Presented as a poster “Moving the needle forward for low- and intermediate-risk pediatric rhabdomyosarcoma in LMIC: outcomes from a cancer center in Pakistan” at the The Pediatric Oncology East and Mediterranean (POEM) Group 3^rd scientific meeting on March 3-5, 2023. No online publication available.

Abstract

Background

Pediatric rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. In low- and middle-income countries (LMIC) such as Pakistan, problems with delayed diagnosis, decreased access to care, treatment abandonment and lack of multidisciplinary care may lead to poor outcomes.

Methods

A retrospective chart review was conducted from January 1, 2017, to January 1, 2022 to identify patients with low- and intermediate-risk RMS at a tertiary cancer center in Pakistan. Curative treatment was given per the standard arms of the Children’s Oncology Group (COG) studies ARST0331 and ARST1431.

Results

Forty-eight patients were eligible for survival analysis. The most common tumor region was parameningeal (31.3%). The 3-year overall survival (OS) was 100% for the 14 low-risk patients and 76.5% for the 34 intermediate-risk patients. The worst performing tumor regions were “other sites”. The 3-year event-free survival (EFS) for radiation alone (55%) as a local control modality was worse than for surgery alone (66.7%) or a combination of surgery and radiation (66.7%). One-third of the patient cohort had severe malnutrition (< 5th percentile by weight) which was associated with lower 3-year OS of 75% vs 85.7%. Eight patients (17%) died (3 due to sepsis, 5 due to disease progression), 11 (23%) abandoned treatment and 15 (31%) had progressive disease.

Conclusions

There was a preponderance of intermediate-risk RMS in this cohort, with 3-year OS approaching that of high-income countries but with a lower PFS and EFS. Sepsis-related deaths, treatment abandonment, and malnutrition remain significant challenges.

Introduction

Pediatric rhabdomyosarcoma (RMS) is the most common childhood sarcoma.^1,2 Historically, RMS was classified as alveolar (ARMS) or embryonal (ERMS) type based on histologic features.³ The current risk stratification predicts prognosis on modern treatment protocols and is based on multiple factors including age, tumor site, modified TNM stage, surgicopathologic findings (clinical group), and the presence or absence of FOXO1gene rearrangement which has replaced histologic classification of RMS.^4,5 Survival varies significantly across the risk groups, ranging from an overall survival (OS) of 20% for high risk RMS to greater than 90% for low risk RMS.⁴ The treatment of RMS requires multimodal therapies including chemotherapy, radiation and surgery. In low- and middle-income countries (LMIC) such as Pakistan, there are significant challenges faced by cancer patients including delayed diagnosis, reduced access to specialized care, and treatment abandonment which may lead to poor outcomes.⁶

Methods

We conducted a retrospective chart review of the electronic medical health record of patients who presented to a tertiary cancer center in Pakistan from January 1, 2017, to January 1, 2022 including review of patient notes, radiologic imaging, histopathology diagnosis, and multidisciplinary tumor board (MDT) recommendations.

Patients who were accepted for treatment at the cancer center were required to have a confirmed histologic diagnosis of RMS based on morphology and detection of myo D1, myogenin and desmin on immunohistochemical staining. Testing for FOXO1 gene rearrangement was performed using fluorescent in situ hybridization (FISH) on formalin fixed paraffin embedded (FFPE) tissue with commercially available Vysis FOXO1 Break Apart Fish Probe kit (Abbott, Illinois, USA) using Fluorescent Microscope (Olympus®, Tokyo, Japan) to enumerate the signals.

All patients with RMS underwent staging evaluation with computed tomography (CT) chest, technetium-99 bone scan and dedicated magnetic resonance (MR) imaging of primary tumor site and regional lymph nodes. Patients with ERMS without nodal or lung metastases did not undergo bone marrow evaluation due to very low likelihood of bone marrow involvement.⁷ Cerebrospinal fluid (CSF) cytology was performed for all patients with parameningeal RMS.

Patients classified as low-risk RMS fulfilled the following criteria: ERMS (or FN) with either (i) group I, II and stage 1,2 or (ii) group III, stage 1 orbit. Intermediate- risk RMS included: FP RMS with group I-III disease with stage 1-3 or ERMS (or FN) RMS with either (i) group I/II, stage 3 disease, (ii) group III with any stage disease (except orbit) or, (iii) group IV, stage 4 disease with age < 10 years. High-risk RMS patients were excluded from the analysis as they were not offered curative therapy due to resource limitations. These included FN-RMS with age > 10 years and group IV, stage 4 disease, or FP-RMS of any age with group IV, stage 4 disease.

