Abstract

Introduction?The overall cure rate of childhood cancers is above 79% in the developed world, whereas in the developing world, like in India, it is around 50%. It is vital to know the routes of presentation and factors affecting the presentation of childhood cancers in primary, secondary, and tertiary care to design a better survival strategy in childhood cancer.

Objective?The aim of this study was to know the factors affecting the time to diagnosis and time to treatment in children with cancers in a single center in South India.

Materials and Methods?It was a retrospective cohort study of children diagnosed with cancer between January 1, 2014 and December 31, 2016 at the pediatric oncology unit, KMC Hospital Mangalore, India. The patient interval, time to diagnosis, patient's family, economic background, parental education, and referral pattern were recorded, and its impact on the time taken to diagnosis was studied. The data was analyzed using SPSS 20.0 software.

Results?Out of 111 children, 72 were boys (64.8%). Fifty-one (46%) children belonged to the less than 5-year age group. The most common cancer was acute lymphoblastic leukemia, diagnosed in 50% (56/111) children, followed by acute myeloid leukemia in 14/111(12.6%), brain tumors in 9 (8.1%), and neuroblastoma in 10 (9%) children. The median patient interval/patient delay was 14 days (1?90 days), referral interval was 14 days (1?150 days), and overall time to diagnosis was 41 days (1?194 days). The first contact was the pediatrician in 86/111 (77.4%). Sixty-four percent (71/111) referral came from a secondary care hospital, and the remaining from the outpatient clinics. There was no difference in sex and patient interval (p?= 0.278) and overall time to diagnosis (p?= 0.4169), age (p?= 0.041), mother?s education (p?= 0.034), and type of cancer (p?= 0.013) were three critical factors that determined the time to diagnosis.

Conclusion?Majority of the children diagnosed with cancer presented via referral from pediatricians. An equal number of them were referred to as routine and emergency patients. Age, mother's education, and type of cancers were the crucial factors associated with the overall time taken to diagnosis.

Keywords

childhood cancer - acute lymphoblastic leukemia - Time to diagnosis - diagnostic delay

Introduction

Cancer is an important cause of death in both children and adults. Around 70% of these cancer-related deaths happen in low- and middle-income countries such as India.[1] As per the Population-Based Cancer Registry (2012?2014) report, childhood cancer accounts for 0.7 to 4.4% of total cancer diagnoses in India.[2] [3] [4] [5] The reported standardized incidence rate for India varies from 38 to 124 per million children per year.[6] Childhood cancer is predominantly not amenable to preventive strategies. Over the last few decades, in the developed world, the overall cure rate of childhood cancers has been above 70%, whereas in India, we struggle to cross 50%.[6] India's low survival is due to various factors such as presentation in an advanced stage of cancer, delay in diagnosis, poor access to treatment, treatment abandonment, poor supportive care, and poor infection control practices.[6] [7] With the significant progress in the treatment and survival of childhood cancers in the developed world, the focus has shifted to early detection to reduce the treatment-related side effects, especially for those types of cancer, which carry an excellent prognosis.[8] [9]

In the initial part of cancer, signs and symptoms could mimic the common childhood illnesses, which may cause a delay in diagnosis.[10] [11] It is essential to know the patient?s pathway from the onset of symptoms to final diagnosis, to avoid a delay in diagnosis, which plays an essential role in better survival strategy.[10] [11] [12] There are many studies published on delay in diagnosis in children with cancer in developed countries.[9] [11] [13] [14] [15] However, only a few articles have been published on this subject from developing countries.[16] [17] [18] [19] We do not have any study from the author's region in India done on routes of presentation of childhood cancer, time to diagnosis (TTD), and time to start treatment.

