|Year : 2019 | Volume
| Issue : 1 | Page : 4-9
Outcomes in rhabdomyosarcoma: Experience from a tertiary cancer center in India
LP Bhaskar Bhuvan1, Venkatraman Radhakrishnan1, Anand Raja2, Selvaluxmy Ganesarajah3, Tenali Gnana Sagar1
1 Department of Medical Oncology, Cancer Institute (WIA), Chennai, Tamil Nadu, India
2 Department of Surgical Oncology, Cancer Institute (WIA), Chennai, Tamil Nadu, India
3 Department of Radiotherapy, Cancer Institute (WIA), Chennai, Tamil Nadu, India
|Date of Web Publication||9-Sep-2019|
Department of Medical Oncology, Cancer Institute (WIA), Adyar, Chennai - 600 020, Tamil Nadu
Source of Support: None, Conflict of Interest: None
Background: Rhabdomyosarcoma (RMS) is an embryonal tumor seen commonly in children. There is a paucity of literature on RMS from India. The present study was conducted to look at the disease characteristics and outcome of RMS patients treated at our center.
Methods: This was a retrospective study that included patients with RMS of all age groups treated at our center between 2001 and 2016. Overall survival (OS) and event-free survival (EFS) were calculated using the Kaplan–Meier method.
Results: The study included 70 patients with a median age of 7 years (1–70 years) and 42/70 (60%) were male. The common sites of disease were parameningeal in 31 (44%) and extremity in 17 (24%) patients. Metastasis at presentation was seen in 22/70 (31%) patients. Embryonal (66%) followed by alveolar (9%) and pleomorphic (4%) were the common histologic subtype. The risk stratification showed good-risk in 13 (18%), intermediate-risk in 35 (50%), and high-risk in 22 (32%) patients. The median duration of follow-up was 70.4 months (Confidence interval: 26.1–114.8 months). The median EFS and OS in the study were 11 months and 21 months, respectively. The factors associated with better OS were male gender (P = 0.038), nonmetastatic disease (P = 0.028), good- and intermediate-risk subgroup (P = 0.002), complete surgical excision (P = 0.002), and radiotherapy (P = −0.002).
Conclusion: Outcomes in RMS remain dismal with most patients presenting with advanced disease. Multimodality management with chemotherapy, surgery, and radiotherapy in patients with nonmetastatic disease improves outcome.
Keywords: Chemotherapy, pediatric cancer, rhabdomyosarcoma
|How to cite this article:|
Bhaskar Bhuvan L P, 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
|How to cite this URL:|
Bhaskar Bhuvan L P, Radhakrishnan V, Raja A, Ganesarajah S, Sagar TG. Outcomes in rhabdomyosarcoma: Experience from a tertiary cancer center in India. Cancer Res Stat Treat [serial online] 2019 [cited 2020 Aug 7];2:4-9. Available from: http://www.crstonline.com/text.asp?2019/2/1/4/266441
| Introduction|| |
Rhabdomyosarcoma (RMS) is a small-round-cell tumor of mesenchymal origin commonly seen in childhood with an incidence of 4.5/1 million children., It accounts for approximately 3.5% of the cases of cancer among children aged 0–14 years and 2% of the cases among adolescents and young adults aged 15–19 years., Prognosis in RMS is determined by various factors that include histological subtype (embryonal vs. alveolar), site of the disease (favorable vs. unfavorable site), clinical group (based on extent of biopsy or resection), stage, and chromosomal translocations [t(2;13) or t(1;13)].,, The stage, clinical group, site, and histology are combined to classify the patients into three risk groups: low-risk, intermediate-risk, and high-risk, respectively. There is a paucity of data on outcomes in RMS from India. The present study was conducted to look at the disease characteristics and outcomes of pediatric and adult patients with RMS treated at our center.
