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Year : 2019  |  Volume : 2  |  Issue : 1  |  Page : 69-71

Improving outcomes in Rhabdomyosarcoma-The way ahead

Department of Pediatric Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India

Date of Web Publication9-Sep-2019

Correspondence Address:
Badira Cheriyalinkal Parambil
Department of Pediatric Oncology, Tata Memorial Hospital, Mumbai, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/CRST.CRST_47_19

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How to cite this article:
Parambil BC, Ramanathan S. Improving outcomes in Rhabdomyosarcoma-The way ahead. Cancer Res Stat Treat 2019;2:69-71

How to cite this URL:
Parambil BC, Ramanathan S. Improving outcomes in Rhabdomyosarcoma-The way ahead. Cancer Res Stat Treat [serial online] 2019 [cited 2022 Aug 19];2:69-71. Available from: https://www.crstonline.com/text.asp?2019/2/1/69/266464

Rhabdomyosarcoma (RMS), the most common soft-tissue sarcoma of childhood, accounts for approximately 3.5% of malignancies in this group with varied prognostic factors such as age, histology, stage, clinical group, site, and translocation status affecting outcomes as identified in several Western collaborative studies. The treatment of RMS that is essentially a multidisciplinary one employing dose-intensive combination chemotherapy and local treatment in the form of surgery and/or radiotherapy (RT) has evolved through these cooperative group trials to a risk-adapted approach maximizing cure and minimizing late side effects. With current therapy, localized disease has an over 70% 5-year event-free survival (EFS), and metastatic disease has survival rates varying from 5% to 38% depending on the site and other adverse prognostic features.[1] However, data from developing countries including India are limited, with the available information being restricted to retrospective case series, most of which have shown inferior remission and cure rates (13% and 43%) despite a similar clinical profile and treatment. The way forward is identifying the major impediments to improved outcomes encompassing both the implementation of an orchestrated treatment as well as identifying the major prognostic factors associated with survival in our population. These studies could serve as a foundation for further collaborative research in India that could potentially improve the otherwise inferior outcomes seen in these patients. This article looks at the clinical characteristics and outcomes of RMS treated at a tertiary cancer centre.

In the study published in this issue of Cancer Research, Statistics, and Treatment, Bhuvan et al. have performed a retrospective audit on patients with RMS treated with a uniform chemotherapy protocol between 2001 and 2016 at the Cancer Institute (WIA), a tertiary cancer center in Adyar, Chennai (Tamil Nadu, India).[2] The eligible cohort of 70 patients (63% being children <18 years) with biopsy-proven disease was analyzed for clinical profiles and outcomes. Unfavorable sites had a higher representation in this case series with 44% parameningeal, 24% extremity, and around 20% truncal sites as did metastatic disease which was seen in 31% of patients compared to 15% in the western cohorts. Good-risk patients constituted approximately half the proportion of the corresponding western cohorts (18% vs. 35%), and there was a higher proportion of high risk or advanced disease (32% vs. 15%) in this study. Local treatment in the form of complete surgical resection was performed in 34% of patients, and RT to the primary site was administered in 55% of patients. Treatment abandonment was seen in 23% of patients, with disease progression being the major cause for this. There was no nonrelapse mortality with Grade 3 or 4 febrile neutropenia seen in 11% of patients. The 3-year EFS and overall survival (OS) for all patients were 21% and 40%, respectively. For patients who abandoned treatment versus those who did not abandon treatment, the 3-year EFS was 6.3% and 25.7%, respectively (P = 0.004), and 3-year OS was 12.5% and 49%, respectively (P < 0.001). The 3-year EFS for patients with good-risk, intermediate-risk, and high-risk disease was 52%, 14%, and 12%, respectively (P = 0.02). The 3-year OS for patients with good-risk, intermediate-risk, and high-risk were 57%, 41%, and 18%, respectively (P = 0.003).

Although this study analyzes the outcomes of patients with RMS in India treated in recent times, it enrolled only 70 patients over a very long time period and was a retrospective analysis of the outcomes.[3],[4],[5] Treatment abandonment was a major obstacle to improved outcomes and was similar in proportions to the contemporary Indian studies. The greater proportion of advanced disease and unfavorable sites at presentation also contribute to the poor outcomes seen in the cohort. The fact that around a third of disease progressions occurred while on treatment points to an underlying poor biology of the disease in the population which warrants further research for designing future successful treatment approaches. This study does not look into the fusion status of the tumor, which is an established prognostic factor and has replaced histology in contemporary trials, better classifying these patients and guiding treatment. [Table 1] provides a bird's-eye view of recent pediatric RMS studies in India.
Table 1: Summary of pediatric rhabdomyosarcoma studies in India

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The reasons for the relatively poor survival in our population are multifactorial. Some of the reasons are listed below with the possible future directions to tackle them.

