Abstract
Background:
Rhabdomyosarcoma patients with metastatic disease have a poor prognosis despite therapy intensification. The aim of this study was to investigate the efficacy of whole lung irradiation (WLI) in patients with rhabdomyosarcoma and lung metastases.
Methods:
Rhabdomyosarcoma patients with lung metastases enrolled on four Children’s Oncology Group protocols (D9802, D9803, ARST08P1, ARST0431) were retrospectively reviewed. Event-free (EFS) and overall survival (OS) were compared between patients who received and did not receive WLI.
Results:
In 143 rhabdomyosarcoma patients with lung metastases, 65 patients (45.5%) received WLI, 78 patients (54.5%) did not receive WLI despite protocol requirements. 5-year EFS was 38.3% (95% CI 24.8%–51.8%) in patients who received WLI and 25.2% (95% CI 13.8%–36.6%) in patients who did not receive WLI, (p=0.0496). 5-year OS was 45.5% (95% CI 31.8–59.3%) in patients who received WLI and 32.4% (95% CI 20.4%–44.4%) in patients who did not receive WLI (p=0.08). In exploratory subgroup analyses, the benefit of WLI on EFS and OS was significant in patients 10 years and older. Other clinical factors associated with EFS on univariate analysis included age, histology FOXO1 fusion status, number of metastatic sites, location of metastatic sites, and Oberlin Score.
Conclusion:
WLI is associated with improved EFS in rhabdomyosarcoma patients with lung metastases. These results highlight the potential importance of WLI and need for more stringent protocol compliance for administering WLI.
Introduction
Pediatric patients with metastatic rhabdomyosarcoma have a poor prognosis, with an estimated 3-year event-free survival of 16% in the most recent high-risk Children’s Oncology Group (COG) ARST08P1 Study.1,2 Despite efforts at treatment intensification and modification over the past few decades, the outcome has unfortunately remained similar.3–5 Lung is the most common metastatic site on presentation and the most common metastatic site at the time of death. Therefore, efforts to improve the treatment of lung metastases are critical.
Whole lung irradiation (WLI) was first shown to improve event-free survival and overall survival in rhabdomyosarcoma patients with isolated lung metastases.6 The benefit of WLI has been extrapolated to all rhabdomyosarcoma patients with lung metastases. WLI has also been used in other pediatric solid tumors, such as Ewing sarcoma and Wilms’ tumor with an acceptable side effect profile.7–10
Though WLI has been incorporated into current rhabdomyosarcoma cooperative group study protocols, the efficacy of WLI in patients with lung metastases, including those with other sites of metastatic disease, is unclear. In addition, protocol non-compliance has been an issue. This is demonstrated by only 54% of patients in the Intergroup Rhabdomyosarcoma Study-IV receiving appropriate lung radiation for metastatic disease as outlined by the treatment protocol.6 Similarly, in patients with isolated lung metastases treated in four recent intermediate- and high-risk studies (D9802, D9803, ARST0431, ARST08P1), 48% (26 out of 54 patients) did not receive WLI.11
It is important to understand the oncologic benefit of WLI and factors that influence the delivery of lung irradiation in rhabdomyosarcoma patients with lung metastases. Accordingly, the aim of this study was to investigate the efficacy of WLI in patients with rhabdomyosarcoma and lung metastases treated on prospective COG trials.
Methods
Patient Population
Patients with newly diagnosed rhabdomyosarcoma with lung metastasis enrolled in 4 previously reported COG studies from 1999 to 2013 (D9802, D9803, ARST08P1, ARST0431)12–15 were included in the analysis. Written informed consent to participate in the study was provided by patients and/or their parents or guardian. Studies were approved by the Institutional Review Board at each participating site.
