SURVIVAL AND TREATMENT OUTCOMES OF PEDIATRIC SOFT TISSUE AND BONE SARCOMAS IN TANZANIA


 Background

Pediatric sarcomas represent an important group of childhood tumors who require treatment at Muhimbili National Hospital (MNH), the largest pediatric oncology center in Tanzania. Treatment is often adapted from established childhood protocols validated in clinical trials from the United States and United Kingdom. There are no studies describing the outcomes of treatment in Tanzania to understand similarities and disparities with other countries. The objective of this study was to describe the treatment outcomes including the overall survival for children seen at MNH.

Methods

Data on treatment outcome was collected on all children seen at MNH pediatric oncology unit between 2011 and 2016 with a confirmed histological diagnosis of either bone or soft tissue sarcoma.

Results

A total of 135 cases were analyzed; 89 (66%) were Soft tissue sarcoma (STS) and 46 (34%) were bone sarcomas. In the STS group, 37 (41.6%) achieved a complete response, 12 (13.5%) achieved a partial response and 40 (44.9%) had no response. Factors found to be significantly associated with a higher complete response rate included early stage disease (stage I or II), embryonal histology, tumor in favorable sites and tumor size of <5cm for STS and <8cm for the bone sarcomas. There was a trend for better 2-year overall survival for STS in early stage disease (74.5%) compared to late stage disease (20.6%), p<0.001. A similar trend was noted for the bone sarcomas; 91.7% versus 25.3% for early stage and late stage disease respectively, p=0.001.

Conclusions

This report is the first study documenting the treatment outcome for pediatric sarcomas seen in Tanzania. Disease stage is strongly related to treatment outcome with later stages of the disease having an overall poor prognosis.


Results
A total of 135 cases were analyzed; 89 (66%) were Soft tissue sarcoma (STS) and 46 (34%) were bone sarcomas. In the STS group, 37 (41.6%) achieved a complete response, 12 (13.5%) achieved a partial response and 40 (44.9%) had no response. Factors found to be significantly associated with a higher complete response rate included early stage disease (stage I or II), embryonal histology, tumor in favorable sites and tumor size of <5cm for STS and <8cm for the bone sarcomas. There was a trend for better 2-year overall survival for STS in early stage disease (74.5%) compared to late stage disease (20.6%), p<0.001. A similar trend was noted for the bone sarcomas; 91.7% versus 25.3% for early stage and late stage disease respectively, p=0.001.

Conclusions
This report is the first study documenting the treatment outcome for pediatric sarcomas seen in Tanzania. Disease stage is strongly related to treatment outcome with later stages of the disease having an overall poor prognosis.

Background
The mainstay of treatment for both pediatric bone and soft tissue sarcomas is surgery. Radiation therapy (RT) and chemotherapy (chemo) may be added in selected cases depending on grade and 3 other factors.
For localized soft tissue sarcomas, wide excision surgery is the standard treatment for all patients. This is done upfront if possible. In general, adjuvant radiation therapy is considered after wide excision for high-grade, deep >5 cm lesions with close or positive microscopic margins, but only for the subgroup of tumors that are known to be radiation sensitive. RT is administered post-operatively at doses ranging from 40-60 gray (Gy) at 1.8-2Gy per fraction [1]. In some non-resectable tumors or borderline resectable tumors, available options include induction chemotherapy with or without RT and reassessment for surgical resection. For patients with advanced metastatic disease, chemotherapy is the standard treatment in Europe and North America [1].
For bone sarcomas, surgery with or without chemotherapy is the mainstay of treatment with the aim of surgery being to preferably preserve limb function as much as possible without compromising disease control [2]. Most current protocols include a period of preoperative chemotherapy, although this has not been proven to add survival benefit compared to postoperative chemotherapy alone [2].
In Tanzania, management is guided through treatment protocols adapted from clinical trials run from Children's Oncology Group (COG) and the International Society of Pediatric Oncology (SIOP) with therapy modified based on drug availability, surgical and radiation therapy resources. Currently, there is no treatment outcome data for pediatric sarcomas in Tanzania. The objective of this study was to establish the outcomes of treatment including overall survival of children with bone and soft tissue sarcomas in Tanzania.

