Real-world incidence of febrile neutropenia despite primary prophylaxis with pegylated G-CSF: a prospective single centre cohort study from India

Real-world incidence of febrile neutropenia despite primary prophylaxis with pegylated G-CSF: a prospective single centre cohort study from India | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Real-world incidence of febrile neutropenia despite primary prophylaxis with pegylated G-CSF: a prospective single centre cohort study from India Ashwin Philips, Asif Rahman K, Sreya Baby, Dona Thampan, Anil Jose Thazath, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8417000/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 4 You are reading this latest preprint version Abstract Background Contemporary trials report febrile neutropenia (FN) rates of 1–2% with primary pegylated G-CSF prophylaxis, but real-world outcomes from low- and middle-income countries (LMICs) remain poorly documented, especially regarding the role and impact of rescue short-acting G-CSF after breakthrough FN. Methods Prospective single-arm cohort study (CTRI/2024/09/073887) of 125 adult patients receiving first-line chemotherapy with primary peg-G-CSF (6 mg SC single dose) at a tertiary cancer centre in India. Primary endpoint was incidence of FN. Secondary endpoints included hospitalisation, chemotherapy modifications, mortality, costs, and detailed utilisation of rescue short-acting G-CSF. Results FN occurred in 14/125 patients (11.2%; 95% CI 6.3–18.1%), generating 19 hospital admissions (recurrent FN in 4 patients). The observed incidence was significantly higher than the expected 1% (one-sample proportion test, p < 0.001). FN rates were similar between high-risk (13.0%) and intermediate-risk patients (10.1%) (p = 0.70). Univariate and multivariable analyses did not identify significant independent predictors of FN. All 14 FN patients received rescue short-acting G-CSF (median 5 doses/episode). Among FN cases, 10 (71.4%) required chemotherapy dose reductions, 2 (14.3%) had regimen changes, 1 (7.1%) discontinued chemotherapy, and 1 (7.1%) died from FN-related sepsis. Median hospital stay per episode was 5 days; total direct cost for 19 episodes was ₹6,01,154 (≈ US $ 7,200). No serious adverse events were attributed to rescue G-CSF (mild bone pain in 21.4%). Conclusions In routine Indian oncology practice, FN incidence despite primary peg-G-CSF prophylaxis is approximately 11%—substantially higher than contemporary trials—with similar rates across risk categories. This breakthrough FN has major clinical and economic consequences. Rescue short-acting G-CSF was universally used and safe. This first prospective LMIC study highlights real-world effectiveness gaps and the need for enhanced vigilance and supportive strategies in resource-constrained settings. Febrile neutropenia pegylated G-CSF primary prophylaxis failure rescue G-CSF real-world evidence India Introduction Febrile neutropenia (FN), characterized by fever and low neutrophil counts, is a dreaded complication in chemotherapy recipients, posing risks of increased morbidity and mortality( 1 ). Granulocyte colony-stimulating factors (G-CSF) play a crucial role in stimulating neutrophil production and function, offering support either as primary prophylaxis, initiated within 5 days of chemotherapy, or as secondary prophylaxis for patients at risk of FN recurrence or prolonged neutropenia. Chemotherapy regimens are classified by risk of FN, guiding prophylactic G-CSF use. Consequently, current NCCN, ESMO and ASCO guidelines strongly recommend primary prophylaxis for regimens with ≥ 20% FN risk and consider it for intermediate-risk patients with additional risk factors( 2 ). Filgrastim and pegfilgrastim, introduced in 1991 and 2002 respectively( 3 ), have become more accessible with decreased costs due to the availability of biologics. While traditional G-CSF requires daily administration, pegylation extends its half-life, allowing for less frequent dosing, typically given 24 to 72 hours post-chemotherapy. Although literature mentions potential side effects such as bone pain and respiratory distress, these are rarely observed in practice. Pegylated G-CSF as primary prophylaxis has effectively reduced FN incidence, aiding in maintaining chemotherapy dose intensity and density, thus improving outcomes( 4 , 5 ). However, despite prophylactic use, FN still occurs in a significant number of patients, posing management challenges. Guidelines currently do not advocate rescue G-CSF use for these cases, yet there is a lack of study or data on optimal management strategies. This is particularly pertinent in low- and middle-income countries (LMICs) where resources and expertise for managing FN are limited. To address this gap, our research aims to evaluate and optimize FN management strategies in LMIC settings, potentially contributing valuable insights to enhance patient care and outcomes in chemotherapy recipients facing FN. We therefore conducted a prospective cohort study to estimate the real-world incidence of FN despite primary peg-G-CSF prophylaxis and to describe the role and safety of rescue G-CSF. Methods Study design and participants : This prospective study was conducted in accordance with the Declaration of Helsinki and the National Ethical Guidelines for Biomedical and Health Research Involving Human Participants, 2017 issued by the Indian Council of Medical Research (ICMR). The study was approved by the Institutional Ethics Committee, Amala Institute of Medical Sciences, Thrissur, Kerala, India (Reference No: 30/EC/24/AIMS-07). The study was prospectively registered with the Clinical Trials Registry of India (CTRI/2024/09/073887). Written informed consent was obtained from all individual participants included in the study. Adult patients (≥ 18 years) with histologically proven malignancy planned for first-line chemotherapy (curative or palliative) were eligible if the regimen was classified as high-risk (≥ 20% FN risk) or intermediate-risk (10–20%) with ≥ 1 patient-related risk factor (age ≥ 65, ECOG ≥ 2, significant comorbidity, prior, etc.) according to NCCN guidelines and primary prophylaxis with peg-G-CSF 6 mg SC was planned. Key exclusion criteria were: prior chemotherapy or radiotherapy, prior G-CSF exposure, active infection at enrolment, leukaemia, and regimens not requiring routine peg-G-CSF. Procedures Peg-G-CSF 6 mg was administered 24–72 hours after each chemotherapy cycle. Complete blood counts were performed on day 8 of cycle 1 and repeated every 2–3 days if TLC was low or borderline. FN was defined as single oral temperature ≥ 38.3°C or ≥ 38.0°C sustained for ≥ 1 hour with ANC < 0.5 × 10⁹/L (or expected to fall below this level within 48 h). Rescue G-CSF (filgrastim 300–600 µg/day SC) was initiated at the treating physician’s discretion for documented FN or prolonged grade 4 neutropenia and continued until ANC > 1.0 × 10⁹/L after nadir recovery. Every effort was made to ensure the cold chain was maintained and logs from the hospital information system was checked to ensure the timing of peg gcsf release from the pharmacy and delivery to the patient. Outcomes Primary outcome: incidence of FN despite primary peg-G-CSF. Secondary outcomes: rescue G-CSF utilisation, hospital/ICU admissions, microbiological profile, chemotherapy