Study objectives, risk group classifications, and number of patients from each study are shown in Table S1. All four COG studies required patients with lung metastases to receive WLI at various time points of chemotherapy, specifically at week 12 on D9803, week 15 on D9802, and week 20 on ARST0431 and ARST08P1. WLI in the form of 15 Gy in 10 daily fractions was to be administered simultaneously with radiation to the primary site. Detailed radiation records including prescriptions, daily and cumulative doses to all body sites, and dates of radiation treatment, were required to be submitted for central review by the Quality Assurance Review Center. Radiation-specific data including radiation site and dose, dates of radiation treatments, protocol compliance, and reasons for protocol deviation were obtained from the Imaging and Radiation Oncology Core (IROC) Group.
Statistical Analyses
Baseline patient clinicopathological and treatment characteristics and outcomes were summarized and compared between patients who received and did not receive WLI using the Chi-Square test or Fisher’s Exact test. A landmark analysis was performed to exclude patients with disease progression prior to designated time for WLI on each protocol. The landmark time was determined based on the protocol-designated time for WLI, specifically at week 12 on D9803, week 15 on D9802, and week 20 on ARST0431 and ARST08P1. We also performed as-treated analysis that included patients who had progression of disease before the protocol-designated time for WLI. The 5-year event-free survival (EFS) and overall survival (OS) with 95% confidence intervals (CI) were estimated using the Kaplan-Meier method. EFS was defined as the time from study enrollment to the time of disease relapse or progression. OS was defined as the time from enrollment to death from any cause. EFS and OS were compared between patients who did and did not receive WLI using a log-rank test. A p value of less than 0.05 was considered significant. All data analyses were performed using SAS statistical software (SAS Institute, Cary, NC, USA).
Results
Patient Characteristics
In total, 143 patients with newly diagnosed metastatic rhabdomyosarcoma with lung metastases were included in our analysis (Figure 1). Among this cohort, 65 patients (45.5%) received WLI, 78 patients (54.5%) did not receive WLI. In the 65 patients who received WLI, median WLI dose and fractionation was 15Gy in 10 fractions (range 10.5 – 15Gy). Regarding the timing of WLI, 46 patients (70.8%) received WLI at the same time as primary site radiotherapy, 18 patients (27.7%) had delayed WLI, defined as more than 90 days after primary site radiotherapy, and 1 patient did not have radiation dates available.
Figure 1.
CONSORT diagram depicting rhabdomyosarcoma patient cohorts for analysis. RMS, rhabdomyosarcoma; RT, radiotherapy; WLI, whole lung irradiation.
There was no statistically significant difference in known prognostic factors between those who did and did not receive WLI, including patient age, tumor histology, FOXO1 fusion status, tumor primary site, tumor size, lymph node status, number of metastatic sites, and Oberlin score (Table 1). As expected, no patients <1 year of age at diagnosis received WLI (n=3).
Table 1.
Demographic and clinical characteristics of rhabdomyosarcoma patients who received whole lung irradiation versus did not receive whole lung irradiation. Statistical analysis for distribution between two groups was performed with either Chi-Square test (1) or Fisher-Exact test (2).
