|Ahead of print
Safety profile of G-CSF in chemotherapy-induced neutropenia: A prospective observational study in Eastern India
Uttiya Deb1, Sandip Mukhopadhyay1, Sanatan Banerjee2, Supreeti Biswas1
1 Department of Pharmacology, Burdwan Medical College, Burdwan, West Bengal, India
2 Department of Radiotherapy, Burdwan Medical College, Burdwan, West Bengal, India
|Date of Submission||12-Nov-2019|
|Date of Decision||25-Jan-2020|
|Date of Acceptance||27-Feb-2020|
|Date of Web Publication||27-Jan-2021|
Department of Pharmacology, Burdwan Medical College, Burdwan, West Bengal
Source of Support: None, Conflict of Interest: None
Background: Granulocyte-colony stimulating factor (G-CSF) is used in cancer patients to treat chemotherapy-induced neutropenia (CIN). However, G-CSF poses few risks. Despite the regular use of G-CSF in CIN management, there is a paucity of published data on its safety profile in the management of CIN in India. Hence, the present study was designed to demonstrate the safety profile of G-CSF in patients with CIN.
Methods: A prospective observational study was conducted over a period of 5 months enrolling 100 cancer patients aged from 18 years to 70 years. Patients with a diagnosis of CIN who received G-CSF were included. Patients were followed up for 15 days. Adverse events (AEs) were graded according to US National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The system organ class and preferred term of Medical Dictionary for Regulatory Activities (MedDRA) were used for reporting the AEs. Causality assessment was done by using the WHO-Uppsala Monitoring Centre scale.
Results: The most frequently reported AEs were musculoskeletal and connective tissue disorders which included bone pain, myalgia, arthralgia, and pain in the extremity. Other AEs reported were general disorders and administration site conditions, and gastrointestinal disorders. The highest grade of toxicity reported was of grade 3 among all AEs. The majority of AEs had a “probable” type of causality relationship with G-CSF.
Conclusion: G-CSF has a safety profile consistent with previous G-CSF studies.
Criteria for Adverse Events, filgrastim, granulocyte-colony stimulating factor, Medical Dictionary for Regulatory Activities
Keywords: Criteria for Adverse Events, filgrastim, granulocyte-colony stimulating factor, Medical Dictionary for Regulatory ActivitiesKey Message Granulocyte-colony stimulating factor (G-CSF) is used in cancer patients to treat chemotherapy-induced neutropenia. It has a safety profile which is consistent with previous G-CSF studies and can be safely used
|How to cite this URL:|
Deb U, Mukhopadhyay S, Banerjee S, Biswas S. Safety profile of G-CSF in chemotherapy-induced neutropenia: A prospective observational study in Eastern India. Indian J Cancer [Epub ahead of print] [cited 2021 May 5]. Available from: https://www.indianjcancer.com/preprintarticle.asp?id=308065
| » Introduction|| |
Patients treated with chemotherapy for malignant tumors often have the risk of developing potentially life-threatening chemotherapy-induced neutropenia (CIN) or febrile neutropenia (FN). Cancer patients often become more susceptible to infections because of CIN and FN, resulting in reduced or delayed chemotherapy dosing. Granulocyte-colony stimulating factor (G-CSF) administration has shown a reduction in duration of CIN, incidence of FN, duration of hospitalization and antibiotic usage in patients receiving myelosuppressive chemotherapy.,, The guidelines for G-CSF usage have been set up by the European Society for Medical Oncology (ESMO), the European Organisation for the Research and Treatment of Cancer (EORTC), and the American Society of Clinical Oncology (ASCO).,, These guidelines recommend that G-CSF prophylaxis should be given when the risk of FN due to chemotherapy is =20% and for patients with intermediate-risk (10–20%) who have additional risk factors (mainly age ≥65 years, advanced stage of the disease, previous episodes of FN, low-performance status and comorbidities).
Filgrastim was the first recombinant G-CSF approved for clinical practice in 1991. In 2015, United States Food and Drug Administration (USFDA) had approved filgrastim-sndz (Zarxio; Sandoz) as the first-ever biosimilar to receive approval in the United States. Since then filgrastim biosimilars have been approved in the USA, Europe, as well as in India. In India, filgrastim is included in the National List of Essential Medicines (NLEM, 2015).
