels [111]. These findings have been confirmed in clinical studies, with noninferiority observed versus pegfilgrastim in the number of days of severe neutropenia in a phase 2 randomized study of plinabulin versus pegfilgrastim in 55 NSCLC patients treated with docetaxel [112]. Additionally, results of the phase 3 PROTECTIVE-2 study of plinabulin plus pegfilgrastim compared to pegfilgrastim alone demonstrated that the plinabulin combination results in a significant reduction in the incidence of grade 4 neutropenia, febrile neutropenia, and the duration of profound and severe neutropenia in cycle 1 during TAC treatment in 211 randomized breast cancer patients [113]. The combination regimen also increased the percentage of patients achieving RDI >85% [114]. The safety profile of plinabulin appears manageable. In a phase 1 study in 15 NSCLC patients treated with docetaxel plus plinabulin, the most common adverse events were fatigue, pain, nausea, diarrhea, and vomiting [115]. Furthermore, less bone pain and fewer grade 4 adverse events occurred with plinabulin plus pegfilgrastim versus pegfilgrastim alone in the PROTECTIVE-2 study, and less bone pain was also observed with plinabulin versus pegfilgrastim in the phase 2 study highlighted above in NSCLC [112,113].

Plinabulin has received breakthrough therapy designation for the treatment of CIN by the United States Food & Drug Administration (U.S FDA) and China’s National Medical Products Administration [113]. Plinabulin is currently being investigated as a CIN-preventative agent versus pegfilgrastim in a phase 3 study in NSCLC patients receiving docetaxel (NCT03102606), and as both an anti-cancer agent and CIN-preventative agent in a phase 3 study in advanced NSCLC patients treated with docetaxel (NCT02504489) [98].

5.6. Trilaciclib: G1 Therapeutics, Inc

Similar to plinabulin, trilaciclib is also being investigated as both a CIN-preventative agent and an anti-cancer agent. Trilaciclib is a small-molecule inhibitor of cyclin-dependent kinase 4/6 that is administered intravenously. Preclinically, trilaciclib coadministration with cytotoxic chemotherapy protects murine hematopoietic stem cells from chemotherapy-induced exhaustion by causing transient and reversible G1 cell cycle arrest, resulting in a faster peripheral blood count recovery, enhanced serial transplantation capacity, and reduced myeloid skewing [116]. These benefits have been confirmed in clinical trials. Phase 2 randomized, placebo-controlled clinical studies in extensive-stage small cell lung cancer (SCLC) revealed that trilaciclib administration prior to chemotherapy significantly reduced the duration of severe neutropenia in cycle 1 and the occurrence of severe neutropenia during carboplatin/etoposide, carboplatin/etoposide/atezolizumab, or topotecan treatment (77, 107 and 61 randomized patients, respectively). Improvements in red blood cell and platelet counts, and health-related quality-of-life were also observed [117–119]. Despite these positive results in SCLC, a phase 2 study in 102 randomized TNBC patients treated with gemcitabine/carboplatin revealed that trilaciclib administration did not prevent myelosuppression in this patient population; however, improvements in PFS and OS were observed in the trilaciclib group [120,121]. Across the SCLC trials, trilaciclib appeared to be fairly well-tolerated with no reports of bone pain and fewer grade 3 or higher adverse events than placebo-treated groups, primarily due to fewer hematologic toxicities [117–119,122]

Trilaciclib was approved the US. FDA in February 2021 to reduce the incidence of chemotherapy-induced myelosuppression in adult patients when administered prior to a platinum/etoposide-containing regimen or topotecan-containing regimen for extensive-stage SCLC [123]. Additional ongoing studies are investigating trilaciclib as an anti-cancer agent and a CIN-preventative agent in two phases 3 studies in metastatic colorectal cancer patients treated with FOLFOXIRI/bevacizumab (PRESERVE1; NCT04607668) and metastatic TNBC patients treated with gemcitabine and carboplatin (PRESERVE2; NCT04799249), and a phase 2 study in metastatic NSCLC patients treated with docetaxel (PRESERVE4; NCT04863248).