| Characteristics | WLI (n=65) | No WLI (n=78) | Total (n=143) | P value |
|---|---|---|---|---|
| Age, n (%) | 0.3142 | |||
| <1 | 0 (0.0%) | 3 (3.8%) | 3 (2.1%) | |
| 1–9 | 25 (38.5%) | 32 (41.0%) | 57 (39.9%) | |
| ≥10 | 40 (61.5%) | 43 (55.1%) | 83 (58.0%) | |
| Histology, n (%) | 0.2122 | |||
| Alveolar | 20 (30.8%) | 30 (38.5%) | 50 (35.0%) | |
| Embryonal | 41 (63.1%) | 38 (48.7%) | 79 (55.2%) | |
| NOS | 3 (4.6%) | 3 (3.8%) | 6 (4.2%) | |
| Spindle cell | 0 (0.0%) | 4 (5.1%) | 4 (2.8%) | |
| Other | 1 (1.5%) | 3 (3.8%) | 4 (2.8%) | |
| Fusion Status, n (%) | 0.6141 | |||
| FOXO1− | 9 (50.0%) | 11 (42.3%) | 20 (45.5%) | |
| FOXO1+ | 9 (50.0%) | 15 (57.7%) | 24 (54.5%) | |
| Unknown | 47 | 52 | 99 | |
| Primary Site, n (%) | 0.1731 | |||
| Favorable | 13 (20.0%) | 9 (11.7%) | 22 (15.4%) | |
| Unfavorable | 52 (80.0%) | 68 (88.3%) | 120 (84.6%) | |
| Unknown | 0 | 1 | 1 | |
| Tumor Size, n (%) | 0.7531 | |||
| ≤5cm | 8 (12.3%) | 11 (14.1%) | 19 (13.3%) | |
| >5cm | 57 (87.7%) | 67 (85.9%) | 124 (86.7%) | |
| Nodal Status, n (%) | 0.5411 | |||
| No, N0 | 35 (53.8%) | 38 (48.7%) | 73 (51.0%) | |
| Yes, N1 | 30 (46.2%) | 40 (51.3%) | 70 (49.0%) | |
| Number of Metastatic Sites, n (%) | 0.3221 | |||
| 1 | 27 (41.5%) | 23 (29.5%) | 50 (35.0%) | |
| 2 | 14 (21.5%) | 20 (25.6%) | 34 (23.8%) | |
| ≥3 | 24 (36.9%) | 35 (44.9%) | 59 (41.3%) | |
| Oberlin Score*, n (%) | 0.7171 | |||
| 0 | 8 (12.3%) | 8 (10.4%) | 16 (11.3%) | |
| 1 | 23 (35.4%) | 20 (26.0%) | 43 (30.3%) | |
| 2 | 13 (20.0%) | 17 (22.1%) | 30 (21.1%) | |
| 3 | 11 (16.9%) | 18 (23.4%) | 29 (20.4%) | |
| 4 | 10 (15.4%) | 14 (18.2%) | 24 (16.9%) | |
| Missing | 0 | 1 | 1 |
Chi-square P-value
Fisher exact P-value
Oberlin score: age, favorable vs. unfavorable. primary site, ≥3 metastatic site, bone, or bone marrow involvement.
Abbreviations: WLI, whole lung irradiation; NOS, not otherwise specified.
Patient Outcomes
5-year EFS was 38.3% (95% CI 24.8%–51.8%) in patients who received WLI versus 25.2% (95% CI 13.8%–36.6%) in patients who did not receive WLI, (p=0.0496) (Figure 2). 5-year OS was 45.5% (95% CI 31.8–59.3%) in patients who received WLI and 32.4% (95% CI 20.4%–44.4%) in patients who did not receive WLI (p=0.08) (Figure S1).
Figure 2.
Event-free survival for patients who received versus did not receive whole lung irradiation.
In exploratory subgroup analyses, a trend towards improved EFS with WLI was observed across various subgroups of patients, without a clearly identifiable cohort of patients who benefited more or less than others (Figure 3). 5-year EFS was improved in subgroups of patients 10 years or older (Hazard ratio 1.90, 95% CI 1.14–3.16) (Figure 3). 5-year OS was also significantly improved in subgroup of patients 10 years or older (Hazard ratio 2.06, 95% CI 1.21–3.52) (Figure S2).
Figure 3.
Event-free survival for patients according to each subgroup. CI, confidence interval; WLI, whole lung irradiation.
We also performed as-treated survival analysis on an expanded cohort of patients regardless of early progression status. This cohort included a total of 157 patients, of which 67 patients received WLI and 90 patients did not receive WLI. 5-year EFS was 37% in patients who received WLI versus 22% in patients who did not receive WLI, (p<0.01) (Figure S3). 5-year OS was 44% in patients who received WLI and 29% in patients who did not receive WLI (p=0.03) (Figure S4).