| Methods|| |
The study included consecutive patients of all age groups treated at our center for RMS between 2001 and 2016. Data were extracted retrospectively from the case records. Patients underwent biopsy or surgical excision of the primary tumor, followed by a histopathological examination to confirm the diagnosis of RMS and were subclassified as embryonal, alveolar, pleomorphic, or RMS unspecified. Molecular studies to confirm PAX3–FKHR [t(2;13)] or PAX7-FKHR [t(1;13)] fusion genes were not performed. Tumors of the orbit; nonparameningeal head and neck; genitourinary tract other than the bladder, and prostate and biliary tract were considered as favorable sites, and remaining sites were considered as unfavorable. Based on the Intergroup Rhabdomyosarcoma Study (IRS) staging system, patients were classified as low-, intermediate- or high-risk subgroups. Patients were treated according to the IRS-IV protocol. Patients in the intermediate-risk and the high-risk group received vincristine, actinomycin-D, and cyclophosphamide (VAC) chemotherapy every 3 weeks along with vincristine every week in the intervening period between two VAC cycles. Vincristine was given at a dose 1.5 mg/m 2 (capped at 2 mg) intravenous bolus on day 1, actinomycin-D at a dose of 45 micrograms/kg (capped at 2.5 mg) on day 1, and cyclophosphamide at a dose of 1.8 g/m 2 on day 1. The dose of cyclophosphamide in our study was 1.8 g/m 2 rather than 2.2 g/m 2 prescribed in IRS-4 protocol due to the anticipated poor tolerance and increased toxicity in our patients with a higher dose. Patients received mesna 1.8 g/m 2 along with cyclophosphamide to prevent hemorrhagic cystitis. Chemotherapy was given for 43 weeks in intermediate- and high-risk subgroups and 32 weeks for the good-risk subgroup. Patients were assessed after 4–5 cycles of VAC chemotherapy (9–12 weeks from treatment initiation) with contrast-enhanced computed tomogram (CT) scan or magnetic resonance imaging or positron-emission tomography with CT of the primary and metastatic sites to assess response. Complete surgical excision of the primary tumor after 4–5 cycles of neoadjuvant chemotherapy was attempted if it was feasible and without significant functional and cosmetic morbidity. Radiotherapy to the primary site was offered to patients in intermediate- and high-risk groups. Patients with gross residual disease received a total radiotherapy dose of 50.4 Gy and those with no residual or microscopic residual disease received 41.4 Gy to the primary tumor bed using conventional fractions. Metastatic sites were irradiated if they caused symptoms. Patients were given vincristine 1.5 mg/m 2/week (maximum 2 mg) concurrent with radiotherapy. All treatment decisions were taken by the multidisciplinary tumor board. Patients who progressed during or after first-line therapy were offered either oral etoposide or cyclophosphamide or ifosfamide, etoposide, and carboplatin (ICE) chemotherapy. All the patients who completed treatment were kept under 3 monthly follow-up for the first 2 years, 6 monthly follow-up for the next 3 years, and annual follow-up then onward. The event in the study was described as recurrence, progression of the disease, or death of the patient. Event-free survival (EFS) was calculated from the date of treatment initiation to the date of the event. Overall survival (OS) was calculated from the date of treatment initiation to date of death of the patient. For survival analysis, all patients were censored at the date of the last follow-up or date of telephonic/postal contact if lost to follow-up or December 1, 2017, whichever was earlier. EFS and OS were analyzed using the Kaplan–Meier method and risk factors were compared using the log-rank test for univariate analysis and Cox proportional-hazards model for multivariate analysis. SPSS software version 17.0 (SPSS Inc., IBM, Chicago, USA) was used for statistical analysis. A value of P < 0.05 was considered statistically significant. Median follow-up was calculated using the reverse Kaplan–Meier method. Treatment abandonment was defined as discontinuation of the treatment by the patient.
| Results|| |
The study included 70 patients with a median age of 7 years (range 1–70 years). There were 42 male and 28 female patients in the study. The median duration from the onset of symptom to first hospital visit was 2 months. The common sites of disease presentation were parameningeal in 31 (44%) patients, extremity in 17 (24%), chest in 7 (10%), pelvis in 7 (10%), and para testicular in 6 (8%) patients. Metastasis at presentation was found in 22/70 (31%) patients. Tumors with size more than or equal to 5 cm were seen in 31 (44%) patients, and regional nodal involvement was seen in 26 (37%) patients. The most common histology was embryonal RMS in 46 (66%) patients, followed by alveolar in 6 (9%), pleomorphic in 3 (4%), and 15 (21%) patients had unspecified RMS histology. The risk stratification showed good-risk in 13 (18%), intermediate-risk in 35 (50%), and high-risk in 22 (32%) patients.