5.7. Myelo001: Myelo Therapeutics, Inc

Myelo001 is an oral, small molecule that induces differentiation of immature myeloid precursors and has shown CIN-preventative properties in preclinical studies in mice [124]. Data from a randomized phase 2 study of myelo001 versus placebo in 130 breast cancer patients treated with epirubicin/cyclophosphamide suggest that myelo001 may be effective at preventing CIN, though additional follow-up data are needed to confirm these findings because of batch variations noted within the study [125]. Myelo001 is also being investigated for the prevention and treatment of acute radiation syndrome [126].

5.8. EC-18: Enzychem Lifesciences Corporation

EC-18 is a synthetic, orally available, lipid-based small molecule that prevents CIN by attenuating neutrophil extravasation by down-regulation of adhesion molecules, cytokines, and chemokines [127]. In preclinical studies, EC-18 reduced fluorouracil-induced CIN in a mouse model [128], and preliminary results from a phase 1/2 study in metastatic breast cancer suggest that EC-18 combined with AC, has a tolerable safety profile and may prevent CIN [129].

5.9. Romyelocel-L (CTL-008): Cellerant Therapeutics, Inc

Romyelocel-L is a cryopreserved, off-the-shelf human allogeneic myeloid progenitor cell therapeutic manufactured by ex vivo expansion of CD34+ cells isolated from G-CSF–mobilized peripheral blood from healthy donors. The cells are intended to engraft transiently and produce effector cells that migrate to tissues damaged by chemotherapy. In a randomized phase 2 study in 160 acute myeloid leukemia patients treated with standard 7 + 3 induction/consolidation or high-dose cytarabine chemotherapy, romyelocel-L combined with G-CSF reduced infections, antibiotics use, and the length of hospitalization when compared to G-CSF use alone. The safety profile was generally similar between the two arms, including an equal incidence of febrile neutropenia [130].

6. Conclusions

Studies have shown the importance of maintaining RDI to improve overall and disease-free survival, including in elderly and obese patient populations. However, CIN often leads to chemotherapy-dose delays and reductions, subsequently adversely impacting RDI and patient outcomes [7–11]. G-CSF is a well-established prophylactic agent that is recommended by guidelines to reduce neutropenia/febrile neutropenia and improve RDI [12,22,23]. Although G-CSF has been shown to significantly reduce the risk of CIN in those at high risk, there remain several limitations to its use, including side effects and cost [15,22,30,80,81]. Therefore, there is a need to develop and evaluate additional therapies to prevent and manage CIN, which would likely improve RDI and patient outcomes, while simultaneously limiting the potential side effects associated with G-CSF.

7. Expert opinion

Reduced RDI of chemotherapy may be associated with poor outcomes in patients with solid tumors and NHL. CIN is the primary inciting adverse event leading to dose reductions, treatment delays and early treatment cessation, culminating in low RDI. Furthermore, CIN is associated with increased risk of infection, mortality, hospitalizations, and greater financial burdens [2]. We believe it is critical that clinicians identify those patients who are at a high-risk of developing CIN and administer prophylactic G-CSF in a timely and appropriate manner in order to maintain RDI and improve patient outcomes.

Despite the increased use of G-CSF prophylaxis throughout the past decade, many physicians are still not administering G-CSF according to evidence-based recommendations [8,80]. Physicians need to be aware of the importance of maintaining RDI and how to administer G-CSF optimally in their clinical practice. Reasons that may explain deviations from recommended practice include not identifying patients at high risk of CIN, and concerns about G-CSF side effects and costs.

Changing practice patterns for G-CSF administration has also arisen due to the COVID-19 pandemic. In order to reduce the need for hospitalizations and frequent visits to outpatient centers, NCCN provided short-term recommendations specific to COVID-19 for neutropenia-related complications. NCCN recommended expanded prophylactic G-CSF to intermediate-risk patients and therapeutic use to all patients if previously not on G-CSF and febrile neutropenia occurred on a prior cycle. NCCN also has recommended self-administration of G-CSF to avoid frequent visits to outpatient centers [131]. As COVID-19 infections and hospitalizations decrease, how these short-term recommendations will impact long-term clinical practice have yet to be determined. An additional practice pattern that has been occurring is the increased administration of filgrastim over single-injection pegfilgrastim. Anecdotal evidence suggests that U.S. payers are increasingly denying prophylaxis with pegfilgratim and authorizing up to 7 days of daily filgrastim instead due to potential cost savings [84]. While many patients prefer the convenience of once-per-cycle administration [132], how potential changing patterns of U.S. payer approvals will impact future practice is currently unknown. Importantly, these cost savings of daily filgrastim biosimilars over standard filgrastim and pegfilgrastim [83–85] may support the wide-spread use of filgrastim biosimilars as a preferred prophylactic and treatment option for developing countries to increase access to cancer care.

