Spinal sarcomas have been one of the most challenging diseases for orthopedic surgeons. The objective of this study was to retrospectively analyze carbon ion radiotherapy (CIRT) treatment results for spinal sarcoma.
Spinal sarcomas have been one of the most challenging diseases for orthopedic surgeons. The objective of this study was to retrospectively analyze carbon ion radiotherapy (CIRT) treatment results for spinal sarcoma.
Forty-seven patients with 48 medically unresectable spinal sarcomas, excluding sacral tumors, received treatment with CIRT between 1996 and 2011. All patients were enrolled in phase 1/2 and phase 2 clinical trials of CIRT for bone and soft tissue sarcoma. The applied dose ranged from 52.8 gray equivalents (GyE) to 70.4 GyE (median, 64.0 GyE) in 16 fixed fractions over 4 weeks.
The median patient age was 54 years, and the cohort included 24 men and 23 women. Thirty-five patients were without prior treatment, and 12 patients had locally recurrent tumors after previous resection. The median follow-up was 25 months, and the median survival was 44 months (range, 5.2-148 months). The 5-year local control, overall survival, and progression free rates were 79%, 52%, and 48%, respectively. None of the 15 patients who had tumors measuring <100 cm3 had a local recurrence. No fatal toxicities occurred during follow-up. One patient each had a grade 3 late skin reaction and a grade 4 late skin reaction. Vertebral body compression was observed in 7 patients. One patient had a grade 3 late spinal cord reaction. Twenty-two of the surviving 28 patients who had primary tumors remained ambulatory without supportive devices.
CIRT appears to be both effective and safe for the treatment of patients with unresectable spinal sarcoma. Cancer 2013;119:3496–3503.. © 2013 American Cancer Society.
Malignant and benign primary spinal tumors are particularly rare, accounting for between 4% and 13% of all orthopedic tumors. The standard treatment for spinal sarcomas has been en bloc resection. However, sarcomas of the spinal region, particularly those involving the spinal canal, have been one of the most challenging diseases for orthopedic surgeons.[3, 4] Since its introduction in 1971, spondylectomy has developed greatly as a surgical procedure. However, it is often impossible to achieve sufficient tumor excision margins when the tumor is adjacent to critical organs. When en block resection is not possible, curettage or piecemeal excision has been carried out to avoid tumor invasion-related paralysis; nevertheless, this has inevitably resulted in a high incidence of local recurrence.
For patients who have spinal sarcomas that are not suitable for surgery with sufficient margins, radiotherapy has been considered the second best local treatment option. In conventional x-ray radiation therapy, the radiation dose is usually restricted as a tolerable dose to the spinal cord, leading to a low probability of local control. To improve dose distribution, several new radiation modalities, such as intensity-modulated radiation therapy (IMRT) and particle therapy, have been introduced in recent decades. For particle therapy, proton and carbon ion beams are used. Compared with photons, ion beams provide more beneficial dose distribution. Along the pathway of ion beams in the body, they have fewer effects on the normal tissue before reaching a tumor; subsequently, they release maximum energy to the tumor. At deeper levels in the body, the irradiated dose falls off significantly in a formation known as the Bragg peak, which takes into consideration the lesser irradiated volume of the surrounding normal tissues and the reduction in the frequency and severity of radiation morbidity. Carbon ions are heavier than protons and their greater relative biologic effectiveness (RBE) associated with higher linear energy transfer leads to a greater probability of achieving tumor control. Although most sarcomas are considered radioresistant and difficult to control with conventional radiotherapy, these advantageous treatment profiles with carbon ion beams contribute toward achieving a lower irradiated dose to the spinal cord and an improved local control rate for spinal sarcomas.
In 1996, we commenced clinical trials with carbon ion radiotherapy (CIRT) for medically inoperable bone and soft tissue sarcomas at the National Institute of Radiological Sciences (NIRS) in Chiba, Japan. The first phase 1/2 dose-searching clinical trial was implemented between June 1996 and February 2000; this was followed by a phase 2 fixed-dose clinical trial in April 2000 and has continued the protocol as Highly Advanced Medical Treatment approved by the Ministry of Health, Labor and Welfare. All patients in this analysis were enrolled on those trials.