Study design and setting
This was a descriptive retrospective review of pediatric patients aged between 0 to 18 years with a histopathologically confirmed diagnosis of either a soft tissue or bone sarcoma at Muhimbili National Hospital Pediatric Oncology unit from January 2011 to December 2016.

Study participants
Patients aged between 0 to 18 years were recruited in this study

Data collection tool
Data extraction forms were used to retrieve data from patients' records stored in manual files and or files on the computer and it captured type of treatment modalities and outcome of treatment.

Sample size
A total of 135 paediatric patients with histopathologically confirmed diagnosis of either a soft tissue or bone sarcoma

Data processing and analysis
The statistical analysis was done using the SPSS version 20.0 for windows. Continuous variables were summarized by means, medians, standard deviation and range. Categorical variables were summarized by frequencies, percentages and bar graphs for general description. Kaplan Meier curves were used to identify and compare overall survival. As one of the assumptions of using the log rank test, outcomes consisted of two mutually exclusive and collective exhaustive states; 'censored' and 'events'. 'Events' was the outcome of interest, in this case death. 'Censored' included outcomes such as alive and/or lost to follow up. A probability value of <0.05 was considered statistically significant.
The outcome variables were: Complete response (CR) -Disappearance of all target lesions.
Partial response (PR) -At least a one third (30%) decrease in the sum of the largest diameter (LD) of target lesions.
No response (NR) -Shrinkage of measurable disease but one which does not achieve a one third (30%) or greater reduction which is insufficient tumor shrinkage to qualify as PR.
Overall survival -Interval between diagnosis and death from any cause.
Recurrence -Disease that has come back usually after a period of time during which the cancer could not be detected

Ethical considerations
Ethical clearance was obtained from the Muhimbili University of Health and allied sciences (MUHAS) Research Ethics and Publication Committee prior to implementation of this study. A waiver of informed consent was also requested and granted by the same committee and permission to conduct the study was obtained from MNH as per hospital management protocols.