The proper recognition of CIN risk is critically important in order to administer G-CSF in a timely manner. Clinicians need to adequately communicate with patients and their caregivers about the signs and symptoms of CIN and its associated risks and encourage them to immediately report if they develop concerning symptoms to receive prompt and proper management. Regular monitoring and early detection of reduced absolute neutrophil count levels is also critically important to prevent complications of neutropenia.

Several available guidelines and risk models can help physicians identify patients at high-risk of developing CIN [12,22,23]. However, providers may be unsure how to manage patients who are characterized as intermediate-risk for the development of CIN. These patients may not receive prophylactic G-CSF and may then experience febrile neutropenia during their first cycle of treatment. This may result in serious consequences including hospitalization and even death. Subsequent chemotherapy cycles may be delayed or administered at reduced and less effective doses. More research is needed on patients receiving intermediate risk chemotherapy regimens to identify which patients are more likely to develop CIN.

G-CSF products have several limitations that may deter physicians from administering them, including side effects and cost [22,24,81]. One of the reported side effects of G-CSF is bone pain, which can significantly impact patient quality-of-life [22,24]. Furthermore, G-CSF administration is an additional financial burden for patients who are increasingly bearing large portions of the cost of their own care. While the approval of G-CSF biosimilars has some promise of reducing cost moving forward, these agents have a similar side effect profile to first generation G-CSFs [81]. These observations suggest the importance of the development of novel therapies to prevent CIN which may have better safety profiles and lower costs.

Several emerging novel therapies have the potential to change the treatment landscape in the future. Some new drugs represent G-CSF that has been modified to improve availability and decrease administration burden, others have more novel mechanisms of action that may have a greater impact on the treatment landscape used either alone or in combination with G-CSF [25]. Approval of these new agents should be based on randomized-controlled trials demonstrating a reduction in the incidence of neutropenic complications. While we believe that G-CSF will still be widely used as a cancer treatment adjunct in the future, new agents that have both anti-tumor and myeloid-supportive properties look very promising.

Article highlights

• CIN is the most common adverse event leading to dose alterations and low RDI.

• The RDI of chemotherapy received is directly associated with patient outcomes.

• G-CSF prophylaxis is recommended to prevent CIN of select chemotherapy regimens.

• Novel drugs in development to prevent CIN may change the treatment landscape.

Declaration of interest

M Shayne has served as a consultant for BeyondSpring.

G Lyman’s institution has received funding from Amgen, Lyman has also served as a consultant for G1 Therapeutics, BeyondSpring, Samsung, TEVA and Merck.

DR Harvey’s institution that supports his salary received research funding from Abbisko, AbbVie, Actuate, Alkermes, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Boston Biomedical, Calithera, Fujifilm, Genmab, GlaxoSmithKline, Infinity, lnhibRx, Lycera, Merck, Mersana, Meryx, Nektar, Pfizer, Puma, RAPT Therapeutics, Regeneron, Rgenix, Sanofi, Seattle Genetics, Sutro, Takeda, Xencor. Harvey has also served as a consultant with Amgen and GlaxoSmithKline.

Medical writing support was provided by Rebecca Bigelow (Publication Practice Counsel™; Truposha LLC), which was funded by BeyondSpring, Inc.

Reviewer disclosures

A reviewer on this manuscript holds equity in Matrix45, LLC. Matrix45 has had and/or currently holds contracts with Amgen, Roche, Sandoz/Novartis, Coherus, Teva, Hospira/Pfizer, Mylan (now Viatris).

Reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

This paper received funding from BeyondSpring Inc.