dose modifications, direct hospital costs, and adverse events attributable to rescue G-CSF. Statistical analysis Sample size was calculated using the single proportion formula. Based on the pivotal registration trial of pegfilgrastim (Vogel et al., J Clin Oncol 2005) and the largest post-marketing surveillance study of pegfilgrastim in India (Talwar et al., South Asian J Cancer 2017), both of which reported an FN rate of approximately 1% with primary pegfilgrastim prophylaxis, we set the null hypothesis at 1%. A sample size of 120 patients (final 125 after adjusting for 20% dropout) provided 80% power (α = 0.05, one-sided) to detect a clinically meaningful increase to ≥ 10%. Categorical variables are presented as frequencies (%); continuous variables as mean ± SD or median (IQR). One-sample proportion test was used to compare observed FN incidence against the null hypothesis. Associations were explored using χ² or Fisher’s exact test. Multivariable logistic regression identified independent predictors of FN. Analyses were performed in R 4.3.2 and Jamovi 2.3. Results Patient characteristics Between October 2024 and April 2025, 125 patients were enrolled and all were evaluable (Table 1). Mean age was 57.2 ± 10.9 years; 77.6% were female. Breast cancer (52.8%) and lymphoma (9.6%) were the most common diagnoses (supplementary Figure1). The most frequently used regimens were dose-dense Adriamycin cyclophosphamide → taxane Q2W (22.4%), Docetaxel carboplatin trastuzumab (12.8%), Paclitaxel Carboplatin (8.0%), and Rituximab-Cyclophosphamide adriamycin vincristine prednisolone/ CHOP (8.0%). Overall, 36.8% received guideline-defined high-risk regimens and 76.0% received chemotherapy with curative intent. Table 1: Baseline Demographics (N=125) Variable Level Count (%) Age Mean ± SD 57.2 ± 10.9 years Gender Female 97 (77.6%) Male 28 (22.4%) Comorbidities Present 77 (61.6%) Absent 48 (38.4%) Risk Category High 46 (36.8%) Intermediate 79 (63.2%) Intent of Treatment Curative 95 (76.0%) Palliative 30 (24.0%) ECOG 1 54 (43.2%) 2 71 (56.8%) Incidence and characteristics of febrile neutropenia FN occurred in 14 patients (11.2%; 95% CI 6.3–18.1%), generating 19 hospital admissions (recurrent FN in 4 patients). The observed incidence was significantly higher than the pre-specified null hypothesis of 1% (p < 0.001). (Table 2). Most first FN events with recorded timing (78.5%; 11/14) occurred within the first 3 cycles, with peak incidence in cycle 2 (28.6%). One patient experienced recurrent FN across cycles 3, 4, and 6 (Table 2 and Supplementary Table 1). Table 2: Characteristics of FN Admissions (19 Episodes) Characteristic FN Admission (N=19 episodes) Median rescue GCSF doses Median 5 doses/episode, (range 1–8) Risk Category - High 8 (42.1%) - Intermediate 11(57.9%) Recurrence Rate 28.5% (4 out of 14 patients had multiple admissions) Avg. Length of Stay (IPD) 5.0 Days (Range: 2 – 13 days) Total IPD Days 95 Days Clinical course and resource utilisation (Table 2) Median length of stay was 5 days (range 2–13); total inpatient days for FN were 95. Microbiological evaluation (blood/urine/other cultures) was performed in all cases. The culture positivity rate was low at 21.1% (4/19 episodes). Identified pathogens included Enterococcus spp. (tissue), Streptococcus gallolyticus (blood), Burkholderia cepacian (blood), and Pseudomonas (urine); the remaining 82.4% of cultures were sterile. All 14 FN patients received rescue G-CSF (median 5 doses/episode, range 1–8). An additional 4 patients (3.2%) received rescue G-CSF for severe neutropenia without fever (median 1 dose). No serious adverse events were attributed to rescue G-CSF. Impact on chemotherapy delivery Among FN cases, 10 (71.4%) required chemotherapy dose reductions, 2 (14.3%) had regimen changes, 1 (7.1%) discontinued chemotherapy, and 1 (7.1%) died from FN-related sepsis Side effects to rescue GCSF The incidence of bone pain due to rescue GCSF use in this cohort was 21.4% (3 out of 14 patients). The majority of bone pain episodes were Grade 1 (mild), with Grade 2 (moderate) pain observed in one patient across multiple cycles. Among the 3 patients who experienced bone pain, 2 patients had recurring episodes across multiple chemotherapy cycles. There was no documented case of splenic rupture, lung injury related to GCSF use. Economic burden Average direct hospital cost per FN episode was ₹31,640 (range ₹5,005–₹1,31,250). Total cost for managing 19 episodes was ₹6,01,154 (≈US$7,200). Predictors of FN : Univariate and multivariable logistic regression did not identify any significant independent predictors of FN, consistent with the similar risk observed across HR and IC subgroups. Discussion This is the first prospective study to systematically document the real-world incidence of FN despite guideline-directed primary peg-G-CSF prophylaxis and to evaluate the role of rescue GCSF in these patients. We observed an 11.2% incidence — which was similar to the registration trials(6–8) but approximately ten times higher than the 1–2% reported in contemporary studies(9,10). The registration studies used Adriamycin + docetaxel combination regimens in breast cancer showed FN rates of 7-20%, however these regimens are no longer considered standard. The contemporary studies, including post-marketing studies, show FN rates ranging between 1–25% (Table 3). This stark difference provides critical, real-world evidence challenging the generalizability of trial data to low- and middle-income countries (LMICs). A key novel finding is the comparable FN risk between guideline-defined high-risk patients (13.0%) and intermediate-risk patients with added risk factors (11.8%), with no significant difference in FN rates, contribution to total FN events. Moreover, intermediate-risk patients with comorbidities had poorer baseline functional status (74.5% ECOG 2 vs 43.5% in high-risk), suggesting they may be particularly vulnerable. These data provide real-world evidence supporting current guidelines that recommend primary peg-G-CSF prophylaxis for intermediate-risk patients when additional risk factors (especially comorbidities) are present and further suggest that such patients warrant the same level of clinical vigilance as high-risk patients. The significant incidence of breakthrough FN observed carries substantial clinical and economic consequences. FN led to 71.4% of patients requiring chemotherapy dose reductions or 14.3% needing regimen changes, indicating a major failure to maintain optimal dose intensity—a cornerstone of curative therapy. Furthermore, the single FN-related death (7.1% mortality rate among FN cases) underscores the measurable, life-threatening risk associated with breakthrough FN in this setting. The high resource consumption, with a median hospital stay of 5 days and a total direct cost of approximately ₹6,01,154 (≈US$7,200) for 19 episodes, imposes a significant economic burden on the healthcare system and patients in resource-constrained environments. Potential Explanations for High Incidence FN Patient-Related Factors: Patients in LMICs often present with poor baseline nutritional status, co-existing subclinical infections, or anemia, leading to reduced bone marrow reserve compared to highly selected trial populations in HICs. These factors may increase the bone marrow's