Other patient, tumor, and treatment-related clinical factors associated with EFS on univariate analysis included age, histology, FOX01 fusion status, number of metastatic sites, location of metastatic site, and Oberlin Score (Table 2). Clinical factors associated with OS on univariate analysis included histology, location of metastatic sites, number of metastatic site, and Oberlin score (Table S2). On multivariate analysis, single metastatic site (i.e., isolated lung metastases) was associated with improved EFS and OS compared to patients with 3 or more metastatic sites, and age less than one was associated with worse EFS compared to patients 10 years or older (Table S3).
Table 2.
Univariate analysis for factors associated with 5-year event-free survival and 5-year overall survival in rhabdomyosarcoma patients with lung metastases.
| Risk Factors | Number at risk | 5-Year Event-Free Survival (95% Confidence Interval) | P value |
|---|---|---|---|
| Age (years) | |||
| <1 | 3 | 0.00% (. , . ) | |
| 1–9 | 57 | 42.0% (27.2%, 56.8%) | 0.024 |
| ≥10 | 83 | 25.3% (14.2%, 36.3%) | |
| Histology | |||
| Alveolar | 50 | 11.3% (2.0%, 20.7%) | 0.001 |
| Non-Alveolar | 93 | 41.8% (30.0%, 53.6%) | |
| FOXO1 Fusion Status | |||
| Fusion Negative | 20 | 40.0% (12.8%, 67.2%) | 0.020 |
| Fusion Positive | 24 | 4.2% (0.0%, 12.2%) | |
| Unknown | 99 | 36.5% (25.5%, 47.4%) | |
| Primary Site | |||
| Favorable | 22 | 54.2% (24.8%, 83.5%) | 0.080 |
| Unfavorable | 120 | 27.5% (18.7%, 36.3%) | |
| Tumor Size | |||
| ≤5cm | 19 | 36.8% (15.2%, 58.5%) | 0.361 |
| >5cm | 124 | 30.7% (20.9%, 40.5%) | |
| Number of Metastatic Sites | |||
| 1 | 50 | 53.1% (37.2%, 69.1%) | <.001 |
| 2 | 34 | 26.5% (9.7%, 43.3%) | |
| ≥3 | 59 | 15.1% (4.0%, 26.2%) | |
| Location of Metastatic Sites | |||
| Lung Only | 50 | 53.1% (37.2%, 69.1%) | <.001 |
| Lung and Other Sites | 93 | 19.1% (9.8%, 28.5%) | |
| Oberlin Score * | |||
| 0 | 16 | 0.00% (. , . ) | |
| 1 | 43 | 42.9% (16.9%, 68.8%) | <.001 |
| 2 | 30 | 55.8% (38.2%, 73.5%) | |
| 3 | 29 | 27.6% (10.2%, 45.0%) | |
| 4 | 24 | 21.4% (0.0%, 42.9%) | |
| Missing | 1 | ||
| Whole Lung Irradiation | |||
| No | 78 | 25.2% (13.8%, 36.6%) | 0.0496 |
| Yes | 65 | 38.3% (24.8%, 51.8%) |
Oberlin score: age, favorable vs. unfavorable. primary site, ≥3 metastatic site, bone, or bone marrow involvement.
Discussion
Patients with metastatic rhabdomyosarcoma continue to have poor prognosis despite multi-modality therapy and the intensification of systemic therapy over the years.1,4,16–19 This cohort of patients desperately needs alternative treatment strategies.20 Here, we report significant improvement in EFS in patients with lung metastases who received WLI compared to patients who did not receive WLI. To our knowledge, this is the largest study on the efficacy of WLI in rhabdomyosarcoma patients enrolled in cooperative group trials.