Materials and Methods

It was a retrospective cohort study of 111 children diagnosed with cancer between the January 1, 2014 and December 31, 2016 (3 years) at a teaching hospital, Mangalore, India. All children aged between 0 and 18 years diagnosed with cancer during the study period were included in the study, while in those where we could not retrieve the required information were excluded. It is a private tertiary care teaching hospital with a dedicated pediatric hematology/oncology unit, which is the only center in Dakshina Kannada district. The majority of patients are from below poverty line (BPL) as per the Government of India criteria and remaining from lower-middle socioeconomic status. The catchment area has been quite large, around 400 km but an average of 100 km. All those from BPL background received treatment under government scheme (Suvarna Arogya trust),[20]and others received treatment by obtaining funds from various nongovernment organizations or self-funds. The details of age, sex, address, distance from the treatment center, rural/urban area, parents, education status, parents economic status, number of siblings, duration of symptoms before seeing a doctor (symptom interval), time to presentation to a pediatric oncologist, TTD (diagnosis interval) and time to initiate treatment after confirming the diagnosis, and type of cancer were captured. An interview with all parents conducted in the year 2017 to collect the information not available from the case notes. The primary outcome was to know the factors affecting the overall time taken to diagnosis. The secondary outcomes were to know the patient interval, referral interval, and time taken to treatment.

|?Fig. 1?Schema of patient interval, referral interval, diagnostic interval, and symptom interval.|

Patient interval?[21] [22]: It is defined as the time between symptom onset and first clinical presentation. It is also called patient delay, duration of symptoms before the presentation

Referral interval:?It is defined as the time from first seen by a pediatrician or a general practitioner to presentation to a pediatric oncologist.

Diagnostic interval:?It is referred to the period from direct engagement with a healthcare professional to a definitive diagnosis (also referred to as doctor, physician, or healthcare delay)

Overall TTD/symptom interval:?It is defined as the time from initial symptoms to diagnosis at our pediatric oncology unit. The time between symptom recognition and a definitive diagnosis was described as TTD.

Treatment interval (time to initiate treatment):?It is defined as time taken to commence treatment from the diagnosis.

Time to treatment: It is defined as time from initial symptoms to commencement of treatment; whether surgery or chemotherapy.

The date of onset of symptoms and first contact with a healthcare professional were based on recall by the parents (parents interview), while the date of the first visit to the pediatric oncology center, date of confirmation of diagnosis, and date of initiation of treatment were recorded from the hospital case records.

Statistical Analysis

Univariate analysis was used to know the factors associated with total delays and assess each factor's impact separately on the patient interval, and total time taken to diagnosis. We also used it to determine correlations between possible contributing variables and time taken to diagnosis. For comparison of two groups of categorical variables, independent?t-tests were used (as in sex variable). To compare more than two categorical variables (as in age groups, family size, father and mother's education, residence, and family income variables) one-way analysis of variance (ANOVA) was used. We used Tamhane's T2 multiple comparison tests to compare total intervals between different groups between other group pairs after ANOVA. In multivariable analysis, statistically significant variables in the ANOVA were included using a linear regression model for continuous data to estimate independent factors associated with patient interval and time taken to diagnosis. All analyses were performed using SPSS software (IBM SPSS Statistics for Windows, version 20.0, Armonk, New York, United States: IBM Corp). A?p-value ? 0.05 was considered statistically significant at a 95% confidence level. The missing data were addressed by complete case wise analysis or list wise deletion.

Ethics

The Institutional Ethics Committee of of Kasturba Medical College Hospital Mangaluru (IEC KMC MLR 09?16/245) approved this study. The procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation and with the Helsinki Declaration of 1964, as revised in 2013. Consent has been obtained initially at the time of commencement of treatment to collect the data about the family size, socioeconomic status, parents? education, and underlying type of cancer.

