Keywords
chemotherapy-induced myelosuppression - myelosuppression - risk factors - myeloprotective
agents - complete blood count
Introduction
Cancer is a group of diseases, where some of the body's cells grow uncontrollably
and spread in the body. Cancer is among the leading causes of death worldwide. According
to National Cancer Institute (NCI) in 2018, there were 18.1 million new cases and
9.5 million cancer-related deaths worldwide; accounting for nearly 10 million deaths
in 2020. Chemotherapy is treatment of cancer with drugs that uses powerful chemicals
to kill fast growing tumor cells in your body. There are many different chemotherapy
drugs that are used alone or in combination to treat different types of cancers.[1] In chemotherapy, drugs interfere with DNA synthesis and mitosis to destroy the cancer
cells. Hence, it is not only effective to treat most types of cancers, but also possesses
a series of side effects. These chemotherapy side effects may be mild and treatable
or can cause life threatening complications.
Chemotherapy-induced myelosuppression (CIM) is the most common dose-limiting and fatal
complication of cancer treatment. Myelosuppression is caused by destruction of proliferating
progenitor cells that produce mature red and white blood cells and platelets in peripheral
circulation. As immature cells in the marrow are destroyed, pre-existing mature cells
are eliminated, and the nadir of the individual's blood cell count is attained. At
that time, cells are maturing and are ready to release into peripheral blood so within
a short period the blood count has returned to near normal state and the next dose
of chemotherapy is administered.[2]
Myelosuppression is a crucial factor in determining how much drug is to be given.
After treatment has begun, if bone marrow has not recovered before the next cycle
of chemotherapy, dosage reduction or delay starting the cycle will depend primarily
on intent of treatment.[3]
If the patient is in a clinical trial, the grade of toxicity will correspond with appropriate course of action. According
to NCI grading scale, myelosuppression is graded, and the type is decided. Myelosuppression
is the umbrella term for anemia, thrombocytopenia, and neutropenia.[4] Grade I myelosuppression may require no modification in the treatment plan, whereas
a grade III or IV toxicity may require not just a delay in treatment but dose reduction,
depending on the outcome.[5] Transfusions of packed red blood cells (PRBC) and platelets are common treatments
when chemotherapy causes anemia and thrombocytopenia.[2]
The granulocyte colony-stimulating factors (G-CSF) and granulocyte macrophage-colony
stimulating factors (GM-CSF) reduce the severity and duration of neutropenia after
therapy. Antibiotics are given to prevent infection.[6] Regular peripheral blood count monitoring is the standard practice. The other mainstay
of early detection is education of patients, caretakers, and healthcare staff with
the signs and symptoms suggestive of cytopenia's, and importance of prompt blood count
confirmation and appropriate management. Dose reduction or delay before scheduled
courses maybe suggested if unexpectedly severe or prolonged cytopenia occur. Primary
or secondary prophylaxis happens by giving G-CSF.[7]
In this study, the association of risk factors (age, gender, body surface area, comorbidities
and chemotherapeutic drug combinations) with myelosuppression is studied. To identify
myelosuppression, data from complete blood count (CBC)- platelets, RBC and white blood
cells along with absolute neutrophil count (ANC) were noted on the day 8 and the nadir
day reports.[8] The risk factors of CIM were studied using five chemotherapeutic drugs that are
commonly used in chemotherapy (paclitaxel, carboplatin, cyclophosphamide, doxorubicin,
and 5-fluorouracil).[9]
Therefore, this study aims to serve as a resource for healthcare professionals to
enhance their understanding of myelosuppression and its regular monitoring in patients
receiving chemotherapy. The primary objective of our study is to determine the prevalence
rate of myelosuppression and its risk factors in cancer patients. The secondary objective
was to identify the cycle in which increased myelosuppression occurs and the treatment
options used.