The routine and wide-spread use of WLI has been hampered by a lack of strong evidence showing the benefit of WLI in pediatric rhabdomyosarcoma patients and consideration of the therapeutic ratio. The limited use of WLI was evident in our study, with only 43% of eligible patients receiving WLI. We hypothesize that the low rate of WLI was due to a combination of factors, including uncertainty of benefit of WLI based on existing literature and concern over toxicity related to WLI. Previous evidence supporting the use of WLI in rhabdomyosarcoma has been limited to 46 patients with isolated lung metastases from IRS-IV6 and small single-institutional studies.21–23 In addition, conflicting evidence regarding the benefit of WLI in patients with isolated lung metastases has been reported on more recent cooperative studies.11 Therefore, our study provides much-needed data supporting the use of WLI in patients with lung metastases.
Our finding also highlights the issue of protocol non-compliance that results in negative patient outcomes and difficulty in interpreting trial results. Patients included in our study were uniformly required to receive WLI at the time of primary site irradiation. However, we found that 54% of patients did not receive WLI. We have seen a similar omission of radiation as a deviation from protocol guidelines in rhabdomyosarcoma patients in IRS I through IV.24 Among Group II rhabdomyosarcoma patients with microscopic disease, omission of postoperative radiation was the most frequent protocol deviation and resulted in a higher rate of operative bed recurrences. As the appropriate delivery and quality of radiation therapy correlate with outcomes across pediatric cancer studies25–27, we need robust quality assurance metrics in cooperative trials, particularly regarding radiation therapy. While there is no clear evidence that the timing of WLI influences the oncologic outcome, there are several factors that should be considered when deciding to deliver WLI at the time of primary site treatment versus delayed until the completion of systemic therapy. The primary benefit of WLI at the time of primary site treatment is the convenience of consolidating all radiation treatments. It can lead to reduced travel burdens for patients and potentially increased compliance. Concurrent treatment of primary and metastatic sites can also lead to less radiation exposure to normal tissue if the radiation fields of the primary site and WLI are in proximity or overlap. In comparison, delaying WLI until after the completion of systemic therapy minimizes the interruption of chemotherapy and allows the initial response to systemic therapy to guide treatment sites.
Our study benefits from prospectively collected data with a central review process that ensures the accuracy of radiation history and patient outcomes. It also represents the largest cohort of rhabdomyosarcoma patients with lung metastases used to study the efficacy of WLI. The analyses of patient outcomes between the two cohorts were strengthened by statistically balanced clinical and pathologic prognostic factors. Furthermore, the benefit of WLI was seen across subgroups of patients based on age, tumor histology, primary site location, and number of metastatic sites. Nevertheless, we recognize certain limitations of our analyses. There are likely unmeasured confounding factors that are inherent to the non-randomized and retrospective nature of this study. Although we have attempted to analyze as many variables as possible to account for any difference in prognosis between two groups, we cannot entirely replicate the decision-making process by the clinician at the time of treatment to either administer or withhold WLI. On multivariate analysis for EFS and OS, WLI did not meet statistical significance criteria (Table S3). This likely reflects the interaction between WLI and other prognostic factors as well as undetected selection bias. Similar to our analysis, in the BERNIE trial by the European pediatric Soft tissue sarcoma Study Group (EpSSG) evaluated the benefit of radical radiotherapy to metastatic sites (including non-lung) in rhabdomyosarcoma.28 There was a significant survival benefit of radical radiotherapy compared to partial or no radiotherapy. However, the significance was clouded after adjusting for prognostic factors such as age and number/location of metastatic disease.28
Future studies will be important to further investigate the efficacy of WLI and construct additional strategies to increase the uptake of WLI. We will continue to address the efficacy of WLI through analysis of the most recent high-risk rhabdomyosarcoma study COG ARST2031 that will complete accrual in the near future. In parallel, the FaR-RMS (Frontline and Relapsed Rhabdomyosarcoma) study developed by EpSSG contains multiple arms including randomization of radiation to all metastatic sites versus no radiation in patients with Oberlin score of 2 or higher.29 We envision a similar approach to definitively delineate the role of WLI in patients with lung metastases in future COG studies.