Despite the regular use of filgrastim biosimilar in CIN, there is a paucity of data on its safety profile in Indian cancer patients. A thorough literature search in PubMed, Cochrane Library and Embase databases has failed to yield substantial data on the safety profile of filgrastim biosimilar in Indian cancer patients. Pharmacovigilance Programme of India has successfully detected many previously unreported side effects of chemotherapy drugs; however, the side effects of filgrastim biosimilar in CIN have vastly gone under-reported. Since the safety data of filgrastim biosimilar in CIN is scarce in India, this study was conducted.
The primary objective of this study was to assess the incidence of adverse events (AEs) associated with G-CSF administration in CIN patients. Here, we report the safety of the biosimilar filgrastim (Grafeel®; Dr. Reddy's Laboratories) which is used in routine clinical practice across eastern India. The secondary objectives of the study were to grade and code the AEs according to standardized toxicity criteria used in oncology studies and to investigate the causal association between G-CSF and AEs using a causality assessment scale.
| » Methods|| |
All cancer patients aged from 18 to 70 years who were admitted to the department of radiotherapy from January 2019 to May 2019 were screened for their eligibility to participate in the study. Only those patients who gave written informed consent were enrolled in our study. The study was approved by the institutional ethics committee. The study was conducted in accordance with the Declaration of Helsinki—1964 and its later amendments.
This was a prospective observational study enrolling 100 patients with histologically proven malignancy and having a diagnosis of CIN or FN. We included only those cancer patients who received G-CSF. The G-CSF prescribed to our patients (Filgrastim, Grafeel®; Dr. Reddy's Laboratories) was supplied from the institution. Therefore, the G-CSF administered to the patients in our study had received the same brand of filgrastim biosimilar during the entire period of our study.
Patients who received G-CSF but had any other comorbidity were excluded from our study. Other exclusion criteria were—life expectancy <3 months, receiving any other concurrent medication other than chemotherapy regimen, not giving written informed consent to participate in our study.
Assessment and follow-up
Baseline demographic details and relevant hematological investigations were recorded from the enrolled patients. Patients were followed up for 15 days by direct contact, follow-up visits, or by electronic means. Any AE was carefully noted. AEs were graded according to the US National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. We collected the AE reported by the patient and collated with the suitable system organ class (SOC) and preferred term (PT) of Medical Dictionary for Regulatory Activities (MedDRA) to code the AEs. Causality analysis was done for each AE using the World Health Organization-Uppsala Monitoring Centre scale (WHO-UMC scale).
Descriptive statistics were used to analyze the data. Results were reported as number of patients, mean, and standard deviation. The incidence of AE was calculated based on the present chemotherapy cycle. All statistical analysis was done using SPSS 21 software and Microsoft Excel.
| » Results|| |
A total of 100 patients were analyzed, and their characteristics are summarized in [Table 1]. The mean age was 51.3 (range: 38.1 - 64.5) years, and 42% of the patients were men. 59% of the patients were married and 7% were widowed. A total of 25% of the patients completed their graduation and 18% of the patients completed higher secondary education.
The patients had a mean hemoglobin level of 10.2 (range: 9.1 to 11.3) g/dL. The European Cooperative Oncology Group (ECOG) performance status was 1 and 2 for 47% and 32% of the patients, respectively [Table 2]. The prophylactic administration of G-CSF was found in 67% of the patients. A total of 29% of the patients had a diagnosis of breast cancer followed by lung cancer (28%), ovarian cancer (18%), and rectal cancer (12%).
The total number of AEs reported during the entire follow-up period was 198 [Table 3]. The maximum number of AE reported per patient was 4. A maximum number of patients (54%) reported two AEs while 24% of the patients reported one AE. No serious AE (hospitalization during study period or death or disability due to G-CSF) was reported during the follow-up period.