  • Advanced, unfavorable site presentations (leading to upfront palliation in majority of advanced stages with disseminated metastases) with poor response or progression while on chemotherapy reflecting a bad biology of the disease. With different chemotherapy drugs, doses, combinations, and schedules having been tested in multiple trials over the past few decades, no substantial improvement in survival has been noticed in recent years. Any further progress would warrant a more comprehensive study of the tumor tissue at baseline and at the time of relapse to understand the genomic profile and possible targetable mutations. The identification of targetable mutations could lead to the addition of targeted therapy to an upfront or relapse chemotherapy backbone, without any added toxicity
  • Imprecise staging– A complete staging workup at baseline is imperative for prognostication, proper risk stratification, and multidisciplinary treatment planning addressing both local and metastatic sites. This would entail a Fluorodeoxyglucose-Positron Emission Tomography/Computed Tomography (FDG-PET/CT) scan and bilateral bone marrow aspiration and biopsies where PET-CT facilities are available or a CT scan of the thorax, bone scan, and bilateral bone marrow aspiration and biopsies where PET-CT is unavailable, for identifying the sites of metastases, and CT or magnetic resonance imaging for local staging
  • Inadequate local control – Locoregional recurrence is the most common cause of treatment failure in patients with RMS, underscoring the importance of timely and adequate local control in the form of surgery and/or RT. Use of RT either as an adjuvant or definitive modality is applicable in majority of RMS. Only Group 1, completely resected fusion-negative RMS can be treated with surgery and chemotherapy. Treatment abandonment, young age, and refusal to consent for RT are some of the reasons for low application of RT, thereby compromising outcomes. With the current advanced RT techniques such as intensity-modulated radiation therapy and brachytherapy in carefully selected patients and even proton therapy for patients who can afford it, it is possible to deliver targeted RT at a very young age with minimal acute and long-term sequelae and better compliance and acceptance
  • Environmental and social factors contributing to malnutrition and treatment abandonment – Malnutrition contributes to treatment toxicities with subsequent delays and treatment interruptions including delivery of local therapy and needs to be addressed from the beginning with strong and proactive rehabilitation strategies. A holistic support group comprising the hospital team and other governmental and nongovernmental organizations, providing support to patients and family, including financial, psychosocial, lodging, educational and bereavement support, and prospective tracking of all children significantly reduced treatment abandonment in a resource-constrained setting as shown in the article from the Tata Memorial Hospital.[7] This strategy should be widely implemented to curb this major cause of poor outcomes
  • Objective assessment of response to neoadjuvant chemotherapy is lacking in many of the Indian studies. This could provide an early opportunity for intervention in the form of alternative treatment strategies [8]
  • More accurate prognostic assessment of our population is needed with treatment reduction in the good prognostic group and alternative treatment approaches in the poor prognostic group.

The optimal dose of cyclophosphamide to be incorporated is still a matter of debate. The recent ARST0531 study in patients with intermediate-risk RMS showed comparable outcomes to its predecessor studies on decreasing the dose of cyclophosphamide to 1.2 g/m 2/cycle from 2.2 g/m 2/cycle.[9] There was a decrease in the 4-year EFS in patients with embryonal RMS who received the lower cyclophosphamide dose in this study, though the 4-year OS was the same, but the overall outcomes were comparable in the intermediate-risk groups. This study employed a dose of 1.8 g/m 2/cycle anticipating toxicity and poor tolerance with higher doses and has been reasoned as one of the causes for the poor outcomes. It remains unclear whether the dose/cycle (intensity), total cumulative dose, or prolonged administration (sustained exposure) of cyclophosphamide have any impact on the outcome. Recent evidence also suggests that there is a role for metronomic cyclophosphamide in combination with vinorelbine as a maintenance regimen in high-risk localized RMS.[10] Similar maintenance metronomic chemotherapy postintensive treatment can also be explored in situations with a high risk of relapses such as those with metastatic disease at presentation and poor response to neoadjuvant chemotherapy. A recently identified subset of patients with RMS, who received definitive RT as local therapy and had persistent FDG-avid metabolic residual disease when assessed by PET-CT done after completion of RT, has been shown to have poor outcomes and would benefit from alternative treatment strategies which need to be further explored.[8]