We recommend more stringent protocol compliance in current cooperative trials and proper administration of WLI in patients with lung metastases. We recognize a challenge with delivering WLI at the same time as primary tumor site treatment with increased radiation planning complexity and concern of toxicity with concurrent chemotherapy. Therefore, the timing of WLI in the current COG high-risk rhabdomyosarcoma study and often in clinical practice off-protocol is at the end of treatment to facilitate compliance and tolerability.
In conclusion, rhabdomyosarcoma patients with lung metastases who received WLI had improved 5-year EFS compared to patients who did not receive WLI. These results support the use of WLI and highlight the need for more stringent protocol compliance for administering WLI.
Supplementary Material
Supplemental Table 1 COG clinical trials and number of patients from each trial included in the analysis.
Supplemental Table 2 Univariate analysis for factors associated with 5-year overall survival in rhabdomyosarcoma patients with lung metastases. *Oberlin score: age, favorable vs. unfavorable, primary site, ≥3 metastatic site, bone, or bone marrow involvement.
Supplemental Table 3 Multivariate analysis for factors associated with 5-year event-free survival and 5-year overall survival in rhabdomyosarcoma patients with lung metastases. WLI, whole lung irradiation.
Supplemental Figure 1 Overall survival for patients who received versus did not receive whole lung irradiation.
Supplemental Figure 2 Overall survival for patients according to each subgroup. CI, confidence interval; WLI, whole lung irradiation.
Supplemental Figure 3 Event-free survival for patients who received versus did not receive whole lung irradiation, including patients with early progression.
Supplemental Figure 4 Overall survival for patients who received versus did not receive whole lung irradiation, including patients with early progression.
Context.
Key objective:
Rhabdomyosarcoma patients with metastatic disease have a poor prognosis. What is the efficacy of whole lung irradiation (WLI) in rhabdomyosarcoma patients with lung metastases?
Knowledge generated:
We pooled 143 rhabdomyosarcoma patients with lung metastases from four large prospective Children’s Oncology Group studies. Only 65 patients (45%) received WLI according to protocol. We found an improvement in eventfree survival in the patients who received WLI compared to the patients who did not.
Relevance:
This study contributes additional evidence of the importance of radiation to the management of the primary site and metastatic disease in pediatric rhabdomyosarcoma.
Relevance section written by JCO Associate Editor Jonathan P.S. Knisely, MD
Acknowledgment
The authors would like to thank Fran Laurie, Matthew Landoli, and the staff at Imaging and Radiation Oncology Core (IROC), for their assistance with radiation data collection.
Grant Support
This study is supported by NCTN Operations Center Grant U10CA180886, NCTN Statistics and Data Center Grants U10CA180899 and U10CA098413, Chair’s Grant U10CA098543, and St. Baldrick’s Foundation.
Footnotes
Conflicts of Interest
LYL receives travel reimbursement from GT Medical Technologies, unrelated to this work. The other authors declare there are no conflicts of interest.
Prior Presentation
Presented in part at the Children’s Oncology Group Annual Fall Meeting, September 5–8, 2023.
Disclaimer
The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplemental Table 1 COG clinical trials and number of patients from each trial included in the analysis.
Supplemental Table 2 Univariate analysis for factors associated with 5-year overall survival in rhabdomyosarcoma patients with lung metastases. *Oberlin score: age, favorable vs. unfavorable, primary site, ≥3 metastatic site, bone, or bone marrow involvement.
Supplemental Table 3 Multivariate analysis for factors associated with 5-year event-free survival and 5-year overall survival in rhabdomyosarcoma patients with lung metastases. WLI, whole lung irradiation.
Supplemental Figure 1 Overall survival for patients who received versus did not receive whole lung irradiation.
Supplemental Figure 2 Overall survival for patients according to each subgroup. CI, confidence interval; WLI, whole lung irradiation.
Supplemental Figure 3 Event-free survival for patients who received versus did not receive whole lung irradiation, including patients with early progression.
Supplemental Figure 4 Overall survival for patients who received versus did not receive whole lung irradiation, including patients with early progression.