The most frequently reported AEs were musculoskeletal and connective tissue disorders (64%) which included bone pain (29%), myalgia (15%), arthralgia (10%), and pain in extremity (10%). Other AEs reported were general disorders and administration site conditions (38%), gastrointestinal disorders (55%), metabolism and nutrition disorders (10%), nervous system disorders (6%), psychiatric disorders (18%), respiratory thoracic and mediastinal disorders (6%), and skin and subcutaneous disorders (1%). [Table 4] summarizes the AEs according to SOC and PT of MedDRA.
|Table 4: Adverse events with a suspected relationship with G-CSF by system organ class and preferred term|
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The maximum grade of AE reported according to CTCAE version 5.0 was grade 3 [Table 5]. Out of 29 patients reporting bone pain, 8 had grade 3, 17 had grade 2, and the remaining 4 had grade 1 toxicity. Fatigue of grade 2 variety was present in 17% of patients while grade 3 fatigue was present in 2% of patients. Among gastrointestinal disorders, 27% of patients had nausea of grade 1 variety and 6% of patients had grade 2 variety. Dyspnea of grade 1 variety was present in 5% of patients.
Causality analysis by WHO-UMC scale showed bone pain having a “probable” type of causal association with G-CSF in 21% of the patients and “possible” type in remaining 8% of the patients [Table 6]. None of the causal associations were “certain” or “unlikely”.
|Table 5: Toxicity grading using common terminology criteria for adverse events version 5.0|
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| » Discussion|| |
Safety monitoring is an essential requirement for the detection of AEs which emerge during post-approval phase of a drug in patient population. Due to the increasing use of chemotherapy drugs, the incidence of CIN has increased over the past few decades. With the introduction of G-CSF biosimilars in CIN management, it has become a lot more important to document the risks associated with G-CSF which did not emerge during its pre-approval phase.
Our findings showed that G-CSF is generally well-tolerated in CIN patients with no serious AE. This result is similar to findings in studies done in western academic health centres. All patients reported at least one AE. Bone pain was the most frequent AE in our study; however, the incidence was much higher (29%) compared to HEXAFIL study (2.9%) but almost similar to the MONITOR-GCSF study (24.7%)., This difference can be attributed to the difference in patient population, chemotherapy regimen used or how bone pain was defined and reported. Musculoskeletal and connective tissue disorders constituted the maximum AEs in our study which was similar to a meta-analysis drawn from large G-CSF trials in breast cancer patients. Gastrointestinal disorders, and general disorders and administration site conditions constituted the other major reported AEs, which was similar to previous phase III trials on the safety analysis of G-CSF biosimilar with the reference product.
In terms of grading of AEs, we used CTCAE version 5.0. Most of the patients had bone pain of grade 2 variety (moderate bone pain limiting instrumental activities of daily living ADL). More patients had myalgia of grade 1 variety (mild pain) than grade 2 variety (moderate pain limiting instrumental ADL). The other notable AE reported apart from musculoskeletal and connective tissue disorders was nausea. The majority of nausea reported was of grade 1 variety (loss of appetite without alteration of eating habits).
Most of the causal association using the WHO-UMC scale was found to be “probable” because of pharmacological plausibility and reasonable time relationship with G-CSF administration. We did the causal association on a case-by-case basis. We could not be “certain” in our assertion that G-CSF caused the AEs because rechallenge with G-CSF was not done due to ethical reasons and we did not follow-up the patient in the subsequent chemotherapy cycles. Based on our observations, we can say that most of the AEs were probably caused by G-CSF. Some of the reported AEs like nausea, vomiting, fatigue, depression, and anorexia had more of a “possible” type of causal relationship than “probable” type. This can be attributed to the association of these symptoms with the chemotherapy regimen received as we had excluded any other drugs received by the patients before enrolling them in our study.
The limitation of this study was small sample size. Also, we relied on clinician grading of AEs using CTCAE than depending on patient-reported outcomes. More comprehensive tools like PRO-CTCAE in future studies may address this issue which includes the patient's perspective into AE reporting. To the best of our knowledge, our study is first of its kind study in Indian cancer patients where we have done safety monitoring of G-CSF in CIN patients and graded the AEs of G-CSF according to the latest CTCAE version 5.0. This gives novelty to our present work.
| » Conclusion|| |
G-CSF is well tolerated in cancer patients receiving G-CSF. Musculoskeletal and connective tissue disorders including bone pain occur mostly with G-CSF. Further studies are needed to evaluate the correlation between AEs and G-CSF, taking into account other factors that may affect the results.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]