susceptibility to myelotoxicity despite standard prophylaxis. Environmental/Microbial Factors: Differences in environmental hygiene, microbial exposure, or background infection rates may predispose patients to sepsis once neutropenia occurs, leading to a higher rate of documented FN admissions. Adherence/Access: While we rigorously checked the cold chain and timing of peg-G-CSF administration, differences in patient self-care, timely symptom reporting, and rapid access to care once fever develops may influence the classification and severity of FN in the real-world setting. Cold Chain Maintenance and Peg-G-CSF Stability A common concern in LMIC settings is whether suboptimal cold chain logistics contribute to breakthrough FN. However, pegfilgrastim is highly stable to temperature excursions: the product insert specifies 2–8°C storage, but confirms no loss of efficacy after up to 72 hours or brief exposure to 30°C. In this study, pharmacy logs verified 100% administration within 2 hours of 2–8°C removal, with no excursions >25°C documented. Thus, storage is unlikely to explain the observed 11.2% FN rate, which aligns more closely with inherent regimen myelotoxicity and LMIC-specific vulnerabilities (e.g., baseline anemia, microbial burden) than with drug degradation. Table 3: Comparison of FN rates with other studies 2003 Green et al.(6) (pivotal registration study) Phase III RCT (pegfilgrastim vs filgrastim) Breast cancer Doxorubicin 60 + Docetaxel 75 mg/m² Q3W Duration of severe neutropenia 13% (cycle 1) 2003 Citron et al. (CALGB 9741)(4) Phase III RCT (dose-dense vs Q3W) Node-positive breast cancer Dose-dense AC→P Q2W (supported by daily filgrastim; pegfilgrastim widely adopted later) Disease-free survival ≈2–4% (with G-CSF support) 2005 Vogel et al.(9) Phase III RCT (pegfilgrastim vs placebo) Breast cancer Docetaxel 100 mg/m² Q3W Incidence of FN 1% (vs 17% placebo) 2009 Jacobs et al.(11) Prospective real-world cost analysis Breast cancer Adjuvant AC or AC→T FN rates & hospital costs 24% (despite G-CSF in many cases; exact pegfilgrastim use not separated) 2010 Hecht et al.(8) Randomized phase II (pegfilgrastim vs placebo) Metastatic colorectal cancer Q2W FOLFOX or FOLFIRI Grade 3/4 neutropenia 2% (vs 8% placebo) 2013 Cunningham et al. (5) Phase III RCT-. (R-CHOP-14 vs R-CHOP-21 DLBCL R-CHOP-14 vs R-CHOP-21 (pegfilgrastim mandatory in R-CHOP-14 arm) Overall survival 11% (R-CHOP-14 + peg) vs 5% (R-CHOP-21, G-CSF discretionary) 2015 Weycker et al(3) Retrospective cohort Mixed metastatic cancers FN and the consequences FN :13.1% to 20.6% 2017 Talwar et al. (10) Prospective post-marketing surveillance Mixed cancers (predominantly breast) Various regimens Safety & tolerability 0.96–1.2% 2022 Zhao et al.(12) Real-world cost-effectiveness model (China) Breast cancer TC, AC-T, dose-dense regimens Neutropenia/FN events 5% (model input for high-risk regimens) *RCHOP- Rituximab, cyclophosphamide, Adriamycin, vincristine, Prednisolone AC- Adriamycin, Cyclophosphamide, TC: Docetaxel, Cyclophosphamide Limitations and Strengths Our study's strength is its prospective design and strict adherence to the FN definition and G-CSF administration protocol. A key limitation is the single-centre nature, lack of comparator arm which may limit generalizability, although the findings are highly representative of current oncology practice across Kerala and potentially India. We did not collect granular data on baseline nutritional status or serum G-CSF levels and the small sample size limitation for multivariate analysis. Conclusion In this prospective real-world cohort from India, the incidence of febrile neutropenia despite guideline-directed primary pegylated G-CSF prophylaxis was approximately 11%, substantially higher than rates reported in contemporary clinical trials. Breakthrough FN occurred at comparable frequencies in both guideline-defined high-risk and intermediate-risk patients with additional risk factors and was associated with significant clinical consequences, including chemotherapy dose reductions, treatment discontinuation, prolonged hospitalisation, increased healthcare costs, and measurable mortality. Rescue short-acting G-CSF was universally employed for FN management in this setting and was well tolerated, although its impact on clinical outcomes cannot be inferred from this study. These findings highlight an important effectiveness gap between trial data and routine practice in low- and middle-income countries and underscore the need for heightened vigilance, context-specific supportive care strategies, and further research to optimise FN prevention and management in resource-constrained oncology settings. Declarations Funding None Declaration of interests None declared References Kasi PM, Grothey A. Chemotherapy-Induced Neutropenia as a Prognostic and Predictive Marker of Outcomes in Solid-Tumor Patients. Drugs. 2018;78(7):737–45. Smith TJ, Bohlke K, Lyman GH, Carson KR, Crawford J, Cross SJ, et al. Recommendations for the Use of WBC Growth Factors: American Society of Clinical Oncology Clinical Practice Guideline Update. 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The Lancet. 2013;381(9880):1817–26. Green MD, Koelbl H, Baselga J, Galid A, Guillem V, Gascon P, et al. A randomized double-blind multicenter phase III study of fixed-dose single-administration pegfilgrastim versus daily filgrastim in patients receiving myelosuppressive chemotherapy. Ann Oncol Off J Eur Soc Med Oncol. 2003;14(1):29–35. Holmes FA, O’Shaughnessy JA, Vukelja S, Jones SE, Shogan J, Savin M, et al. Blinded, randomized, multicenter study to evaluate single administration pegfilgrastim once per cycle versus daily filgrastim as an adjunct to chemotherapy in patients with high-risk stage II or stage III/IV breast cancer. J Clin Oncol Off J Am Soc Clin Oncol. 2002;20(3):727–31. Hecht JR, Pillai M, Gollard R, Heim W, Swan F, Patel 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. Clin Colorectal Cancer. 2010;9(2):95–101. Vogel CL, Wojtukiewicz MZ, Carroll RR, Tjulandin SA, Barajas-Figueroa LJ, Wiens BL, 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. J Clin Oncol Off J Am Soc Clin Oncol. 2005;23(6):1178–84. Talwar V, Nirni SS, Mallavarapu KM, Ramkumar A, Sinha N. Safety and tolerability of Peg-grafeel ™ , a pegfilgrastim, for the prophylactic treatment of chemotherapy-induced neutropenia and febrile neutropenia: A prospective, observational, postmarketing surveillance study in India. South Asian J Cancer. 2017;6(1):20–4. Jacobs VR, Mayer SC, Paessens B, Anker G, Schwarz-Boeger U, Paepke S, et al. Prospective study comparing hospital costs and DRG reimbursement of inpatient treatment of febrile neutropenia during adjuvant anthracycline-based CTX for primary breast cancer. J Clin Oncol [Internet]. 2009 May 20 [cited 2025 Dec 11]; Available from: https://ascopubs.org/doi/10.1200/jco.2009.27.15_suppl.e11570 Zhao J, Qiao G, Liang Y, Li J, Hu W, Zuo X, et al. Cost-Effectiveness Analysis of PEG-rhG-CSF as Primary Prophylaxis to Chemotherapy-Induced Neutropenia in Women With Breast Cancer in China: Results Based on Real-World Data. Front Pharmacol. 