A study was undertaken to assess clinical outcome and the role of proton therapy for local control of osteosarcoma (OSA).
A study was undertaken to assess clinical outcome and the role of proton therapy for local control of osteosarcoma (OSA).
All patients who received proton therapy or mixed photon-proton radiotherapy from 1983 to 2009 at the Massachusetts General Hospital were reviewed. Criteria for proton therapy were the need for high dose in the context of highly conformal radiotherapy of unresected or partially resected OSA, positive postoperative margins, postoperative imaging studies with macroscopic disease, or incomplete resection as defined by the surgeon. The primary endpoint was local control of the site treated; secondary endpoints were disease-free survival (DFS), overall survival (OS), long-term toxicity, and prognostic factors associated with clinical outcome.
Fifty-five patients with a median age of 29 years (range, 2-76 years) were offered proton therapy. The mean dose was 68.4 gray (Gy; standard deviation, 5.4 Gy). Of the total dose, 58.2% (range, 11%-100%) was delivered with protons. Local control after 3 and 5 years was 82% and 72%, respectively. The distant failure rate was 26% after 3 and 5 years. The 5-year DFS was 65%, and the 5-year OS was 67%. The extent of surgical resection did not correlate with outcome. Risk factors for local failure were ≥2 grade disease (P < .0001) and total treatment length (P = .008). Grade 3 to 4 late toxicity was seen in 30.1 % of patients. One patient died from treatment-associated acute lymphocytic leukemia, and 1 from secondary carcinoma of the maxilla.
Proton therapy to deliver high radiotherapy doses allows locally curative treatment for some patients with unresectable or incompletely resected OSA. Cancer 2011;. © 2011 American Cancer Society.
Osteosarcoma (OSA) is a disease typically of young patients, with a peak incidence in the second decade; when arising in adults, the highest incidence appears after the age of 55 years. In the young, OSA generally presents as an osteoid-forming tumor around the epiphyses of the long bones. Besides local destruction, metastatic dissemination to the lungs or other bones can also occur. As chemotherapy is highly active and the risk for metastatic disease is high, treatment generally starts with induction chemotherapy as soon as pathologic diagnosis has been confirmed. Anthracyclines and cisplatin, as well as methotrexate or ifosfamide, form the backbone of systemic treatments.1 After chemotherapy induction, complete surgical resection generally yields high rates of local control in patients with extremity lesions. Chemoresponsiveness can be assessed after resection, and the degree of chemotherapy-induced necrosis carries important prognostic information.2 Postoperative chemotherapy usually continues for nearly a year.
Local tumor control, an important component of successful treatment, may be improved in selected patients with external beam radiation, although the potential of radiotherapy (RT) as an integral therapeutic component for local curative treatment has been debated.3, 4 Depending on the clinical presentation, function-sparing surgery might be difficult to achieve in certain anatomical sites, such as the head, the spine, and the pelvis. Furthermore, OSA has been traditionally viewed as a neoplasm that responds poorly to radiation,5 and current knowledge about the role of high-dose RT in the setting of nonresectable or marginally resectable OSA has remained limited. Overall survival can be expected in ∼70% of cases with modern chemotherapy and surgery with anticipated local control in ≥90% of extremity osteosarcomas. Overall survival and local control, however, have been significantly worse for craniofacial, spine, and pelvic tumors.6, 7, 8, 17 The Cooperative Osteosarcoma Study Group used photon-based RT in a minority of their trial patients; in the case of unresectable disease they used doses of 30 to 56 gray (Gy) for disease of the spine, and 56 to 68 Gy for OSA of the