Results

A total of 115 children were registered with childhood cancer during the study period. We could record the details of 111 children, while we could not collect data for remaining four children due to insufficient information in the case records ([Table 1]). The median duration of the patient interval, meaning onset of symptoms to the first contact of a doctor, was 14 days (95% confidence interval [CI]: 14?19; range: 1?90 days). The median duration of diagnostic interval (from the first contact of a doctor to final diagnosis by a pediatric oncologist) was 21 days (95% CI: 18?31 days). For the parents and patient, the first contact was the pediatrician in 86/111 (77.4%) patients, followed by a general practitioner in eight children; a pediatric surgeon, general surgeon and general physician saw four children each. A total of 71/111 (64%) referral came from a secondary care hospital and remaining from the outpatient clinics. Fourteen (12.6%) children were directly admitted to the intensive care unit. The referral was an emergency in 56 (50.5%) patients. There was no difference in sex and patient interval (p?= 0.278), time to present to a pediatric oncologist, time taken to diagnosis (p?= 0.976), (p?= 0.4169), and time to commence treatment (p?= 0.688) on unpaired?t-test. The number of siblings did not make any difference in the duration of various intervals (p?= 0.16). Forty-nine children were from families with monthly income < Rs> Rs 50,000/month. Family income was an essential factor in the patient interval (p?= 0.02). An equal number of children were from within and outside the district. Six fathers (5.4%) and nine (8.1%) mothers were illiterate. High school level education was completed in 70/111 (64.1%) fathers and 76/111 (67.1%) mothers. On ANOVA test, only the mother's education levels were significant (p?= 0.038) in determining the time taken to presentation to a doctor (patient interval) as well as for time taken to diagnosis ([Table 1]). The majority of children 70/111 (63.8%) were residing in a rural area. It does not have any correlation with the TTD (p?= 0.97). The distance from the hospital is an essential factor in the patient interval as well as for the overall time taken to diagnose (p?= 0.02). Sixty-four children (58%) had insurance schemes, of which 60 (54%) had the government insurance schemes meant for children from an economically poor background. This factor also played important role in determining the time taken for an overall diagnosis (p?= 0.023). The most common cancer diagnosed in 50% (56/111) patients was acute lymphoblastic leukemia (ALL),[23] followed by acute myeloid leukemia (AML) in 14/111(12.6%) children. The brain tumors were noted in nine (8.1%) and neuroblastoma in ten (9%) children. The median overall time taken to diagnosis was 70 days for lymphomas (32?195 days), 63 days for brain tumors (12?157) days, and 33 days for ALL (5?175) days ([Table 2]).The one-way ANOVA test on comparing the means of patient interval and diagnosis, referral interval and underlying diagnosis, diagnostic interval and diagnosis, and the overall time taken to diagnosis showed that patient interval, diagnosis interval, and the overall time taken to diagnosis were significant between the different types of cancer (p?< 0>Table 2]).

Age, mothers' education, distance from the hospital, family income, insurance schemes, and underlying diagnoses were significant for patient interval and the overall time taken to diagnosis on the ANOVA test. On multivariable analysis using a linear regression model of the above variables, age (p?= 0.041), mothers? education (p?= 0.034), and type of cancer (p?= 0.013) were three critical factors that determined the time taken to diagnosis.

Discussion

Overall TTD of childhood cancer varies between cancer types. In our study, the overall time taken to diagnosis was better than the study reported by Verma and Bhattacharya.[24] This is likely due to primary care pediatricians and general practitioners quickly referred these children to a pediatric oncologist. Also, most of the doctors who have referred to us were working in their establishment clinics, which could have played a role in early referral. The overall time taken to diagnose was maximum for bony sarcomas and least for acute leukemias, similar to a study published by Brasme et al.[25] Earlier studies have shown that TTD depends on the cancer type, shortest for abdominal tumors[26] and the longest time for brain tumors.[27] The median duration of onset of symptoms to confirmation of the diagnosis in acute leukemia was 33 days. Ewing's sarcoma has one of the most prolonged intervals between onset of symptoms and diagnosis.[22] [23] [24] Lethaby et al,[

|?Fig. 1?Schema of patient interval, referral interval, diagnostic interval, and symptom interval.|