Patients who met all of the following eligibility criteria were registered: histologic confirmation by a central pathologist, tumors judged medically inoperable by referring surgeons, grossly measurable tumors <15 cm in greatest dimension, an Eastern Cooperative Oncology Group (ECOG) performance status from 0 to 2, no distant metastasis at initial referral for treatment, no prior radiation therapy at the same site, no prior chemotherapy within 4 weeks before CIRT, no infection at the tumor site, and no intravascular tumor embolism. The objective of this study was to evaluate the efficacy and safety of CIRT for patients with cervical, thoracic, and lumbar spinal sarcomas. The irradiation technique to cervical, thoracic, and lumbar vertebras using carbon ion beams was different from that to sacral vertebras because of differences in their shapes and dose constraints to the spinal cord and cauda equina; thus, in this report, results in cervical, thoracic, and lumbar spinal sarcomas were evaluated, and sacral sarcomas were excluded. All patients signed an informed consent form that was approved by the local institutional review board. The details of eligibility of these trials have been described in previous articles. Surgical instruments also were obstructions to CIRT, because they could disturb accurate dose distribution planning and scatter carbon ion beams. To avoid these influences, we used CIRT either before fixation or after the elimination of instruments by the referring surgeon.
The specific CIRT technique used at NIRS has been described previously in detail.[9-12] The Heavy Ion Medical Accelerator in Chiba (HIMAC) generates carbon ion beams with the accelerated energies of 290 megaelectron volts per nucleon (MeV/n), 350 MeV/n, and 400 MeV/n. These energy beams have a range between 15 cm and 25 cm of water equivalent depth. For the Bragg peak modulation to conform to the target volume, the treatment beam lines are equipped with a pair of wobbler magnets, beam scatters, ridge filters, multileaf collimators, and compensation boluses. The ridge filter produces biologically equal effects along the spread-out Bragg peak.
Patients were positioned in customized cradles and immobilized with a low-temperature thermoplastic sheet. A series of 2.5-mm or 5-mm slice thickness computed tomography (CT) images were taken for treatment planning purposes. Respiratory gating of both CT acquisition and therapy was performed when indicated. Respiratory gating was applied after observing moving skin lines on planning CT images. Three-dimensional CIRT treatment planning was performed using the HIPLAN software program (NIRS, Chiba, Japan). Tumor extent was evaluated by magnetic resonance imaging (MRI), CT scanning, and positron emission tomography (PET). The clinical target volume (CTV) included the gross tumor volume plus a 5-mm margin for potential microscopic invasion irrespective of the histology. The planning target volume included the CTV plus a 5-mm safety margin for positioning errors. When the tumor was located close to critical organs (eg, intestines), the margin was reduced accordingly.
The CTV was covered by at least 90% of the prescribed dose. We used dosages ranging from 52.8 gray equivalents (GyE) to 70.4 GyE (carbon physical dose in grays [Gy] × RBE) based on results from a previous bone and soft tissue tumor trial. CIRT was performed once a day, 4 days per week (Tuesday through Friday), in a total of 16 fixed fractions over 4 weeks. Two to 14 irregularly shaped ports were applied, and 1 port was treated in each session. At every treatment session, the positioning was confirmed with a computer-aided online positioning system. The median CTV of the tumors was 190 cm3 (range, 25-1259 cm3). One patient received a total dose of 52.8 GyE, 3 patients received 57.6 GyE, 27 patients received 64.0 GyE, and 17 patients received 70.4 GyE. Among those patients, 18 patients who had tumors surrounding the spinal cord were irradiated using the patch-field technique regardless of the spinal level. The target region was divided into 2 volumes, and the divided regions were treated as separate radiation fields. By using a sharp dose fall-off after the Bragg peak, the distal edge of 1 field was matched with the lateral field edge of the second field.
Patients were closely followed with physical examinations, CT scans, and MRI studies. Initial follow-up examinations were performed at the end of CIRT and subsequently were conducted 1 to 2 months after the completion of CIRT. We planned subsequent follow-up at least every 6 months at our hospital to check patient progress. However, some patients who were elderly and lived in remote areas were evaluated by estimating their condition using a combination of imaging films taken at local hospitals and local physicians' medical reports.
The follow-up period was calculated from the initial carbon ion irradiation date. Recurrence was defined as tumor regrowth (ie, observed tumor volume increase in 2 consecutive MRI or CT studies). When another finding, such as emerging enhancement area using contrast medium inside a tumor on CT or MRI studies, was the only sign of recurrence in the absence of an obvious increase in size, then a PET scan was sometimes performed, and the finding was judged comprehensively. Local control and overall survival rates were calculated using the Kaplan-Meier method. Univariate analysis was conducted using the log-rank test, and a Cox proportional hazards model was used for multivariate analysis. Statistical significance was set at P < .05. The last follow-up date was December 2011.