Materials and Methods
The study is a prospective observational cohort study conducted in a tertiary care
hospital in Coimbatore, Tamil Nādu. The sample size of 73 was calculated using the
RAO software from data obtained by daily patient flow and study duration. The study
was carried out for a duration of 4 months, and data was collected from patients who
were prescribed with the inclusion criteria drugs paclitaxel, carboplatin, 5-fluorouracil,
doxorubicin, and cyclophosphamide. The CBC was obtained and followed up to find myelosuppression
occurrence on day 8 of blood reports, since the administration of drug for the first
3 cycles. The NCI grading system was used to assess the severity of myelosuppression
of carboplatin, paclitaxel, 5-fluorouracil, adriamycin, and cyclophosphamide. The
study was done from May 2022 to August 2022. Chi-squared tests and percentages from
SPSS software were used for statistical analysis. The result for primary outcome is
that among the total 73 patients employed, 30 patients were found to be myelosuppressive
(41%) and the prevalence rate was 41%. Risk factors such as age, gender, and diagnosis
showed statistically significant association (confidence interval: 95% and p-value <0.005). The drugs paclitaxel, carboplatin, 5-fluorouracil, cyclophosphamide,
and adriamycin proved to be highly myelosuppressive with a p-value of 0.049. The results
for secondary outcome were that cycle 1 was reported to be highly myelosuppressive
with 27%. The treatment options that was highly used was granulocyte-colony stimulating
factor (90%), followed by packed red blood cell transfusion (7%).
Inclusion Criteria
-
All types of cancer with chemotherapy drugs (paclitaxel, carboplatin, cyclophosphamide,
5-fluorouracil, and doxorubicin) in weekly and 3 weekly dosage regimens.
-
>18 years of age.
-
Cancer patients in cycles 1, 2, and 3.
Exclusion Criteria
-
Patients who are not receiving chemotherapy.
-
Psychiatry patients with cancer.
-
Cycles excluding 1, 2, and 3 due to difficulty to obtain data and patient follow-up.
-
Patients receiving concurrent chemotherapy and radiation therapy.
Statistical Analysis
The data were entered in Ms excel spread sheet and analyzed using Statistical Package
for Social Science (SPSS) version 26.0. Qualitative and Quantitative variables were
compared and analyzed using chi-squared test.
Ethics
The study was approved by Institutional Human Ethics Committee, PSG hospitals, Coimbatore,
Tamil Nadu, India. (Approval no: PSG/IHEC/2022/Appr/Exp/118; approved on May 04, 2022).
All procedures performed in studies involving human participants were in accordance
with the ethical standards of the institutional and/or national research committee
and with the 1964 Helsinki Declaration and its later amendments or comparable ethical
standards.
Results
In this study, 73 patients were recruited based on their inclusion and exclusion criteria.
The age wise distribution was found by grouping the patients according to World Health
Organisation (WHO) scale as age groups (15–24) with 6%, age group (35–64) with 71%,
and more than 65 years with 23%. The gender wise distribution showed 21% male and
80% female in the study. The study categorized the body mass index (BMI) for patients
in C1, C2, and C3. The BMI was categorized as less than 18.5 (underweight), 18.5 to
24.9 (normal range), 25 to 29.9 (overweight) and more than 30 (obese). The highest
distribution of myelosuppression was in the BMI range 18.5 to 24.9 (normal range)
as 48% (n = 35).
In this study, among the total population the social history was taken into accounted
and 10% (n = 7) patients were smokers, 4% (n = 3) were alcoholics, and 3% (n = 2) were smokers and alcoholics. The past medical history showed diabetes mellitus
(DM) 27% (n = 5), hypertension (HTN) 6% (n = 4), both DM 2 and HTN 14% (n = 10), no comorbidities 56% (n = 41), and no past medical history as 18% (n = 13). The past medication history, chemotherapy, and oral hypoglycemic agents (OHA)
showed 7% (n = 5), chemotherapy, and anti-HTN showed 6% (n = 4), chemotherapy, OHA, anti-HTN combined
showed 14% (n = 10), chemotherapy alone showed 56% (n = 41), and none showed 18% (n = 13). Family history was also included based on genetic lineage.