2021;12:754366. Additional Declarations No competing interests reported. Supplementary Files SupplementaryInformation.docx Cite Share Download PDF Status: Under Review Version 1 posted Reviewers invited by journal 19 Jan, 2026 Editor assigned by journal 19 Jan, 2026 Submission checks completed at journal 06 Jan, 2026 First submitted to journal 21 Dec, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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14:52:36","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":19227,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryInformation.docx","url":"https://assets-eu.researchsquare.com/files/rs-8417000/v1/d8a224a8f57501c4a3806acf.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eReal-world incidence of febrile neutropenia despite primary prophylaxis with pegylated G-CSF: a prospective single centre cohort study from India\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eFebrile neutropenia (FN), characterized by fever and low neutrophil counts, is a dreaded complication in chemotherapy recipients, posing risks of increased morbidity and mortality(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). Granulocyte colony-stimulating factors (G-CSF) play a crucial role in stimulating neutrophil production and function, offering support either as primary prophylaxis, initiated within 5 days of chemotherapy, or as secondary prophylaxis for patients at risk of FN recurrence or prolonged neutropenia. Chemotherapy regimens are classified by risk of FN, guiding prophylactic G-CSF use. Consequently, current NCCN, ESMO and ASCO guidelines strongly recommend primary prophylaxis for regimens with \u0026ge;\u0026thinsp;20% FN risk and consider it for intermediate-risk patients with additional risk factors(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eFilgrastim and pegfilgrastim, introduced in 1991 and 2002 respectively(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e), have become more accessible with decreased costs due to the availability of biologics. While traditional G-CSF requires daily administration, pegylation extends its half-life, allowing for less frequent dosing, typically given 24 to 72 hours post-chemotherapy. Although literature mentions potential side effects such as bone pain and respiratory distress, these are rarely observed in practice.\u003c/p\u003e \u003cp\u003ePegylated G-CSF as primary prophylaxis has effectively reduced FN incidence, aiding in maintaining chemotherapy dose intensity and density, thus improving outcomes(\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). However, despite prophylactic use, FN still occurs in a significant number of patients, posing management challenges. Guidelines currently do not advocate rescue G-CSF use for these cases, yet there is a lack of study or data on optimal management strategies. This is particularly pertinent in low- and middle-income countries (LMICs) where resources and expertise for managing FN are limited. To address this gap, our research aims to evaluate and optimize FN management strategies in LMIC settings, potentially contributing valuable insights to enhance patient care and outcomes in chemotherapy recipients facing FN. We therefore conducted a prospective cohort study to estimate the real-world incidence of FN despite primary peg-G-CSF prophylaxis and to describe the role and safety of rescue G-CSF.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cb\u003eStudy design and participants\u003c/b\u003e : This prospective study was conducted in accordance with the Declaration of Helsinki and the National Ethical Guidelines for Biomedical and Health Research Involving Human Participants, 2017 issued by the Indian Council of Medical Research (ICMR). The study was approved by the Institutional Ethics Committee, Amala Institute of Medical Sciences, Thrissur, Kerala, India (Reference No: 30/EC/24/AIMS-07). The study was prospectively registered with the Clinical Trials Registry of India (CTRI/2024/09/073887). Written informed consent was obtained from all individual participants included in the study.\u003c/p\u003e \u003cp\u003eAdult patients (\u0026ge;\u0026thinsp;18 years) with histologically proven malignancy planned for first-line chemotherapy (curative or palliative) were eligible if the regimen was classified as high-risk (\u0026ge;\u0026thinsp;20% FN risk) or intermediate-risk (10\u0026ndash;20%) with \u0026ge;\u0026thinsp;1 patient-related risk factor (age\u0026thinsp;\u0026ge;\u0026thinsp;65, ECOG\u0026thinsp;\u0026ge;\u0026thinsp;2, significant comorbidity, prior, etc.) according to NCCN guidelines and primary prophylaxis with peg-G-CSF 6 mg SC was planned. Key exclusion criteria were: prior chemotherapy or radiotherapy, prior G-CSF exposure, active infection at enrolment, leukaemia, and regimens not requiring routine peg-G-CSF.\u003c/p\u003e \u003cp\u003e \u003cb\u003eProcedures\u003c/b\u003e Peg-G-CSF 6 mg was administered 24\u0026ndash;72 hours after each chemotherapy cycle. Complete blood counts were performed on day 8 of cycle 1 and repeated every 2\u0026ndash;3 days if TLC was low or borderline. FN was defined as single oral temperature\u0026thinsp;\u0026ge;\u0026thinsp;38.3\u0026deg;C or \u0026ge;\u0026thinsp;38.0\u0026deg;C sustained for \u0026ge;\u0026thinsp;1 hour with ANC\u0026thinsp;\u0026lt;\u0026thinsp;0.5 \u0026times; 10⁹/L (or expected to fall below this level within 48 h). Rescue G-CSF (filgrastim 300\u0026ndash;600 \u0026micro;g/day SC) was initiated at the treating physician\u0026rsquo;s discretion for documented FN or prolonged grade 4 neutropenia and continued until ANC\u0026thinsp;\u0026gt;\u0026thinsp;1.0 \u0026times; 10⁹/L after nadir recovery. Every effort was made to ensure the cold chain was maintained and logs from the hospital information system was checked to ensure the timing of peg gcsf release from the pharmacy and delivery to the patient.\u003c/p\u003e \u003cp\u003e \u003cb\u003eOutcomes\u003c/b\u003e Primary outcome: incidence of FN despite primary peg-G-CSF. Secondary outcomes: rescue G-CSF utilisation, hospital/ICU admissions, microbiological profile, chemotherapy dose modifications, direct hospital costs, and adverse events attributable to rescue G-CSF.\u003c/p\u003e \u003cp\u003e \u003cb\u003eStatistical analysis\u003c/b\u003e Sample size was calculated using the single proportion formula. Based on the pivotal registration trial of pegfilgrastim (Vogel et al., J Clin Oncol 2005) and the largest post-marketing surveillance study of pegfilgrastim in India (Talwar et al., South Asian J Cancer 2017), both of which reported an FN rate of approximately 1% with primary pegfilgrastim prophylaxis, we set the null hypothesis at 1%. A sample size of 120 patients (final 125 after adjusting for 20% dropout) provided 80% power (α\u0026thinsp;=\u0026thinsp;0.05, one-sided) to detect a clinically meaningful increase to \u0026ge;\u0026thinsp;10%.\u003c/p\u003e \u003cp\u003eCategorical variables are presented as frequencies (%); continuous variables as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD or median (IQR). One-sample proportion test was used to compare observed FN incidence against the null hypothesis. Associations were explored using χ\u0026sup2; or Fisher\u0026rsquo;s exact test. Multivariable logistic regression identified independent predictors of FN. Analyses were performed in R 4.3.2 and Jamovi 2.3.