Results
A total of 135 cases of histologically confirmed either bone or soft tissue sarcoma fulfilled the criteria and were included in the final analysis; 89 (66%) of the cases were STS and 46 (34%) were bone 5 sarcomas. Table 1 shows the modality of treatment received by the eligible patients. Surgery was the most commonly applied modality of treatment across both soft tissue and bone sarcomas followed by chemotherapy. Table 1 shows modality of treatment given to the patients. Surgery 82 (60.7%) was the most commonly applied modality of treatment followed by chemotherapy 74 (54.8%). The palliation group included those patients who were palliated upfront with best supportive care only 26 (19.3%). Figure 1 shows the type of surgery done (either curative or palliative) in these patients. Wide local excision (WLE) was the most common surgical method used for the STS patients (41% for RMS and 52% for the NRSTS). WLE for the bone cases included procedures such as hemi-mandibulectomy.
About one half of bone sarcoma cases were treated with curative surgery (amputation) and the other half were not treated with any surgical method but were rather given best supportive care. About 15% of the patients received palliative surgery (debulking/salvage). Table 2 shows the type of chemotherapy regimen prescribed for these patients. MAP (30%) was the most commonly prescribed regimen in the bone sarcoma category while IVA (62.1%) was the most common regimen among the STS although about half of the patients not given any chemo but rather received best supportive care. Table 3 shows treatment response in relation to tumor size. In the STS category, patients with tumor size of >5cm had higher no response rates(43.1%) compared to patients with tumor size of <5cm who had higher complete response rates(47.4%).
In the bone sarcoma category, the same trend was noted, patients with tumor size of >8cm had higher no response rates (75%) compared to those with tumor size of <8cm who had higher complete response rates (50%).
6       In this study, low risk RMS patients were initially treated using the IVA regimen (in 9 blocks) until August 2016 when the protocol was changed to the VAC regimen (change of the alkylating agent from Ifosfamide to Cyclophosphamide for dosage and toxicity reasons). The VAC regimen is also used in 8 Europe and America for low risk patients [3]. In India however, a 22 week VA (Vincristine and Actinomycin D) regimen is considered effective for low risk RMS patients [4].
Children with high risk RMS in India and America are treated with VI chemotherapy followed by RT from week 13 or concurrent VI or VC chemotherapy plus RT from week 1 for those requiring emergency RT from week 1 [3,4]. In this study, patients with high risk RMS (like the alveolar RMS) were palliated upfront as these tumors have shown to frequently relapse or progress despite initial chemotherapy and are associated with an overall poor prognosis (although previously they were treated with IVA or IVADo chemotherapy regimens). The NRSTS were treated using either IVA or VAC regimens in this study.
A significant percentage of children with osteosarcoma in this study had stage IV disease at presentation (47.8%) and were palliated upfront. The remaining percentage of osteosarcoma cases who presented with early stage disease were treated with pre and post-operative chemotherapy using a modified version of the EURAMOS protocol; the MAP regimen (omitting high dose methotrexate).
Europe and America use a similar protocol [5]. The Ewing's sarcomas were treated with the VIDE regimen in this study.
In the STS category in this study, patients with smaller tumor size (less than 5cm) had higher rates of complete response (47.4%) compared to those with larger tumor size (more than 5cm) who had higher rates of no response (43.1%) and the difference was statistically significant, p=0.03. Size was reported to be an important treatment outcome determinant in STS studies done in India and Korea [4,6]. In the bone sarcoma category, the same trend was noted; patients with smaller tumor size (less than 8cm) had higher complete response rates (50%) compared to those with a larger tumor size (more than 8cm) who had a higher no response rate (75%) and the difference was borderline significant, p=0.05.
With regard to site in this study, in the STS category, patients with non PM sites involvement had better response to treatment (CR) compared to those with PM sites involvement (40.5% vs. 5.4%) respectively. Patients with GU non B/P sites involvement had better CR rates compared to those with B/P sites involvement (8.1% vs. 2.5%) respectively but these differences were not statistically significant, p=0.7. In the bone sarcomas category, patients with disease at the extremities had a higher complete response rate (80%) compared to those with head and neck disease (20%) though again the difference was not statistically significant, p=0.5.
In this study, the 3 year and 5-year overall survival rates for the STS were 38.4% and 26.4% while the 3 year and 5-year overall survival rates for RMS in particular were 39.2% and 36.8% respectively. This varies slightly with overall survival data from other studies. In the SEER data for RMS, the 5-year overall survival rate was about 64% [7]. According to Lim Sun Min et al in a study done in Korea the 5 year overall survival was 45% for RMS (6) while it was also 45% in the South African study by Aziza V.D.S et al [9] and 58.7% according to the study by Hendricks et al [8]. of the survivors had stage III disease while only 13% had stage IV disease. Early stages of the disease had survival rates of up to 70% [9]. The 3-year OS for the bone sarcomas was 37.5% in this study.
The 5-year overall survival for osteosarcoma in the study done in Netherlands was 66.9% [10].
Similarly, for bone sarcomas early stages of the disease (stage I and II) had better 2-year overall survival rates (91.7%) compared to the late stages (stage III and IV) 25.3%, p=0.001.
With respect to histology for the RMS in this study, patients with embryonal RMS had better 2-year overall survival rates compared to those with alveolar RMS, 57% vs. 6.4% (p=0.006). This could be explained by the fact that alveolar RMS is known to frequently relapse and even progress despite initial chemotherapy. For bone sarcomas and in relation to histology, the Ewing's sarcoma surprisingly had better 2-year overall survival rates compared to the osteosarcomas (60% vs. 40%) but the difference was not statistically significant (p=0. 8). This non-statistically significant difference may be explained by the significantly lower number of Ewing's sarcoma cases demonstrated in this series.

Conclusions
Site, size, stage and histology of these sarcomas are important outcome determinants. Committee of Muhimbili University of Health and Allied Sciences. Permission to conduct the study was obtained from MNH authority as per hospital management protocols.

Consent for publication: Not applicable
Availability of data and materials: All relevant data pertinent to this research can be obtained from the corresponding author upon a reasonable request.

Competing interests:
The authors declare that they have no competing interests  Tables.pdf