Despite the few limitations, the current study gives us a real-world picture on the outcomes of RMS in a low- and middle-income country setting. Since RMS is a rare disease, such epidemiological and clinical retrospective data are relevant for identifying potential prognostic factors which should be prospectively studied in a multicentric fashion to fine-tune the prognostication of RMS in our population and inform future collaborative studies addressing current and newer treatment approaches in different subsets and risk groups.[11] Reducing treatment abandonment in pediatric cancers can go a long way in improving outcomes in the present scenario.[7],[12] Moving forward, incorporation of the molecular profiles of all RMS including sequencing data, better identification of prognostic factors, objective assessment of chemotherapy response, and exploring the role of maintenance chemotherapy are research goals for a multicentric Indian study on pediatric RMS.

  References Top

Yohe ME, Heske CM, Stewart E, Adamson PC, Ahmed N, Antonescu CR, et al. Insights into pediatric rhabdomyosarcoma research: Challenges and goals. Pediatr Blood Cancer 2019:e27869. [Epub ahead of print].  Back to cited text no. 1
Bhuvan LP, Radhakrishnan V, Raja A, Ganesarajah S, Sagar TG. Outcomes in rhabdomyosarcoma: Experience from a tertiary cancer center in India. Cancer Res Stat Treat 2019;2:4-9.  Back to cited text no. 2
Bansal D, Das A, Trehan A, Kapoor R, Panda NK, Srinivasan R, et al. Pediatric rhabdomyosarcoma in India: A single-center experience. Indian Pediatr 2017;54:735-8.  Back to cited text no. 3
Ramanathan S, Bhat V, Anand KC, Prasad M, Vora T, Chinnaswamy G, et al. Outcomes and prognostic variables in pediatric rhabdomyosarcoma: A study from a tertiary referral cancer center in India. Abstracts from the 50th Congress of the International Society of Paediatric Oncology (SIOP) Kyoto, Japan November 16-19, 2018. Pediatr Blood Cancer 2018;65 Suppl 2:e27455.  Back to cited text no. 4
Dua V, Yadav SP, Prakash A, Sachdeva A. Encouraging treatment outcomes of pediatric rhabdomyosarcoma: A developing world experience. Pediatr Hematol Oncol 2012;29:677-8.  Back to cited text no. 5
Jyothi M, Padma M, Arun Kumar AR, Avinash T, Kumar N, Kumar RV, et al. Paediatric rhabdomyosarcoma: A regional cancer centre experience. Pediatr Hematol Oncol J 2018;3:S54.  Back to cited text no. 6
Jatia S, Prasad M, Paradkar A, Bhatia A, Narula G, Chinnaswamy G, et al. Holistic support coupled with prospective tracking reduces abandonment in childhood cancers: A report from India. Pediatr Blood Cancer 2019;66:e27716.  Back to cited text no. 7
Casey DL, Wexler LH, Fox JJ, Dharmarajan KV, Schoder H, Price AN, et al. Predicting outcome in patients with rhabdomyosarcoma: Role of [(18)f]fluorodeoxyglucose positron emission tomography. Int J Radiat Oncol Biol Phys 2014;90:1136-42.  Back to cited text no. 8
Lucas JT Jr., Pappo AS. Optimal dosing of cyclophosphamide in rhabdomyosarcoma: It's complicated. Cancer 2019. doi: 10.1002/cncr.32205. [Epub ahead of print].  Back to cited text no. 9
Bisogno G, De Salvo GL, Bergeron C, Jenney M, Merks JH, Minard-Colin V, et al. Maintenance low-dose chemotherapy in patients with high-risk (HR) rhabdomyosarcoma (RMS): A report from the European Paediatric Soft Tissue Sarcoma Study Group (EpSSG). Clin Orthod 2018;36 Suppl 18:LBA2.  Back to cited text no. 10
Noronha V. Making a case for cancer research in India. Cancer Res Stat Treat 2018;1:71-4.  Back to cited text no. 11
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Philip CC, Mathew A, John M J. Cancer care: Challenges in the developing world. Cancer Res Stat Treat 2018;1:58-62.  Back to cited text no. 12
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