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003ePatient characteristics\u003c/strong\u003e Between October 2024 and April 2025, 125 patients were enrolled and all were evaluable (Table 1). Mean age was 57.2 \u0026plusmn; 10.9 years; 77.6% were female. Breast cancer (52.8%) and lymphoma (9.6%) were the most common diagnoses (supplementary Figure1).\u0026nbsp;The most frequently used regimens were dose-dense Adriamycin cyclophosphamide \u0026rarr; taxane Q2W (22.4%), Docetaxel carboplatin trastuzumab (12.8%), Paclitaxel Carboplatin (8.0%), and Rituximab-Cyclophosphamide adriamycin vincristine prednisolone/ CHOP (8.0%). Overall, 36.8% received guideline-defined high-risk regimens\u0026nbsp;and 76.0% received chemotherapy with curative intent.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1: Baseline Demographics (N=125)\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 200px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eVariable\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 200px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLevel\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 200px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCount (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 200px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 200px;\"\u003e\n \u003cp\u003eMean \u0026plusmn; SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 200px;\"\u003e\n \u003cp\u003e57.2 \u0026plusmn; 10.9 years\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 200px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGender\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 200px;\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 200px;\"\u003e\n \u003cp\u003e97 (77.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 200px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 200px;\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 200px;\"\u003e\n \u003cp\u003e28 (22.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 200px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eComorbidities\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 200px;\"\u003e\n \u003cp\u003ePresent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 200px;\"\u003e\n \u003cp\u003e77 (61.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 200px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 200px;\"\u003e\n \u003cp\u003eAbsent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 200px;\"\u003e\n \u003cp\u003e48 (38.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 200px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRisk Category\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 200px;\"\u003e\n \u003cp\u003eHigh\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 200px;\"\u003e\n \u003cp\u003e46 (36.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 200px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 200px;\"\u003e\n \u003cp\u003eIntermediate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 200px;\"\u003e\n \u003cp\u003e79 (63.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 200px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eIntent of Treatment\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 200px;\"\u003e\n \u003cp\u003eCurative\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 200px;\"\u003e\n \u003cp\u003e95 (76.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 200px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 200px;\"\u003e\n \u003cp\u003ePalliative\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 200px;\"\u003e\n \u003cp\u003e30 (24.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 200px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eECOG\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 200px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 200px;\"\u003e\n \u003cp\u003e54 (43.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 200px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 200px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 200px;\"\u003e\n \u003cp\u003e71 (56.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eIncidence and characteristics of febrile neutropenia\u003c/strong\u003e FN occurred in 14 patients (11.2%; 95% CI 6.3\u0026ndash;18.1%), generating 19 hospital admissions (recurrent FN in 4 patients). The observed incidence was significantly higher than the pre-specified null hypothesis of 1% (p \u0026lt; 0.001). (Table 2). Most first FN events with recorded timing (78.5%; 11/14) occurred within the first 3 cycles, with peak incidence in cycle 2 (28.6%). One patient experienced recurrent FN across cycles 3, 4, and 6 (Table 2 and Supplementary Table 1).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2: Characteristics of FN Admissions (19 Episodes)\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"601\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 301px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCharacteristic\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 301px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFN Admission (N=19 episodes)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 301px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMedian rescue GCSF doses\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 301px;\"\u003e\n \u003cp\u003eMedian 5 doses/episode, (range 1\u0026ndash;8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 301px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRisk Category\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 301px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 301px;\"\u003e\n \u003cp\u003e- High\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 301px;\"\u003e\n \u003cp\u003e8 (42.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 301px;\"\u003e\n \u003cp\u003e- Intermediate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 301px;\"\u003e\n \u003cp\u003e11(57.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 301px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRecurrence Rate\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 301px;\"\u003e\n \u003cp\u003e28.5% (4 out of 14 patients had multiple admissions)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 301px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAvg. Length of Stay (IPD)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 301px;\"\u003e\n \u003cp\u003e5.0 Days (Range: 2 \u0026ndash; 13 days)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 301px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTotal IPD Days\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 301px;\"\u003e\n \u003cp\u003e95 Days\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eClinical course and resource utilisation\u003c/strong\u003e (Table 2) Median length of stay was 5 days (range 2\u0026ndash;13); total inpatient days for FN were 95. Microbiological evaluation (blood/urine/other cultures) was performed in all cases. The culture positivity rate was low at 21.1% (4/19 episodes). Identified pathogens included \u003cem\u003eEnterococcus spp.\u003c/em\u003e (tissue), \u003cem\u003eStreptococcus gallolyticus\u003c/em\u003e (blood), Burkholderia cepacian (blood), and \u003cem\u003ePseudomonas\u003c/em\u003e (urine); the remaining 82.4% of cultures were sterile. All 14 FN patients received rescue G-CSF (median 5 doses/episode, range 1\u0026ndash;8). An additional 4 patients (3.2%) received rescue G-CSF for severe neutropenia without fever (median 1 dose). No serious adverse events were attributed to rescue G-CSF.