pelvis, resulting in local control rates of <20%.7, 8 Conversely, Machak et al reported local control rates of 60% with photon RT for nonresected OSA in 31 patients with doses of 60 Gy (given in 2.5-3 Gy daily or 1.25-1.5 Gy twice daily fractions), and patients who responded to chemotherapy had even higher rates of response.9 A previous report from the Massachusetts General Hospital on 41 patients reported high-dose RT resulting in local control rates between 50% and 80%, depending of the extent of surgical resection.10 Thus, the current use of RT for OSA follows the concept that high doses of ionizing radiation may add to local control, as has been the case in the treatment of sarcomas in general, when wide surgical margins cannot be achieved.10, 11
The current experience with proton therapy for OSA remains limited. Most of the studies reporting on particle therapy include a variety of histological entities, of which OSA mostly represents the minority, limiting interpretation.11, 12 Thus, it has remained unclear in what context particle therapy should be incorporated a priori in the curative treatment of OSA not amendable to complete surgical resection. Currently, the best data have been reported from Chiba, Japan, using heavy ion-based particle treatment. They reported a local control rate after 5 years of 65%, with an overall survival rate of 29% in 58 patients with OSA of the trunk treated with carbon ions from 1994 until 2007 at the National Institute of Radiological Sciences.13
A reassessment of the role of particle treatment in the multimodality approach to OSA is of growing clinical importance, as access to particle treatment facilities is increasing worldwide. Although the clinical benefits of this costly and complex technology are still being assessed and debated, the reduction in integral radiation dose is likely to be of most importance to the young patient with a large tumor such as patients with pelvic disease.14, 15 Here we review the entire series of OSA patients at Massachusetts General Hospital who were treated with proton therapy for OSA.
During the period from 1983 to 2009, there were 55 patients in the Sarcoma Database of the Department of Radiation Oncology at Massachusetts General Hospital who were treated for OSA with proton therapy. Approval from the investigational review board was obtained to analyze long-term outcome in these patients. All available department and hospital charts and records were reviewed to assess local control as the primary endpoint, as well as secondary endpoints of disease-free survival (DFS), metastasis-free survival, overall survival, and long-term toxicity.
Table 1 summarizes the characteristics of the cohort. The median age was 29 years (range, 2 to 76 years), and the mean age was 32 years (standard deviation, 18). The male to female ratio was 5:6. The median follow-up was 27 months (range, 0-196 months). The distribution of disease manifestations is shown in Figure 1. Histology was available for all patients, and histological subtype was osteoblastic in 29 (52.7%) patients, chondroblastic in 21 (38.2%), OSA with giant cells in 2 (3.6%), fibroblastic in 2 (3.6%), and myxoid in 1 (1.8%). Grade 1 disease was seen in 12 (22%) patients, grade 2 in 23 (41.2%) patients, and grade 3 in 20 (36%) patients. This grade distribution may be more favorable than in some series, perhaps because the patient population is slightly older, likely reflective of the anatomic distribution with more craniofacial lesions, rather than the more common population of adolescents with high-grade extremity lesions. American Joint Committee on Cancer stage IA disease was noted in 3 (5.5%) patients, stage IB in 9 (16.4%) patients, stage IIA in 24 (43.6%) patients, stage IIB in 14 (25.5%) patients, and stage IV in 5 (7.3%) patients. In 23 (41.8%) patients, surgery consisted of biopsy only or minor resection with residual gross tumor. Positive surgical margins were present in 27 (49.1%) patients and surgeon's notes indicating residual disease in 5 (9.1%) patients.