Institutional practice was to treat patients with low-risk RMS per regimen A of the Children’s Oncology Group (COG) study ARST0331 (NCT00075582) and intermediate-risk RMS per regimen A of the COG study ARST1431 (NCT02567435) without maintenance chemotherapy. Growth factor support with granulocyte colony stimulating factor (GCSF) was not routinely used.

Data analysis was performed using SPSS version 27 (IBM Corporation). Comparison of categorical participant characteristics between the groups was conducted using Fisher’s exact test. Kaplan Meier curves were generated in SPSS. Overall survival (OS) was defined as the time from diagnosis to death or last follow up. Progression-free survival (PFS) was defined as time from diagnosis to death, progression or last follow up. Event-free survival (EFS) was defined as time from diagnosis to death, progression, relapse, treatment abandonment or last follow up.

Results

Sixty-three patients with pediatric RMS were identified in the chart review but 48 were eligible for survival analysis. Details of excluded patients are as follows: 6 high-risk RMS, 3 patients were treated at an outside facility, 2 died during staging workup, and 4 absconded before starting treatment (attributed to treatment refusal).

Of the 48 cases analyzed, 22 (45.8%) were female. The average age was 5.8 years (median 5.9 years, range 10 months – 16.8 years). Most patients (62.5%) presented with a large tumor volume (> 5 cm). Of the 48 patients, 14 (29.1%) were severely malnourished at presentation (< 3^rd percentile by weight-for-age). Baseline patient and disease characteristics are summarized in Table 1.

There were 14 patients (29%) with low-risk and 34 (71%) with intermediate-risk RMS. Among the 34 patients in the intermediate-risk group, 24 patients (71%) had ERMS, 7 (21%) had ARMS, and 3 had spindle cell histology. FOXO1 gene rearrangement was detected in 7 (15%) of the 48 cases analyzed, negative in 26 (54%), not checked in 15 (31%) patients due to failed assay or insufficient tissue specimen. Of the 15 patients with no available FOXO1 testing, 12 were ERMS and 2 had spindle cell histology. The most common tumor region was parameningeal (31.3%) followed by head and neck (20.8%) (Table 1).

Local control was with surgery alone for 5 patients, photon beam radiation therapy (RT) alone for 20 (42%), and a combination of surgery and RT for 15 (31%). Orbital RMS was treated with radical RT, except for one patient who underwent orbital exenteration. Lymph node sampling was performed for 6 patients. Thirteen patients had upfront tumor excision; 8 of these were performed at an outside institution prior to presentation to our cancer center. Eight patients had delayed primary excision (DPE), of which 6 had a reduction in radiation dose (1 refused RT and 1 patient had an amputation of an extremity RMS). Among the 8 patients with DPE, 3 were in the abdomen or pelvis, and one each was in the parameningeal, head & neck, extremity, and orbital regions.

Of the 48 patients, 15 (31%) had disease progression, 8 (17%) died (3 from sepsis, 5 due to disease progression) and 11 (22.9%) abandoned treatment (3 during active curative therapy, 8 after disease progression). The 3-year OS for the entire cohort was 83%, PFS was 58% and EFS was 52% (Table 2, Figure 1A). OS varied significantly by risk group, tumor region, and tumor size, but not by nutritional status (Figure 1A-D).

Discussion

Age at presentation and gender distribution were similar to those reported for the COG studies.⁸ The median duration of symptoms at presentation was 90 days (range 30 – 450 days) and for those with symptoms for ≤ 90 vs > 90 days there was no difference in 3-year OS (p=0.81). This delay in diagnosis far outstrips the median diagnostic interval (DI) of 16.5 days reported for a Canadian cohort of RMS which also did not appear to affect patient survival⁹ as well as the median symptom interval of 2 months for an Indian cohort.¹⁰ Tumor volume and patient weight have been previously shown to predict outcomes in children with intermediate-risk RMS.¹¹ In our cohort, patients with tumor size ≤ 5 cm at diagnosis had a 3-year OS of 100% compared to 73.3% in those with tumor size > 5 cm (p=0.01). Fourteen patients (29.1%) were severely malnourished, but this did not significantly affect their survival.