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eImpact on chemotherapy delivery\u003c/strong\u003e Among FN cases, 10 (71.4%) required chemotherapy dose reductions, 2 (14.3%) had regimen changes, 1 (7.1%) discontinued chemotherapy, and 1 (7.1%) died from FN-related sepsis\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSide effects to rescue GCSF\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe incidence of bone pain due to rescue GCSF use in this cohort was 21.4% (3 out of 14 patients). The majority of bone pain episodes were Grade 1 (mild), with Grade 2 (moderate) pain observed in one patient across multiple cycles. Among the 3 patients who experienced bone pain, 2 patients had recurring episodes across multiple chemotherapy cycles. There was no documented case of splenic rupture, lung injury related to GCSF use.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEconomic burden\u003c/strong\u003e Average direct hospital cost per FN episode was ₹31,640 (range ₹5,005\u0026ndash;₹1,31,250). Total cost for managing 19 episodes was ₹6,01,154 (\u0026asymp;US$7,200).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePredictors of FN\u003c/strong\u003e : Univariate and multivariable logistic regression did not identify any significant independent predictors of FN, consistent with the similar risk observed across HR and IC subgroups.\u0026nbsp;\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis is the first prospective study to systematically document the real-world incidence of FN despite guideline-directed primary peg-G-CSF prophylaxis and to evaluate the role of rescue GCSF in these patients. We observed an 11.2% incidence \u0026mdash; which was similar to the registration trials(6\u0026ndash;8) but approximately ten times higher than the 1\u0026ndash;2% reported in contemporary studies(9,10). The registration studies used Adriamycin + docetaxel combination regimens in breast cancer showed FN rates of 7-20%, however these regimens are no longer considered standard. The contemporary studies, including post-marketing studies, show FN rates ranging between 1\u0026ndash;25% (Table 3). This stark difference provides critical, real-world evidence challenging the generalizability of trial data to low- and middle-income countries (LMICs). A key novel finding is the comparable FN risk between guideline-defined high-risk patients (13.0%) and intermediate-risk patients with added \u0026nbsp;risk factors (11.8%), with no significant difference in FN rates, contribution to total FN events. Moreover, intermediate-risk patients with comorbidities had poorer baseline functional status (74.5% ECOG 2 vs 43.5% in high-risk), suggesting they may be particularly vulnerable. These data provide real-world evidence supporting current guidelines that recommend primary peg-G-CSF prophylaxis for intermediate-risk patients when additional risk factors (especially comorbidities) are present and further suggest that such patients warrant the same level of clinical vigilance as high-risk patients.\u003c/p\u003e\n\u003cp\u003eThe significant incidence of breakthrough FN observed carries substantial clinical and economic consequences. FN led to 71.4%\u0026nbsp;of patients requiring chemotherapy dose reductions or 14.3%\u0026nbsp;needing regimen changes, indicating a major failure to maintain optimal dose intensity\u0026mdash;a cornerstone of curative therapy. Furthermore, the single FN-related death (7.1% mortality rate among FN cases) underscores the measurable, life-threatening risk associated with breakthrough FN in this setting. The high resource consumption, with a median hospital stay of 5 days and a total direct cost of approximately\u0026nbsp;₹6,01,154 (\u0026asymp;US$7,200) for 19 episodes, imposes a significant economic burden on the healthcare system and patients in resource-constrained environments.\u003c/p\u003e\n\u003ch3\u003ePotential Explanations for High Incidence FN\u003c/h3\u003e\n\u003col\u003e\n \u003cli\u003e\u003cstrong\u003ePatient-Related Factors:\u003c/strong\u003e Patients in LMICs often present with poor baseline nutritional status, co-existing subclinical infections, or anemia, leading to reduced bone marrow reserve compared to highly selected trial populations in HICs. These factors may increase the bone marrow\u0026apos;s susceptibility to myelotoxicity despite standard prophylaxis.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eEnvironmental/Microbial Factors:\u003c/strong\u003e Differences in environmental hygiene, microbial exposure, or background infection rates may predispose patients to sepsis once neutropenia occurs, leading to a higher rate of documented FN admissions.\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003e\u003cstrong\u003eAdherence/Access:\u003c/strong\u003e While we rigorously checked the cold chain and timing of peg-G-CSF administration, differences in patient self-care, timely symptom reporting, and rapid access to care once fever develops may influence the classification and severity of FN in the real-world setting.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCold Chain Maintenance and Peg-G-CSF Stability\u003c/strong\u003e A common concern in LMIC settings is whether suboptimal cold chain logistics contribute to breakthrough FN. However, pegfilgrastim is highly stable to temperature excursions: the product insert specifies 2\u0026ndash;8\u0026deg;C storage, but confirms no loss of efficacy after up to 72 hours or brief exposure to 30\u0026deg;C. In this study, pharmacy logs verified 100% administration within 2 hours of 2\u0026ndash;8\u0026deg;C removal, with no excursions \u0026gt;25\u0026deg;C documented. Thus, storage is unlikely to explain the observed 11.2% FN rate, which aligns more closely with inherent regimen myelotoxicity and LMIC-specific vulnerabilities (e.g., baseline anemia, microbial burden) than with drug degradation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3: Comparison of FN rates with other studies\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"602\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e2003\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003eGreen et al.(6) (pivotal registration study)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 105px;\"\u003e\n \u003cp\u003ePhase III RCT (pegfilgrastim vs filgrastim)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003eBreast cancer Doxorubicin 60 + Docetaxel 75 mg/m\u0026sup2; Q3W\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003eDuration of severe neutropenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 103px;\"\u003e\n \u003cp\u003e13% (cycle 1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e2003\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003eCitron et al. (CALGB 9741)(4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 105px;\"\u003e\n \u003cp\u003ePhase III RCT (dose-dense vs Q3W)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003eNode-positive breast cancer Dose-dense AC\u0026rarr;P Q2W (supported by daily filgrastim; pegfilgrastim widely adopted later)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003eDisease-free survival\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 103px;\"\u003e\n \u003cp\u003e\u0026asymp;2\u0026ndash;4% (with G-CSF support)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e2005\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003eVogel et al.