Among 73 patients, 41% (n = 30) were found to have myelosuppression ([Fig. 1]). The objective was met by calculating the prevalence rate by,
Fig. 1 Occurrence and nonoccurrence of myelosuppression in study population.
The occurrence of myelosuppression in the population was 41% (n = 30). [Table 1] shows the relationship of myelosuppression with gender, age, and disease condition
in this study. Also, other postulated risk factors like BMI, past medical and medication
history, social history, and family history did not show significant statistical association.
In this study, a total of 30 patients got myelosuppression among which grade 1 was
27% (n = 20), grade 2 was 10% (n = 7), grade 3 was 11% (n = 8), grade 4 was 3% (n = 2), and prophylaxis was given for 3% (n = 2). The highest distribution was in grade 1 with 27% (n = 20).
Table 1
Significance of risk factors associated with myelosuppression in study population
|
Risk factors
|
p-Value
|
|
Gender
Age
BMI C1
BMI C2
BMI C3
Social history
Family history
Past medical history
Past medication history
Diagnosis
Drugs
|
0.048
0.046
0.313
0.386
0.654
0.674
0.406
0.343
0.343
0.048
0.049
|
Abbreviations: BMI, body mass index; C1, cycle 1; C2, cycle 2; C3, cycle 3.
The cycle in which CIM occurred more was cycle 1 with 56% followed by other cycles
([Fig. 2]). Additionally, grades of myelosuppression were assessed according to NCI guidelines.
The management strategy used in the tertiary care center for the myelosuppressive
patients with myeloprotective agents were found to be G-CSF, PRBC transfusion, and
a combination of both. The myeloprotective agent G-CSF 90% was prescribed the most
([Fig. 3]).
Fig. 2 Cycle wise incidence of myelosuppression in study population.
Fig. 3 Myeloprotective class percentage used to treat myelosuppression. G-CSF, granulocyte
colony-stimulating factor; PRBC, packed red blood cell.
Discussion
CIM is a life-threatening condition and commonly manifests as anemia, neutropenia,
and thrombocytopenia and often results in an increased risk of infections, shortness
of breath, fatigue, and excessive bleeding.
In this study of chemotherapy patients, female patients (80%) have reported to have
more myelosuppression than men (20%). According to Nan Jiang et. Al and WHO Female
gender are scientifically proven to have an increased 35% risk of developing side
effects than men due to sex differences in inflammatory and immune responses.[10] Many biological differences in male and female in patterns of cancer are due to
differences in their sex hormones, such as estrogenic or testosterone.
Age group of 25 to 65 (60%) reported to be more myelosuppressive than other groups
of 19 to 24 and seniors of age above 65, similar to the study of Repetto.[3]
[11] Complications due to age-related physiologic changes that can increase the toxicity
are decreased stem cell reserves, decreased ability to repair cell damage, progressive
loss of body protein, and accumulation of body fat.[12]
Body weight was reported to have increased risk of developing several cancers including
colorectal cancer, breast cancer, renal cell, and pancreatic cancer from studies.[13] One proposed mechanism in increased risk of developing cancer was the reduction
in growth factor production with increased body weight. This study showed an increase
in myelosuppression in patients who fell under the BMI groups 18.5 to 24.9 and 25
to 29.9, with strong support from the study of Weycker et al.[14] BMI classification was done according to standard WHO classification.
Social history denoted as smoking, alcohol consumption, and other substance use were
collected in this study. According to the study of Beyth et al,[15] cigarette smoking was linked to significant decrease in bone marrow concentration
of mesenchymal stem cells. In this study, social history was not found to have any
relationship with CIM.
Family history consists of the collection of information about the patients and their
family members devoted to an understanding of heritable lines. Many diseases have
genetic lineage proposing as one of the significant risk factors. Family lineage of
diseases like diabetes and HTN and others were not found to be a significant risk
factor for CIM in this study.