Bhurgri et al reported outcomes of pediatric RMS in Karachi from 1998-2002, stating a 3-year OS of 30% for all-comers.¹² The survival data from our cohort shows an improvement compared to the historical control and fairs better than contemporary outcomes reported in other LMIC such as neighboring India¹⁰ and Central America¹³ but more ground needs to be covered to approach outcomes of high-income countries (HIC). Most patients in this cohort had intermediate-risk RMS, with a 3-year OS approaching that of HIC but with a lower EFS. Our institutional preference is to treat RMS according to North American COG protocols due to the ease of administering vincristine-actinomycin D-cyclophosphamide (VAC) and vincristine-irinotecan (VI) chemotherapy in the outpatient setting which is the preferred approach in LMIC and has evidence of comparable survivable to European protocols that use the inpatient chemotherapy protocol ifosfamide-vincristine-actinomycin D (IVA).^14,15 Results from ARST0531 (forming the basis of the standard arm of ARST1431) showed a 4-year OS of 72% similar to our 3-year OS of 76.5% but the 4-year EFS of 59% compares poorly to our 3-year EFS of 38%.⁸ This is attributed to poor local control with 7 patients (20.6%) who had no local control (3 died, 3 progressed on neoadjuvant therapy and 1 absconded). For the 11 patients who had surgery included in their local control strategy, 5 underwent upfront resection (2 of these patients had local failures), while 6 underwent DPE (54.5%) all of whom had a reduction in the RT dose. Upfront resection is discouraged in LMIC¹⁴partly because it is performed at local hospitals without the appropriated surgical oncology expertise and an R0 resection is difficult to achieve in these cases. Sixteen (47.15%) patients were treated with radiation alone as local control strategy.

For the 14 patients with low-risk RMS, the 3-year OS of 100% and EFS of 86% was comparable to results of ARST0331 where 3-year OS was 98% and failure-free survival was 89%.¹⁶ Ten of the low-risk RMS patients (71%) had surgery as part of their local control strategy. Of the two patients who progressed, one patient had 4 subsequent surgeries for local failures and another patient had radiation therapy for local failure indicating that low-risk RMS can be salvaged after progression.

Since there were several surgeries performed at local hospitals prior to presentation to our center, we could not acquire adequate specimens to perform FOXO1 testing in 31% of the patients. However, this would not have changed the risk-stratification for any of these patients due to their age, stage, and clinical group and all patients with alveolar histology RMS, were noted to be FOXO1 -rearranged. A recent review recommends focused FOXO1 testing in LMIC in alveolar, mixed, or unspecified RMS histologies due to resource-limitations.¹⁴

Three patients with intermediate-risk RMS died due to sepsis, while there were no sepsis-related deaths reported in ARST0331 and ARST0531.^8,16 Undernutrition may have contricuted to sepsis-related death in one patient who was severely malnourished. Undernutrition may alter the pharmacokinetics (PK) of chemotherapeutic agents in children with cancer leading to decreased clearance and prolonged exposure to drugs.¹⁷ The higher treatment-related mortality may indicate the prophylactic use of GCSF in our setting¹⁴. On the other hand, grade ≥ 3 diarrhea did not occur in any patient in the intermediate-risk cohort while the rates of irinotecan-related diarrhea reported in ARST0531 (forming the basis of the standard arm of ARST1431) were >10%⁸ which may be explained by a lower predicted incidence of UGT1A1 genetic polymorphisms that affect irinotecan metabolism in Asians compared to Caucasians and African-Americans.¹⁸

This study demonstrated a high rate of treatment refusal and abandonment; 4 patients refused treatment (excluded from analysis) while 11 patients abandoned active treatment (23%). This may be attributed to the high financial toxicity of cancer treatment in LMIC.¹⁹ Although cancer treatment is fully funded by our hospital through charity, families still experience hardship due to the cost of relocation and loss of income during the treatment period. Abandonment of active treatment was considered an “event” in EFS analysis as recommended by the International Society of Pediatric Oncology Abandonment Working Group.²⁰ High risk RMS was not studied as these patients are not offered curative therapy at our institute due to a limitation of resources. Therefore, there was only 1 patient with stage 4 disease in our study. In addition, under-representation of bladder RMS is explained by lack of pediatric urologic services at our center including lack of access to post-operative vesicostomy care.

Our study highlights the need for addressing barriers to pediatric RMS care in Pakistan including development of a cancer referral network and specialized pediatric surgical oncology services, access to financial support for families during cancer treatment, and aggressive nutritional rehabilitation of children with cancer.

Acknowledgements

None

Conflict of Interest Statement

None of the authors have any conflicts of interest to disclose.

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Figure 1. 3-year overall survival Kaplan-Meier curves for low- and intermediate-risk rhabdomyosarcoma by (A) risk group, (B) tumor region, (C) tumor size at presentation, and (D) nutritional status at presentation. P < 0.5 for risk group, tumor region, and tumor size, but not for nutritional status.