|Age, y [median]||26.9 [2-76]|
|Pelvis or sacrum||13||24|
|Extent of surgery|
|Grossly resected with positive margins||24||43|
|No systemic treatment||5||9|
|Relapse after curative surgery||17||31|
The initial fields were designed to cover the preoperative clinical tumor. All cases were treated after computed tomography (CT)-based 3-dimensional (3D) planning, and proton therapy was delivered with 160 MV protons via a fixed beam line before 2001 and with 230 MV protons via a rotational gantry after 2001. RT consisted of daily external beam using either protons or a combination of protons and photons, except for 3 cases where hyperfractionation was used (1 in 1994, 1 in 1998, and 1 in 2001). The total dose was selected based on the patient's condition, anatomic localization of the disease, the extent of prior surgery and degree of resection, grading characteristics, and normal critical structures in close proximity to the target volumes. Doses of <60 Gy were given to only 5 (9.1%) patients. One patient had a resected OSA of the third lumbar vertebral body at the age of 37 years and received an adjuvant dose of 50.4 Gy with protons only, 1 patient at the age of 14 years received 57.6 Gy for incompletely resected disease at the lumbosacral junction, 1 patient at the age of 19 years was treated with 59.4 Gy for positive margins for disease of the distal femur, 1 patient at the age of 51 years received 54.6 Gy for resected disease of the fourth and fifth thoracic vertebral bodies, and 1 patient at age 25 received 58 Gy after microscopically incomplete resection of OSA of the maxilla. Twenty-two (40%) patients received a dose between 60 Gy and 70 Gy, and 28 (50.1%) patients received a total dose of ≥70 Gy.
The total dose was applied with protons only in 11 (20%) patients, and 7 (63.6%) of these patients presented with OSA of the bones of the head. Greater than 50% of the total dose was delivered with protons in 31% of the patients. Less than 30% of the total dose was applied with protons in 9 (16.4%) patients. These 9 patients had disease of either the spine, sacrum, pelvis, or femur.
Preoperative RT was used in a total of 7 (13%) patients with a dose of 19.8 Gy, except in 1 case, a dose of 50.4 Gy was used for disease of the spine. The rationale for delivering a portion of the dose before surgery is to minimize the risk of intraoperative tumor cell seeding. Postoperative radiation was started as soon as patients recovered from surgery to minimize overall treatment time. Unplanned treatment breaks were given at the discretion of the treating physician for severe acute mucositis, dermatitis, febrile neutropenia, or other acute radiation-related toxicity. Intraoperative treatment with electrons (6 MV) was used in 2 patients with doses of 7.5 to 15 Gy, and in 1 patient, radioactive 90Y plaques were used to deliver a dose to the dura adjacent to disease invading the spinal canal.
The median volume treated to the maximal dose (boost dose) covering the gross tumor volume or the highest risk area for relapse in the tumor bed in the patients without residual macroscopic tumor as observed on the treatment planning CT was 82.0 mL (range, 8-1090 mL; mean, 194.2 mL), and for the volumes covering the initial clinical target volume, which also included areas at risk for subclinical disease beyond the original gross tumor, was 213.0 mL (range, 14-1624 mL; mean, 380 mL). Four patients had only 1 tumor target volume after microscopically incomplete resection: 1 case of OSA of the maxilla, 1 in the mastoid bone, 1 in the second cervical vertebra, and 1 in the sacrum; all 4 were treated with doses of 67 to 68 Gy.
Chemotherapy was delivered neoadjuvantly in 48 (87%) patients and consisted of anthracyclines in combination with cisplatin, and/or high-dose methotrexate. In the case of undesired side effects or failure to respond, treatment was switched to ifosfamide with etoposide. Ifosfamide was administered during RT in 38 (69%) of the patients, in combination with etoposide (65%), including some recent patients with unresected OSA, or methotrexate (4% of patients). After RT, adjuvant chemotherapy was given in 75% of cases, whereas unknown chemotherapy status after surgery was scored in 6 (11%) patients. Chemotherapy was scored as full intensive standard chemotherapy of intensity defined by the number of cycles and the drugs and drug combinations used. All others were scored as “some chemotherapy.”
Statistical analysis was performed using Stata (release 11.0, 2009; StataCorp, College Station, Tex). Statistical significance of various risk factors for primary and secondary endpoints was assessed using competing risks regression methodology. Death was considered a competing event to local and distant failure. P values of <.05 were considered statistically significant.