Complete surgical excision of the primary site was performed in 24 (34%) patients, and radiotherapy to the primary site was given in 39 (55%) patients. Grade 3 or 4 febrile neutropenia due to chemotherapy was observed in 8 (11%) patients. Sixteen out of 70 (23%) patients abandoned treatment and disease progression was the reason for abandonment in 12/16 (75%) patients. Eight of the sixteen (50%) patients who abandoned treatment had metastatic disease. Six patients were lost to follow-up after completing treatment. There were 48 deaths, among which 16 (33%) were in patients who abandoned treatment, 15 (31%) during treatment and 17 (36%) after completing treatment. All deaths in the study patients were due to progressive disease or relapse. Thirty (43%) patients had a local recurrence at the primary site, distant metastasis was seen in 7 (10%) patients, 5 (7%) patients had both synchronous local and disseminated progression, and remaining 7 (10%) patients' site of disease progression was not documented.
Second-line treatment following relapse/progression was offered to 23 patients, among whom 13 patients received oral cyclophosphamide and etoposide, 4 received ICE chemotherapy, 5 received ifosfamide and etoposide, and 1 patient was treated with surgery and radiation to the recurrence site.
The median duration of follow-up was 70.4 months (Confidence interval: 26.1–114.8 months). The median EFS and OS [Figure 1] in the study were 11 months and 21 months, respectively. The 3-year EFS and OS for all patients was 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 median EFS and OS for patients who abandoned treatment was inferior to those who did not abandon treatment (4 months vs. 12 months for EFS [P = 0.004] and 9 months vs. 36 months for OS [P < 0.001]). Patients with nonmetastatic disease had a median EFS and OS of 13 months and 25 months, respectively, in comparison patients with metastatic disease had an median EFS and OS of 6.6 months and 9 months, respectively (P = 0.07 for EFS and 0.03 for OS). The 3-year EFS for patients with good-risk, intermediate-risk, and high-risk was 52%, 14%, and 12%, respectively (P = 0.02). The 3-year OS for patients with good-risk, intermediate-risk, and high-risk was 57%, 41%, and 18%, respectively (P = 0.003). Outcomes for patients treated before and after 2010 were similar. The factors which were significantly associated with the better EFS were a good risk (P = 0.022), complete surgical excision (P = 0.015) and radiotherapy (P = 0.005) to the primary site. The factors which significantly predicted OS were male gender (P = 0.027), nonmetastatic disease (P = 0.03), good- and intermediate-risk (P = 0.003) [Figure 2], complete surgical excision (P = 0.002), and radiotherapy to the primary site (P = 0.001). The univariate survival analysis results are shown in [Table 1].
|Figure 2: Kaplan–Meier curves depicting the overall survival according to the risk stratification|
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|Table 1: Univariate analysis of factors predicting outcome in the study patients|
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| Discussion|| |
Multi-modality treatment with chemotherapy, radiotherapy, and surgery is the cornerstone of management of RMS. VAC chemotherapy has remained the backbone of treating RMS for the past four decades. The addition of drugs such as ifosfamide, cisplatin, irinotecan, topotecan, and adriamycin has not improved outcomes, and therefore, the focus has shifted toward reducing treatment-related toxicities by decreasing the dose of cyclophosphamide and/or reducing the total duration of treatment.
Fifty percent of all newly diagnosed patients with RMS belong to the intermediate-risk group and have a 5-year OS of 84%–87%.,, Intermediate risk group constituted 50% of our cases, however, the 3-year OS for patients with intermediate risk in our cohort was only 41%.,,
The IRS 4 study observed that intermediate-risk patients with tumors at favorable sites and positive lymph nodes, patients with gross residual disease, or patients with tumors at unfavorable sites who underwent grossly complete resections, but not patients with unresected embryonal RMS at unfavorable sites had a better outcome with a higher dose of cyclophosphamide (2.2 g/m 2). However, this was a post hoc analysis and needs to be confirmed prospectively in a clinical trial. The patients in our study received a cyclophosphamide dose of 1.8 g/m 2 due to the anticipated toxicity with the higher doses. The recently published ARST 0531 is a phase 3 randomized controlled trial that compared replacement of half the cycles of VAC with vincristine and irinotecan (VI) in patients with intermediate-risk RMS, thereby reducing the cumulative dose of cyclophosphamide from 16.8 g/m 2 in the VAC only arm to 8.4 mg/m 2 in the VAC/VI arm. The dose of cyclophosphamide in each cycle of VAC was also reduced to 1.2 g/m 2. The addition of VI to VAC did not improve EFS or OS in ARST 0531 study. However, the hematological toxicities were lower in the VAC/VI arm compared to that of the VAC arm. The authors concluded that VAC/VI and reduced dose cyclophosphamide is an alternative to standard VAC chemotherapy in patients with intermediate-risk RMS without compromising the outcomes.