Medical history denoted the comorbid conditions that coexisted with the primary disease.
Given that most of the cancers are diagnosed, these comorbid conditions are pre-existing.
Examples of comorbid conditions are DM, HTN, cardiovascular diseases, liver diseases,
kidney problems, etc. Some of these have common risk factor with cancer. The type
and severity of comorbidity may affect treatment outcomes and hence require customization.
In this study, comorbid conditions of patients were not found to have significance
in causing CIM.
Medication history is the class of drugs given other than chemotherapy drugs in this
study. Medication history is proposed to have impact on the occurrence of adverse
event due to polypharmacy. Other drugs found to cause myelosuppression are chloramphenicol,
Meclofenamic acid, quinidine, trimethoprim-sulfadiazine, and other antifungals. In
this study, medication history was found to be an insignificant risk factor to cause
CIM.
Breast cancer has been the disease that has reported to show more myelosuppression
in our study. Breast cancer has only been seen in woman and no male breast cancer
cases were reported in this study. Evidence from several studies showed that woman
have more risk of developing adverse reaction to chemotherapy. Women have 100 times
greater risk of developing breast cancer due to presence of more breast cells than
male. Other factors like race and ethnicity, menstrual cycle, lifestyle changes, and
use of contraception can influence the development of myelosuppression in breast cancer.
Drugs in this study are the inclusion criteria drugs, that is, paclitaxel, carboplatin,
cyclophosphamide, 5-fluorouracil, and doxorubicin. Cell cycle specific and cell nonspecific
drugs are reported to cause rapid myelosuppression that is rapid and recovery is quicker,
whereas cell noncycle specific causes myelosuppression that is delayed, prolonged
and cumulative with evidence from study of Maxwell and Maher.[1] The same has been reported in our study with 41%.
WBC nadir occurs during every cycle of chemotherapy in patients. Nadir occurs in chemotherapy
patients alone or in combination around 8 to 14 days of chemotherapy drugs intake
with reference to Barreto et al.[16] Also, myelosuppression can occur in any cycle and it is due to large intrasubject
variability. In this study the cycle that shows increased myelosuppression was cycle
1 with 56% followed by cycle 2 and cycle 3, after follow-up of individual patients
with their CBC reports.
In this study, gender, age, disease condition, and inclusion criteria drugs (paclitaxel,
5-fluorouracil, carboplatin, cyclophosphamide, and adriamycin) were found to be significant
risk factors in the development of myelosuppression.
Limitations
The study was performed in a single-center hospital that resulted in homogenous sample
intake. The follow-up of patient's files and collecting sample details were difficult,
due to record unavailability. Patient flow was affected due to coronavirus disease
2019 pandemic. Febrile neutropenia patients were not included in this study.
Conclusion
The incidence of CIM from this study showed that it was important to monitor the CBC
levels in patients undergoing chemotherapy. Early assessment of risk for developing
myelosuppression may prevent or reduce its severity. Drugs prescribed like paclitaxel,
carboplatin, cyclophosphamide, and doxorubicin have increased risk of causing myelosuppression.
Assessment and prevention of CIM should be considered as one of the important aspects
in clinical practice because negligence of monitoring CBC profile may lead to life
threatening situations.
Pharmacist can improve appropriate medical care to reduce occurrence of myelosuppression.
Dose titrations, capping, prophylactic treatments, and medical intervention provided
by pharmacists can be valuable in reducing the harm of chemotherapy adverse effects.
Medication chart review, follow-up, and checking for adverse drug reactions aid the
process. Further suggesting predictive models allowing better access to a patient's
susceptibility to antineoplastic agent-induced myelotoxicity will enable better individualized
therapy thought to be unpredictable. Finally, the use of modern novel therapies and
molecular information can help mitigate the lethal risks of chemotherapy induced myelotoxicities
in hospital setup.
