Functional And Survival Outcome Of Egyptian Children And Adolescents With Malignant Bone Tumors: An Experience In A Setting Of Limited Health Resource

Primary malignant bone tumours are rare cancers among all type of cancers in paediatric populations accounting with an incidence rate of 9.02 per million population compare to 45.36 per million in leukaemia diagnosis in United States from 2001-2009 [1]. They represent 6 % of all cancers in those less than twenty years old with osteosarcoma and Ewing’s sarcoma being the most common types [2].

Osteosarcoma is considered the most common malignant bone tumour in paediatric population, with an incidence of 4.4 per million [3]. The main therapies of osteosarcoma include chemotherapy and tumour excision strategies, with a 5-year event-free survival in extremity localized, non-metastatic disease reaching up to 60-70% [4].

The second most common malignant bone tumour is Ewing sarcoma, with an incidence of 2.9 per million [5]. The cure rate for patients with Ewing sarcoma has increased with the introduction of ifosfamide and etoposide to standard chemotherapy regimens [5, 6]. With the advances in orthopaedic surgical approaches and the use of prosthesis [7] , the aim is a survival with fair functional outcome, yet mild to moderate disability is still reported in 32% of long term survivors [8].

This work was designed to evaluate clinic-demographic characteristics, survival and functional status of Egyptian paediatric patients with malignant bone tumours.

The present study is a retrospective study that is conducted at Paediatric Haematology/Oncology department, Ain Shams University, Cairo, Egypt. Paediatric patients with primary malignant bone tumour diagnosed and treated in the period from January 2003 to July 2016 were recruited.

The patients’ hospital records were reviewed and personnel interviews with the patients and/or their caregivers were also performed to collect the required data. Special emphasis was laid on demographic characteristics, delay of diagnosis calculated from time of first appearance of complaint until time of diagnosis, residency and family history of bone tumours or other malignancies. Clinical presentation, pathologic diagnosis, disease risk criteria, the used protocol, pathological response, complications occurred while on therapy or after, and causes of death during the defined period of the study were recorded. Baseline laboratory evaluation and initial radiological investigation, type of biopsy, immune histochemistry, pathological diagnosis, and site of tumour were analysed. Enneking surgical staging of musculoskeletal sarcomas was used for staging of bone sarcomas.

Patients with osteosarcoma were treated according to Intergroup Study 0133 (CCG-7921 and POG-9351) and non-randomly assigned to regimen A (cisplatin, doxorubicin, and HDMTX) without muramyl tripeptide, an induction period of chemotherapy lasting 10 weeks, then definitive resection of primary tumor were performed with assessment of necrosis index. Maintenance therapy was scheduled to start at week 12 until week 31 in regimen A [9]. Patients with ES were treated according to protocol POG9354/CCG 7942 standard regimen. Chemotherapy courses were VDC alternating with IE to be administered every three weeks. The standard regimen prescribed seventh cycles of chemotherapy delivered over 48 weeks. Local control of the disease, to be performed after week twelve, consisted of resection or radiotherapy. Those who had close or positive margins received post-resection radiotherapy [6, 10].

Event-free survival (EFS) was calculated from the date of diagnosis to date of events that were identified as resistance, relapse, death, or whichever occurred first, and during analysis patients who neither relapsed, showed resistance, nor died were censored at last assessment before the lost follow-up.. Overall survival (OS) was calculated from the date of diagnosis to date of events that was identified as death from any cause, and during analysis, living patients or patients lost to follow-up were censored on last known date they were alive.

Functional status was assessed by using Musculoskeletal Tumour Society Score (MSTS score) [11]. This MSTS score was established on six items each for upper and lower extremities. Each item was allocated a value from zero to five points, with five demonstrating the best function. The values form each items was added and then the functional score will be presented as a percentage of the maximum possible thirty points score. The MSTS score was then categorised into four categories; poor if less than 25%; fair if from 25% to 49%; good if from 50% to 75% and excellent if the score was above 75% of maximum score [12]. The protocol of the study was approved by the institutional regulatory authority of the Paediatric Department, Faculty of Medicine, Ain Shams University and a verbal informed consent was obtained from patients and/or their legal guardian.

Statistical analysis: Statistical package for social sciences (SPSS), version 20.0 for Windows was used. Quantitative variables were described in the form of mean and standard deviation (SD) or median and interquartile range (IQR: 25th-75th percentiles). Qualitative variables were described as number and percentage. Kaplan-Meier analysis was used to estimate the overall survival and disease-free rates. Log-rank test was used to compare the different prognostic factors. In order to compare two independent groups with quantitative parametric distributed variables, Independent t-test was performed. Pearson correlation coefficients were applied in order to examine the relation between two studied parameters within the same group. The cutoff level for p-value was considered significant if the P value was below 0.05.

We revised data for 37 patients with pathology proven primary malignant bone tumour, they were 20 females (54.1%) and 17 males (45.9%) with median age of 11, (IQR) (5 – 14) and range (2 – 18) years. They were diagnosed among 1581 patients of all malignancy (2.3%). Most of patients 77.3% were resident in Great Cairo and Delta; 11 patients (50%) and six (27.3%) respectively, and five (22.7%) in Upper Egypt. 50% were from urban area and the other half from rural ones.