Twelve patients suffered from local treatment failure (Fig. 2Top). Disease progression within 2 months after RT was observed in 4 patients, and 3 patients suffered from local relapse >3 years after RT. At 3 and 5 years, the local control rate was 82% (95% confidence interval [CI], 68%-90%) and 72% (95% CI, 52%-84%), respectively. No local relapse was seen in grade 1 disease (P < .0001). Prolonged treatment time was a risk factor for local failure, with a hazard ratio of 1.02 (95% CI, 1.01-1.03; P = .008). An indication of increased risk for local failure, with a hazard ratio of 2.6 (95% CI, 0.8-9.0; P = .1) was observed for patients with disease of the skull, as compared with other anatomical sites. Figure 3 illustrates the difference of local control over time in patients with disease in the cranium versus other sites (P = .09). Primary presentation or presentation at relapse did not discriminate for successful local control, as 16 (29.1%) patients presented with local recurrence after prior resection, and another 2 were treated at metastatic sites after successful prior therapy targeting the primary site.
With regard to the pattern of failure, 10 patients failed within the radiation treatment field. Of these, 8 patients had OSA of the bones of the skull. The other 2 cases were 1 patient with extensive disease from the distal cervical spine to the midthoracic spine and another patient with extensive sacral disease spanning S1 to S4. Marginal misses were likely in 2 cases. One patient with disease of the thoracic spine showed disease progression in the vertebral body growing from the irradiated high-dose volume into the contralateral part of the vertebral body and beyond it. Another patient with pelvic disease involving the ileum showed distal disease progression, and retrospectively, a caudal marginal miss cannot be excluded. Treatment volumes or the absence of surgery did not correlate with local treatment failure (P = .5). The fraction of dose delivered with protons or photons was not associated with local disease control or disease progression.
The extent of surgery, however, did impact on local control probability when conducting a meta-analysis of published data based on Table 2, illustrated in Figure 4. Patients who received lower radiation doses seemed to achieve higher local control when combined with surgery, but interestingly the impact on surgery was no longer evident when high-dose radiation was applied.
|Reference||LC Rate||Dose, Gy||Surgery||Site||No. Patients|
|Kassir 199717||50%||ns||100%||Head and neck||46|
|Present series 2011||85%||68.4||58%||Variable||55|
A total of 11 patients suffered from distant failure (Fig. 2Bottom). Four of the 12 patients with local failure also suffered from distant failure 0 to 7 months after RT. Ten of the 11 patients with distant failure had grade 2 or higher disease but the difference was not statistically significant (P = .2).
Chemotherapy was used in most patients. However, the quality of chemotherapy was reviewed, and intensive chemotherapy as defined by the drugs used (anthracyclines and cisplatin alternating with methotrexate) and documentation of the number of cycles given revealed that highly intensive state-of-the art treatment was delivered to only 19 patients. Of these 19, 2 (10.5%) patients suffered local failure, and 5 (26.3%) failed distantly. Of the 31 patients receiving nonintensive chemotherapy, 10 (32.3%) patients failed locally, and 6 (19.4%) patients showed metastatic disease progression. The differences with respect to chemotherapy intensity were not significant, although adherence to standard high-intensity chemotherapy did weakly associate with successful local treatment control in univariate analysis (hazard ratio, 5.9; 95% CI, 0.75-46.5; P = .09), but not in multivariate analysis. None of the 5 patients treated without chemotherapy, 3 with grade 1 disease, and 2 with grade 2 disease showed either local or distant failure.
DFS was 68% (95% CI, 53%-80%) at 2 years and 65% (95% CI, 49%-77%) at 5 years (Fig. 5Top). The overall survival rate at 2 years was 84% (95% CI, 69%-92%), and 67% (95% CI, 47%-80%) at 5 years (Fig. 5Bottom). Four patients died without disease, 2 of therapy-related mortality, 1 at the age of 16 years (1.5 years after completion of treatment) because of acute lymphocytic leukemia, and another patient died 15 years after completion of treatment for OSA from squamous carcinoma of the maxilla. Two patients died to noncancer-related disease 65 and 96 months after the end of RT.
