Balancing the potential for cure with the possibility of incurring harmful late effects is one of the major challenges in treating children with malignancies. As survival for children with rhabdomyosarcoma continues to improve with combined-modality treatment, functional abilities and quality of life after treatment are increasingly important. Our clinical data suggest that proton RT provides tumor control that is comparable to that with conventional photon RT. Moreover, these data demonstrate that patients benefit from the normal tissue-sparing properties of proton RT through a reduction in late effects.
Experience from the IRS and European studies shows that local failure is the most common form of relapse for patients with PM-RMS, and such failures are associated with a dismal salvage rate (3
). In our series, the crude local failure rate was 18% (3 of 17). In comparison, IRS II–IV trials had a cumulative local failure rate of 17% (3
) and 16.5–18.5% on COG D9803 (4
). Though our numbers are small, our follow-up exceeds the typical time period for local recurrences, which is usually within the first 2 to 3 years after diagnosis. Thus, these data suggest that a similar local control rate is achieved using proton RT compared with standard photon external-beam RT.
Our cohort experienced slightly lower 5-year FFS (59%) and OS (64%) compared with the most recent COG trial (4-year FFS and OS at 68–73% and 79%, respectively, on COG D9083). Any difference in these rates is likely due to the greater percentage of patients in our cohort with poor prognostic features compared with the IRS trial population. Most notably, 59% of our patients had intracranial extension, compared with 38% in IRS II–IV (3
). Patients treated on IRS II–IV with meningeal involvement (which includes intracranial extension, cranial base bone erosion, and cranial nerve palsies) had a reduced rate of local failure if RT began within 2 weeks after diagnosis (3
). Unfortunately, the median time from diagnosis to the start of proton RT for our patient cohort was 8 weeks (range, 1–58 weeks) owing to young age or late referral patterns to our institution. Of the 4 patients with a component of local failure in our cohort, 3 had intracranial extension at the time of diagnosis and received proton RT at 8, 8, and 12 weeks after diagnosis.
Additional poor prognostic features in our cohort include parameningeal site, histology, and 2 patients with metastatic disease. Raney et al.
) found that tumors in the paranasal sinus and pterygoid/infratemporal fossa connote a poorer prognosis over tumors located in other parameningeal sites. Sixty-five percent of the tumors in our cohort were located in the paranasal sinuses or pterygoid/infratemporal fossa, compared with 39% in IRS II–IV (5
). Alveolar or undifferentiated histology has also been shown to be an adverse prognostic factor for relapse; the percentage of patients with these adverse histologies in our patient cohort was 35%, compared with 19% in the large national protocols (3
Taken together, these data indicate that our cohort was typified by poor prognostic features and underscores the importance of prompt referral, especially because of the scarce availability of proton RT. However, patients in our cohort had very similar outcomes to the patients with poor prognostic features in IRS II–V (3
). Additionally, our results with proton RT are similar to those from single institutions whose cohorts with parameningeal rhabdomyosarcoma were treated with intensity-modulated radiotherapy (IMRT) and had an abundance of patients with adverse prognostic factors as well (15
The data from our cohort of surviving patients with a median follow-up of 5 years demonstrates the ability of proton RT to reduce the incidence of many clinically significant late effects as compared with the reported toxicities in selected previous studies in (10
). In , we show toxicities likely related to RT from our data and from the University of Iowa and Memorial Sloan-Kettering Cancer Center, and tumor or treatment-related toxicities from the IRS trials. There was no formal system of collecting late sequelae data for the IRS trials, and data regarding many toxicities were not available for all patients, so the true incidence of toxicities is difficult to fully discern. Although follow-up times also differ, the data suggest that the dosimetric advantages of proton RT result in a benefit of proton RT in terms of the risk of significant late effects compared with similar populations treated with photons (8
). Although the data for the IMRT population look good to date (17
), it is important to note a higher median age (8 vs. 3 years), a median follow-up of only 2 years, and inclusion of adults, all of which have a mitigating effect on the development of late effects in the cohort, including growth abnormalities. Deficits in growth velocity were noted in only 3 patients (30%) in our cohort, compared with half of those in the previous IRS studies. No visual deficits have developed to date after proton RT, compared with 45 of 213 patients (21%) with available data in IRS II–III and 9 of 11 patients (82%) in the Iowa series and 10% in the Memorial Sloan-Kettering Cancer Center series. Although longer follow-up may result in the appearance of late toxicities, the median time to development of visual impairments in the Iowa series was approximately 2 years. Proximity of the tumor to the cochlea explains the hearing loss in 4 patients in our cohort, which occurred before proton RT. Proton RT actually improved audition in 2 of these patients, whose tumors were located in the infratemporal fossa; this likely resulted from a reduction in conductive hearing loss without a decrease in sensorineural hearing loss from radiation. Seven of our surviving patients (70%) had minimal to mild facial asymmetry, which is similar to previous trials. Asymmetry may actually be of greater concern in our patients because the absence of exit dose with proton beam RT may increase the differential radiation doses to ipsilateral and contralateral bony structures, yielding greater facial asymmetry. However, to date we have not observed this in our patient population. Half of the survivors in our cohort received extra help with school work or therapy for anxiety and behavioral issues. This is in accord with the prevalence demonstrated in large studies of childhood cancer survivors and highlights the importance of education and social functioning for the general health status and quality of life for survivors of childhood cancers (18
Although cross-trial comparisons of treatment efficacy and toxicity are fraught with difficulties, these data demonstrate that proton RT reduces the long-term toxicities of therapy for PM-RMS compared with historical controls. One important caveat is that conformality of dose to the tumor has improved in the era of good three-dimensional imaging and planning with the use of smaller margins and sophisticated planning techniques, such as IMRT. Thus, larger series and longer follow-up is necessary in cohorts treated with modern photon RT to compare the late-effect profile with those treated with proton RT. The COG will be well placed to discern the clinical differences in late-effects outcomes between proton- and photon-treated patients because both techniques are allowed on many of their protocols and have been for more than 5 years.
Although none of the patients treated with protons in our cohort had a second malignancy to date, further follow-up and greater patient numbers will be necessary to determine whether the second malignancy rate is actually decreased with proton RT. However, emerging evidence suggests a significant reduction in the second malignancy rate with proton RT compared with photon-treated patients matched for site, age, and histology (21
). Furthermore, mathematical modeling studies predict that the lower integral dose of proton RT compared with IMRT or three-dimensional conformal photon RT will decrease the risk of second malignancies (22
). We will continue to follow these patients and others treated at our institution to determine the incidence of second malignancies after proton RT.
Despite radiation doses in excess of 50 Gy, local failures still occurred in a significant percentage of patients. These failures result in profound morbidity and are rarely salvageable. The increased conformality of proton RT may make it possible to escalate doses safely to further improve on local control. Although IRS-IV did not show any improvement in local control or OS when a hyperfractionated schema was used to deliver a higher total dose (59.4 Gy) of radiation compared with the standard dose (50.4 Gy), this escalation represents a very modest increase in biologically equivalent dose due to a decreased dose per fraction (14
). Furthermore, retrospective analysis of IRS trials suggest that there may be a dose–response relationship; for tumors 5 cm or larger, radiation doses of <47.5 Gy are associated with approximately twice as many local failures as doses of >47.5 Gy (3
). This observation suggests that dose escalation may be of interest in select PM-RMS patients, and proton RT may be particularly useful in sparing additional dose to normal structures in the setting of dose escalation.