3.5

Survival of the studied patients

At one-year evaluation, eighteen patients are living (66.7%) while nine patients (33.3%) died. Most common cause of death is relapse in four patients (44.4%), disease progression in two patients (22.3%) and complications of treatment in three (33.3%). Seven patients (25.9%) had relapse after end of treatment and 20 patients (72.1%) were relapse free. Ten patients had lost follow-up.

In Ewing Sarcoma, 28.5% of the treated patients had relapse and 71.1% were relapse free, four (28.5%) died and ten (71.1%) were alive and eight patients lost follow-up. In Osteosarcoma patients treated with regimen A, two relapsed (22.2%) and seven were relapse free (77.8%), four died (44.4) and five are still alive (55.6%). Two patients (15.4%) treated with regimen B; one of them relapsed and both are alive. Two patients refused treatment, one died and one lost follow up. In addition two patients lost follow-up.

Overall survival and event-free-survival for osteosarcoma and ES is illustrated in Figure 1. Associations between both OS and EFS and demographic (age and sex), functional (MSTS), and therapy (chemotherapy regimen and surgical procedures) of Ewing and osteosarcoma patients were not statistically significant except that overall survival for osteosarcoma patients was better for those who did not underwent amputation (P=0.004) and those who had excellent MSTS (P=0.007).

Figure 1

The cumulative frequency of malignant bone tumours (Ewing sarcoma and Osteosarcoma) among all malignancy at our centre was 2.3%. Similarly, Li et al. found that primary bone tumour represented about 2% to 5% of all cancer in those age 0-19 years in SEER data [13] and 3.2% in a national study in Thailand [14] . Ewing sarcoma was found to be the most common primary bone tumour in our studied patients (59.5%). This is in contrast to findings of other authors, who stated that osteosarcoma is considered the most common type of primary bone tumour in childhood and adolescence [15, 16].

We recorded wide range of time lag until diagnosis, this could be explained mostly by difference in healthcare system , healthcare providers misdiagnosis and the presence of pain may lead to misdiagnosed as strains or tendinitis, which finally lead to delay in diagnosis more than 6 months [17]. Some laboratory findings can also promote misdiagnosing the tumour as osteomyelitis as many Ewing’s patients will have high inflammatory markers [18]. These factors highlighted the importance of improve the awareness about paediatrics bone tumour among physicians, especially those in the primary care centres.

Bone tumours commonly manifest with pain and swelling and are often attributed to sports injuries in active adolescents. Failure of symptoms to resolve after several weeks of conservative management should alert the clinician to a more serious underlying cause and prompt further investigation[19]. In our cohort, the systemic symptoms were not common and that is in agreement with other published studies [20, 21].

The MSTS score evaluates the functional condition after completed tumour treatment [22]. The fifteen patients subjected to MSTS scoring system had good to excellent scoring. The amputee had lower MSTS score than patients who had limb-sparing surgery; this is in agreement with previous published data [23]. This highlights the importance of limb salvage procedures on the functional status of those young population that may affect their quality of life. The limb salvage surgery was the mainstay of treatment of extremities at our centre over the last 20 years, and apart from the psychological impact, it may be more cost effective in countries with limited health resources.

Current management of osteosarcoma comprises preoperative chemotherapy followed by surgical resection of all tumour including metastases, and postoperative chemotherapy[4]. In our study the chemotherapy used for treatment of osteosarcoma was based on high dose methotrexate, adriamycin, cisplatin (MAP) with shift to regimen B adding ifosfamide in two patients following aggressive disease progression. However, a different approach in poor responders and those showing progression is warranted as the addition of ifosfamide to standard chemotherapy did not result in improve EFS [9] .

The standard treatment for ES includes the use of multi-agent regimens [20]. We used the standard three weekly regimen; however, it was more recently proven that the interval compression of chemotherapy every two weeks is more effective than the three weekly regimen, without increase in toxicity for those with localized Ewing sarcoma [24] and we planned to change the treatment accordingly although this may portend extra costs due to routine use of growth factors.

With chemotherapy and surgery, OS and EFS at 5-years for patients with non-metastatic osteosarcoma can be expected to be approximately 75% and 65%, respectively [25]. We recorded a much lower 3-year EFS in osteosarcoma and ES of 13.3% and 18.2% respectively. This necessitates a re-evaluation of possible aetiologies, including raising awareness for clinical presentation to reach to an earlier diagnosis, interval compression of chemotherapy in ES and different approaches to poor responders’ osteosarcoma including immunomodulation. Improvements in clinical outcomes may largely been attributable to a multidisciplinary team-based approach consequently at 2014, a multidisciplinary teamwork (paediatrician, orthopaedic surgeon, and nuclear medicine physician) evolved and finally succeeded in establishment of a weekly multidisciplinary solid tumour clinic at Paediatric haematology/ oncology clinic to improve the management and outcome of paediatric bone tumour through better communication and rapid decisions. Furthermore in the developing world, the care of children with cancer could be improved by expand the National financial coverage for treatment and supportive care.

Paediatric bone tumours are rare type of cancer that necessitates improvement of awareness. Our survival results are still lagging behind mostly due to late referral and a large number of poor responders. The functional outcome for survivors of extremity tumours is satisfactory.