Nine patients did not have any significant late treatment-associated toxicity, and were treated to the mastoid (n = 1), maxillary bone (n = 1), cervical spine (n = 3), thoracic spine (n = 2), lumbosacral bones (n = 1), and hip (n = 1). Grade 1 toxicity was reported in 12 patients, receiving treatment targeting the cranium (n = 4), cervical spine (n = 1), chest wall (n = 1), thoracic spine (n = 2), lumbosacral sites (n = 3), and distal femur (n = 1). Grade 2 toxicity, as defined by pain controlled with nonopioid medication and minor complaints interfering with the activities of daily living, were reported in 12 patients, consisting of pain, paresthesia, atrophy (1 patient with cervical spine OSA), ineffective gait and foot drop, radiation myelopathy, and distal neuropathy. Complaints were possibly caused by radiation alone in 3 patients, whereas most cases of neuronal dysfunction were either pre-existing or possibly related to surgery. Grade 3 and 4 toxicity was recorded in 17 patients. Grade 3 toxicity consisted of severe pain requiring morphine-based medication (n = 3), cranial nerve damage with diplopia (n = 1), immobility of limb (n = 2), severe bowel dysfunction with distal functional obstruction because of denervation (n = 1), and severe headaches (n = 1). Grade 4 toxicity was defined by loss of organ or complete loss of organ function and was reported in 9 patients. In 4 patients, the eye had to be removed after RT, 1 patient suffered from ipsilateral loss of vision and orbital pain, and 1 patient suffered from ipsilateral hearing loss and blindness. Two patients were severely handicapped because of immobility or impairment of gait. One patient suffered from extensive structural alteration of the maxillary bone needing repeated adaptation of the prosthesis. Two patients died from treatment-related illnesses; 1 patient developed acute lymphocytic leukemia 1 year and a half after successful treatment of OSA, and the other patient died from a secondary squamous cell carcinoma of the maxilla almost 16 years after successful treatment of the OSA with protons and chemotherapy.
The present series reviews the experience with proton therapy for local control of incompletely or unresected OSA at Massachusetts General Hospital since 1983. In a prior series from the Massachusetts General Hospital spanning from 1980 to 2002, the role of RT in 41 cases of OSA was analyzed. Only 56% of the patients in that series received proton therapy as a part of their treatment. Additional differences from the prior cohort exist: 1) the median dose in the present series was 68.4 Gy compared with 66 Gy in the earlier cohort; 2) no patient received doses <50.4 Gy compared with 10% patients in the former cohort who received ≤30 Gy, and some received <50 Gy; and 3) chemotherapy was given to 91% of patients compared with 85% in the previous cohort. Despite the finding that 22 (40%) patients from the previous analysis were retained in the present series, the results differ significantly. The differences regarding treatment modalities, the doses applied, and the time frame analyzed allow us to more fully explore the role of proton therapy for OSA.
Because patients in this series received high radiation doses, radiation treatment dose per se did not emerge as a significant factor for local control in the present series, and the lack of radical resection did not seem to be detrimental. The reason for this finding may be related to the overall higher mean radiation dose applied in the current series. Proton therapy generally allows more conformal dose application than 3D conformal photons and lower integral doses than either 3D conformal photons or intensity-modulated RT. Treating in high-dose ranges may reduce the importance of the extent of surgery, as illustrated with data derived from reports with photons or particle treatment in Figure 4.