VAC remains the standard of care for patients with metastatic disease and outcomes in these patients have been dismal. Dose intensification, multi-agent chemotherapy, and high-dose chemotherapy with autologous stem cell rescue have failed to show improvement in patients with metastatic disease.,,
Bansal et al. in their study reported a 5-year EFS of 43.6% in patients who did not abandon treatment, and this dropped to 21.3% when patients who abandoned treatment were included in the study. A study from Bengaluru reported a 3-year OS of 29.5% in a cohort of 95 patients, the 3-year OS improved to 41.8% when patients who abandoned treatment were excluded from the study. Dua et al. reported an estimated 5-year OS and EFS of 66.7% and 57.1%, respectively, in a cohort of 14 patients, 50% of whom had intermediate-risk disease. [Table 2] provides the details on the studies from India on RMS. The inferior outcome in our study could be because we used a cyclophosphamide dose of 1.8 g/m 2 instead of the recommended dose of 2.2 g/m 2 due to the anticipated toxicity with the higher dose. Bansal et al. also reported the use of cyclophosphamide at a dose of 1.8 g/m 2 due to the anticipated toxicity with the higher dose. Malnutrition, poor performance status, and resistant infections contribute to treatment-related mortality in low- and middle-income countries and therefore, many centers like us prefer to reduce the chemotherapy dose. There are data to suggest that not all patients with RMS need to be treated with a cyclophosphamide dose of 2.2 g/m 2 and a reduced dose of 1.8 or 1.2 g/m 2 is sufficient, has lesser toxicity and has comparable outcomes; however, the subgroup of patients who would benefit from a lower cyclophosphamide is yet to be clearly defined.,
Local recurrence is common in RMS and was observed in 50% of patients in our study. Therefore, addressing the primary with surgery and/or radiotherapy is important. All patients with RMS except those with low-risk completely excised orbital tumors require radiotherapy to the primary; however, only 55% of patients in the study received radiotherapy and 34% underwent surgical resection of the primary. Similar observations were made by Bansal et al. and Jyothi et al. who reported that only 49% and 30% of their patients, respectively, underwent surgical excision and 42% and 40%, respectively, received radiotherapy., Treatment abandonment, young age, and refusal to consent for radiotherapy are important factors contributing to lesser use of radiotherapy and surgery in our patients. Majority of patients with RMS in India do not receive local radiotherapy or undergo surgical resection of the primary and this could be an important factor responsible for the poor outcomes.,,
Twenty-three percent of the patients in our study abandoned treatment. Bansal et al. reported a treatment abandonment rate of 52% and a study from Kidwai Hospital, Bengaluru, reported a treatment abandonment rate of 28%., Similar high treatment abandonment rates have been reported from other low- and middle-income countries. Disease progression was the most important factor for abandoning treatment in our cohort and accounted for 75% of abandonment. Lack of effective and curative second-line chemotherapy options is an important factor for patients with progressive disease abandoning treatment. Other reasons for treatment abandonment in RMS observed in the literature include frequent hospital visits, advanced disease at presentation, financial constraints, and disease progression. Patients living far away from the hospital find it difficult to travel to the hospital once a week for a minimum duration of 45 weeks to complete their planned treatment.
RMS is rare in adults; however, 27% of patients in our study were older than 18 years. Adults patients with RMS have been reported to have inferior survival outcomes compared to children. We did not observe any significant differences in outcomes between children and adults in our study. A study from India reported a 5-year EFS of 45% in 24 adult patients with RMS, in contrast, the predicted 5-year EFS in our study for adult patients was 13%.
The present study has limitations and these include the retrospective nature, missing data in case records, and long period of enrollment. We could not assess the impact of delays in initiating adjuvant chemotherapy after completion of local treatment due to missing data in the case records.
The present study reports on the real-world outcome of RMS patients including children and adults. The event and outcome of patients who were lost to follow-up or abandoned treatment were captured using active surveillance by the tumor registry, thereby providing a true reflection of the outcome. The study highlights the importance of chemotherapy dose-intensity and local treatment of primary in improving outcomes in patients with RMS in India.
| Conclusion|| |
The survival outcomes in RMS at our hospital were low compared to high-income countries, and this is due to advanced stage at presentation, treatment abandonment, and reduced use of multimodality treatment.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2]