(9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 105px;\"\u003e\n \u003cp\u003ePhase III RCT (pegfilgrastim vs placebo)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003eBreast cancer Docetaxel 100 mg/m\u0026sup2; Q3W\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003eIncidence of FN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 103px;\"\u003e\n \u003cp\u003e1% (vs 17% placebo)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e2009\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003eJacobs et al.(11)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 105px;\"\u003e\n \u003cp\u003eProspective \u0026nbsp;real-world cost analysis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003eBreast cancer Adjuvant AC or AC\u0026rarr;T\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003eFN rates \u0026amp; hospital costs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 103px;\"\u003e\n \u003cp\u003e24% (despite G-CSF in many cases; exact pegfilgrastim use not separated)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e2010\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003eHecht et al.(8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 105px;\"\u003e\n \u003cp\u003eRandomized phase II (pegfilgrastim vs placebo)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003eMetastatic colorectal cancer Q2W FOLFOX or FOLFIRI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003eGrade 3/4 neutropenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 103px;\"\u003e\n \u003cp\u003e2% (vs 8% placebo)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e2013\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003eCunningham et al. (5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 105px;\"\u003e\n \u003cp\u003ePhase III RCT-. (R-CHOP-14 vs R-CHOP-21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003eDLBCL R-CHOP-14 vs R-CHOP-21 (pegfilgrastim mandatory in R-CHOP-14 arm)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003eOverall survival\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 103px;\"\u003e\n \u003cp\u003e11% (R-CHOP-14 + peg) vs 5% (R-CHOP-21, G-CSF discretionary)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e2015\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003eWeycker et al(3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 105px;\"\u003e\n \u003cp\u003eRetrospective cohort\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003eMixed metastatic cancers\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003eFN and the consequences\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 103px;\"\u003e\n \u003cp\u003e\u0026nbsp;FN :13.1% to 20.6%\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e2017\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003eTalwar et al. (10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 105px;\"\u003e\n \u003cp\u003eProspective post-marketing surveillance\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003eMixed cancers (predominantly breast) Various regimens\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003eSafety \u0026amp; tolerability\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 103px;\"\u003e\n \u003cp\u003e0.96\u0026ndash;1.2%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e2022\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003eZhao et al.(12)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 105px;\"\u003e\n \u003cp\u003eReal-world cost-effectiveness model (China)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003eBreast cancer TC, AC-T, dose-dense regimens\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003eNeutropenia/FN events\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 103px;\"\u003e\n \u003cp\u003e5% (model input for high-risk regimens)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e*RCHOP- Rituximab, cyclophosphamide, Adriamycin, vincristine, Prednisolone\u003c/p\u003e\n\u003cp\u003eAC- Adriamycin, Cyclophosphamide, TC: Docetaxel, Cyclophosphamide\u003c/p\u003e\n\u003ch3\u003eLimitations and Strengths\u003c/h3\u003e\n\u003cp\u003eOur study\u0026apos;s strength is its prospective design and strict adherence to the FN definition and G-CSF administration protocol. A key limitation is the single-centre nature, lack of comparator arm \u0026nbsp;which may limit generalizability, although the findings are highly representative of current oncology practice across Kerala and potentially India. We did not collect granular data on baseline nutritional status or serum G-CSF levels and the small sample size limitation for multivariate analysis.\u0026nbsp;\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn this prospective real-world cohort from India, the incidence of febrile neutropenia despite guideline-directed primary pegylated G-CSF prophylaxis was approximately 11%, substantially higher than rates reported in contemporary clinical trials. Breakthrough FN occurred at comparable frequencies in both guideline-defined high-risk and intermediate-risk patients with additional risk factors and was associated with significant clinical consequences, including chemotherapy dose reductions, treatment discontinuation, prolonged hospitalisation, increased healthcare costs, and measurable mortality. Rescue short-acting G-CSF was universally employed for FN management in this setting and was well tolerated, although its impact on clinical outcomes cannot be inferred from this study. These findings highlight an important effectiveness gap between trial data and routine practice in low- and middle-income countries and underscore the need for heightened vigilance, context-specific supportive care strategies, and further research to optimise FN prevention and management in resource-constrained oncology settings.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e None\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeclaration of interests\u003c/strong\u003e None declared\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eKasi PM, Grothey A. Chemotherapy-Induced Neutropenia as a Prognostic and Predictive Marker of Outcomes in Solid-Tumor Patients. Drugs. 2018;78(7):737\u0026ndash;45.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSmith TJ, Bohlke K, Lyman GH, Carson KR, Crawford J, Cross SJ, et al. Recommendations for the Use of WBC Growth Factors: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol Off J Am Soc Clin Oncol. 2015;33(28):3199\u0026ndash;212.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWeycker D, Li X, Edelsberg J, Barron R, Kartashov A, Xu H, et al. Risk and Consequences of Chemotherapy-Induced Febrile Neutropenia in Patients With Metastatic Solid Tumors. J Oncol Pract. 2015;11(1):47\u0026ndash;54.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCitron ML, Berry DA, Cirrincione C, Hudis C, Winer EP, Gradishar WJ, et al. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol Off J Am Soc Clin Oncol. 2003;21(8):1431\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCunningham D, Hawkes EA, Jack A, Qian W, Smith P, Mouncey P, et al. Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone in patients with newly diagnosed diffuse large B-cell non-Hodgkin lymphoma: a phase 3 comparison of dose intensification with 14-day versus 21-day cycles. The Lancet. 2013;381(9880):1817\u0026ndash;26.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGreen MD, Koelbl H, Baselga J, Galid A, Guillem V, Gascon P, et al. A randomized double-blind multicenter phase III study of fixed-dose single-administration pegfilgrastim versus daily filgrastim in patients receiving myelosuppressive chemotherapy. Ann Oncol Off J Eur Soc Med Oncol. 2003;14(1):29\u0026ndash;35.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHolmes FA, O\u0026rsquo;Shaughnessy JA, Vukelja S, Jones SE, Shogan J, Savin M, et al. Blinded, randomized, multicenter study to evaluate single administration pegfilgrastim once per cycle versus daily filgrastim as an adjunct to chemotherapy in patients with high-risk stage II or stage III/IV breast cancer. J Clin Oncol Off J Am Soc Clin Oncol. 2002;20(3):727\u0026ndash;31.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHecht JR, Pillai M, Gollard R, Heim W, Swan F, Patel 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. Clin Colorectal Cancer. 2010;9(2):95\u0026ndash;101.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVogel CL, Wojtukiewicz MZ, Carroll RR, Tjulandin SA, Barajas-Figueroa LJ, Wiens BL, 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. J Clin Oncol Off J Am Soc Clin Oncol. 2005;23(6):1178\u0026ndash;84.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTalwar V, Nirni SS, Mallavarapu KM, Ramkumar A, Sinha N. Safety and tolerability of Peg-grafeel\u003csup\u003e\u0026trade;\u003c/sup\u003e, a pegfilgrastim, for the prophylactic treatment of chemotherapy-induced neutropenia and febrile neutropenia: A prospective, observational, postmarketing surveillance study in India. South Asian J Cancer. 2017;6(1):20\u0026ndash;4.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJacobs VR, Mayer SC, Paessens B, Anker G, Schwarz-Boeger U, Paepke S, et al. Prospective study comparing hospital costs and DRG reimbursement of inpatient treatment of febrile neutropenia during adjuvant anthracycline-based CTX for primary breast cancer. J Clin Oncol [Internet]. 2009 May 20 [cited 2025 Dec 11]; Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://ascopubs.org/doi/10.1200/jco.2009.27.15_suppl.e11570\u003c/span\u003e\u003cspan address=\"https://ascopubs.doi/10.1200/jco.2009.27.15_suppl.e11570\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhao J, Qiao G, Liang Y, Li J, Hu W, Zuo X, et al. Cost-Effectiveness Analysis of PEG-rhG-CSF as Primary Prophylaxis to Chemotherapy-Induced Neutropenia in Women With Breast Cancer in China: Results Based on Real-World Data. Front Pharmacol. 2021;12:754366.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"supportive-care-in-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jscc","sideBox":"Learn more about [Supportive Care in Cancer](https://www.springer.com/journal/520)","snPcode":"520","submissionUrl":"https://submission.nature.com/new-submission/520/3","title":"Supportive Care in Cancer","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Febrile neutropenia, pegylated G-CSF, primary prophylaxis failure, rescue G-CSF, real-world evidence, India","lastPublishedDoi":"10.21203/rs.3.rs-8417000/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8417000/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eContemporary trials report febrile neutropenia (FN) rates of 1\u0026ndash;2% with primary pegylated G-CSF prophylaxis, but real-world outcomes from low- and middle-income countries (LMICs) remain poorly documented, especially regarding the role and impact of rescue short-acting G-CSF after breakthrough FN.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eProspective single-arm cohort study (CTRI/2024/09/073887) of 125 adult patients receiving first-line chemotherapy with primary peg-G-CSF (6 mg SC single dose) at a tertiary cancer centre in India. Primary endpoint was incidence of FN. Secondary endpoints included hospitalisation, chemotherapy modifications, mortality, costs, and detailed utilisation of rescue short-acting G-CSF.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eFN occurred in 14/125 patients (11.2%; 95% CI 6.3\u0026ndash;18.1%), generating 19 hospital admissions (recurrent FN in 4 patients). The observed incidence was significantly higher than the expected 1% (one-sample proportion test, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). FN rates were similar between high-risk (13.0%) and intermediate-risk patients (10.1%) (p\u0026thinsp;=\u0026thinsp;0.70). Univariate and multivariable analyses did not identify significant independent predictors of FN. All 14 FN patients received rescue short-acting G-CSF (median 5 doses/episode). Among FN cases, 10 (71.4%) required chemotherapy dose reductions, 2 (14.3%) had regimen changes, 1 (7.1%) discontinued chemotherapy, and 1 (7.1%) died from FN-related sepsis. Median hospital stay per episode was 5 days; total direct cost for 19 episodes was ₹6,01,154 (\u0026asymp;\u0026thinsp;US\u003cspan\u003e$\u003c/span\u003e7,200). No serious adverse events were attributed to rescue G-CSF (mild bone pain in 21.4%).\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eIn routine Indian oncology practice, FN incidence despite primary peg-G-CSF prophylaxis is approximately 11%\u0026mdash;substantially higher than contemporary trials\u0026mdash;with similar rates across risk categories. This breakthrough FN has major clinical and economic consequences. Rescue short-acting G-CSF was universally used and safe. This first prospective LMIC study highlights real-world effectiveness gaps and the need for enhanced vigilance and supportive strategies in resource-constrained settings.\u003c/p\u003e","manuscriptTitle":"Real-world incidence of febrile neutropenia despite primary prophylaxis with pegylated G-CSF: a prospective single centre cohort study from India","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-21 14:52:00","doi":"10.21203/rs.3.rs-8417000/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewersInvited","content":"","date":"2026-01-20T01:18:22+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-01-20T01:16:27+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-01-07T01:53:13+00:00","index":"","fulltext":""},{"type":"submitted","content":"Supportive Care in Cancer","date":"2025-12-21T11:44:45+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"supportive-care-in-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jscc","sideBox":"Learn more about [Supportive Care in Cancer](https://www.springer.com/journal/520)","snPcode":"520","submissionUrl":"https://submission.nature.com/new-submission/520/3","title":"Supportive Care in Cancer","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"9e7c99ae-6bb7-43b5-8222-a517e3ca607c","owner":[],"postedDate":"January 21st, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-01-21T14:52:00+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-21 14:52:00","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8417000","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8417000","identity":"rs-8417000","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}