High control rates with particle treatment without prior surgical resection have been reported by Kamada et al, based on their analysis of unresected OSA patients treated with carbon ions at the National Institute for Radiological Sciences in Chiba, Japan.13 Table 2 summarizes the current literature in respect to local control and complete surgical resection status. It is noteworthy that the results from particle-based RTs yield high control rates exceeding 70%, which are seemingly superior to the results obtained with conventional RT. Such findings are not surprising, as charged particle treatment is generally associated with the feasibility to deliver higher doses. The lack of association of the extent of surgery with local control in the present series, besides being possibly the result of lack of statistical power, is particularly interesting in reference to the local control data obtained with carbon ions.13 Furthermore, conventional fraction schedules as used for proton therapy in the vast majority of cases in the present series compare favorably with the hypofractionated schedules using 16 fractions over 4 weeks to deliver 64 to 70.4 Gy with carbon ions.16 Figure 4 illustrates the relation between dose and local tumor control rates as reported in the literature in Table 2. The optimal combined approach of surgical resection with RT when proton or carbon ion therapy is available must consider the relative long-term toxicities of the different approaches, especially for disease of the axial skeleton or pelvis.
Another important finding in the present series is the association of lower local control in patients with disease of the skull. This finding has not been anticipated because of prior experience at the Massachusetts General Hospital.10 However, data from the literature have reflected control rates <50% in small series,17, 18 and several hypotheses may explain why proton therapy might have reduced efficacy in the head and neck region. First, the use of induction chemotherapy in patients with OSA in the head has not been uniformly applied. Some patients may require immediate surgery, because disease close to critical structures may mandate immediate surgical decompression.19 Resection, however, is rarely complete because of invasion and spatial relation to critical structures. Another consideration, especially in the maxillary bone and bones close to the ethmoid cavities, is that air-tissue inhomogeneities might affect the accuracy of dose delivery, as noted for other situations when treating areas with air cavities with proton therapy such as in the chest.20 Dose constraints placed on critical structures in close proximity to the tumor, however, are likely the predominant contributing factor. The present finding that the head and neck region may still be a risk factor for local relapse may be of clinical importance.
Chemotherapy in the present series was marginally associated with better local control. However, in the present series considerable uncertainties about chemotherapy delivered after RT persist, because documentation of treatment after RT and during follow-up was incomplete in some cases as this was often given at outside institutions. The importance of optimal chemotherapy has been clearly defined in the pediatric population with OSAs, and the possible association with improved local control is supported by the present series. During RT, chemotherapy with ifosfamide ± etoposide is frequently used at the Massachusetts General Hospital as these agents have both systemic and radiosensitizing activity and have also been successfully combined with radiotherapy for the management of Ewing's sarcomas.
The present cohort analysis highlights an important general consideration with regard to many rare disease entities such as incompletely resected OSA. The difficulty of conducting randomized controlled trials presents challenges in the prospective assessment of novel medical and technical innovations once they are introduced into the clinic.6, 15 Controlled registries or databases collecting data from multiple institutions could facilitate the assessment and implementation of novel technologies and agents in these rare medical conditions. These approaches should be considered as more particle treatment facilities come online and permit the collaborative evaluation of this technology when used for uncommon diseases such as unresectable or incompletely resected OSA.
In summary, particle-based RT can be effective for local control of OSA in areas where radical resection is problematic because of the impossibility of complete resection or potential morbidity of surgery. Proton therapy is especially suitable for young patients with OSA, in whom reductions in the integral dose to nontarget tissue is important to minimize the risk to normal tissue development and of secondary malignancies.21 Even with the use of conformal 3D proton therapy, some patients in this series experienced significant radiation-related toxicity. There may be the possibility of some reduction in this toxicity as well as further improvements with the future implementation of intensity-modulated proton therapy, which will better restrict the prescribed dose to the target than 3D conformal protons, as well as reduce normal tissue dose that is in the beam trajectory proximal to the tumor target.22, 23 Optimal coordination of surgery, chemotherapy, new targeted agents, and particle-based RT is likely to result in the best local control rates while minimizing toxicity; the best sequencing and integration of multimodality approaches, however, remain to be further defined.24
Supported in part by grant PO1CA021239 from the National Cancer Institute and in part by the Zurich Cancer League, Switzerland.
CONFLICT OF INTEREST DISCLOSURES
The authors made no disclosures.