Between June 1996 and November 2011, 47 patients with 48 spinal sarcomas were registered. Patient characteristics are summarized in Table 1. All biopsy specimens were confirmed pathologically by both the referral hospital pathologist and our own pathologist. The study patients comprised of 24 men and 23 women. The median patient age was 54 years (range, 12-82 years). There were 30 patients with an ECOG performance status of 1 and 17 patients with an ECOG performance status score of 2. Among the 47 patients, 35 had received no previous treatment, and 12 had developed recurrent after undergoing previous surgical resection. Eleven patients who had progressing paralysis underwent decompression surgery, which meant an urgent operation and not debulking surgery, before they received CIRT. Various regimens of chemotherapy were received by 15 patients before CIRT at the referral hospitals. All tumor sizes reported here are the postchemotherapy sizes.
|No. of tumors||48|
|Age: Median (range), y||54 (12–82)|
|Total radiation dose, GyE/16 fractions|
|Level of spine|
|Distance between tumor and spinal cord, mm|
|Median tumor volume, cm3||190|
|Tumor volume, cm3|
All 47 patients completed the prescribed CIRT. The median follow-up time was 25 months, and the median survival time was 44 months (range, 5.2-148 months). The 3-year and 5-year local control rates were identical at 79% (Fig. 1). Eight patients had local failure. Three of those 8 patients developed local failure inside the irradiated field at 5 months, 14 months, and 19 months. The patient who developed a local failure at 14 months received salvage CIRT, which controlled the recurrent tumor for 6 months. The other 2 patients died of disease. The remaining 5 patients experienced marginal recurrences, all of which developed at the boundary between the spinal cord and the tumor. We divided all lesions into 2 groups: 1 group with tumors located >5 mm distance from the spinal cord (n = 6 lesions) and another group with tumors located <5 mm distance from the spinal cord (n = 42 lesions). In these 2 groups, the 5-year local control rates were 100% and 75%, respectively. Although there was no significant difference in the local control rate between these groups (P = .1927), all of the 5 marginal recurrences occurred between the spinal cord and the tumor in the <5 mm group. None of the 15 patients who had tumors <100 cm3 developed local recurrence, whereas 8 of 33 patients who had tumors ≥100 cm3 developed local recurrence (P = .0194) (Fig. 2). Large tumors were close to the spinal cord more frequently than small tumors; 31 of 42 tumors located <5 mm from the spinal cord measured >100 cm3, whereas only 2 of 6 tumors located ≥5 mm from the spinal cord measured >100 cm3. There were no correlations between histologic subtypes and tumor volume.
Patients who received irradiation doses <64 GyE developed significantly more local recurrences than those who received ≥64 GyE (P = .0252). Tumor location components, such as spinal levels did not exhibit significant differences in terms of the local recurrence rate. The application of the patch-field technique, which was required when the tumor closely surrounded the spinal cord, did not affect the rate of local recurrence (P = .909). There was no significant difference in the local control rate between histologic subtypes (P = .668). Multivariate analysis did not identify any factors that affected local control.
The 3-year and 5-year overall survival rates were 59% and 52%, respectively (Fig. 1). Among the significant prognostic factors, performance status significantly affected overall survival rate between ECOG performance status of 1 and 2 (P = .0015). The prognosis for patients without previously treated tumors was significantly more favorable than that for patients with recurrent tumors (P = .0362). Patients who had smaller tumors (ie, <100 cm3/5.8 cm in greatest dimension) tended to survive longer (P = .1660).
The 3-year and 5-year progression-free survival rates were 48% and 44%, respectively, and 20 patients died over the entire observation period. Eighteen patients died of the disease. The remaining 2 patients died of intercurrent disease, and their causes of death were myocardial infarction and gastrointestinal bleeding, both of which were unrelated to the primary disease. These 2 patients were followed until death and demonstrated no recurrence on imaging studies. During follow-up, distant metastases were observed in 17 patients, most frequently in the lung (12 patients) and bone (4 patients). There was no correlation between the incidence of local recurrence and metastases (P = .8930).
Acute and late adverse reactions to CIRT were evaluated using the National Cancer Institute Common Toxicity Criteria, version 3.0, and the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer late radiation morbidity scoring scheme, respectively. No fatal toxicities occurred during follow-up. In the acute phase, 1 patient presented with a grade 3 irradiated skin reaction 1 month after ending irradiation; this condition subsequently improved, leaving pigmentation. One patient had a grade 3 late skin reaction. Another patient with a grade 4 late reaction developed a skin ulcer and required skin grafts.
Vertebral body compression was observed inside the irradiated field in 7 patients during follow-up: 1 involved cervical vertebrae, 2 involved thoracic vertebrae, and 4 involved lumbar vertebrae (see Fig. 3). Among these 7 patients, 4 were women and 3 were men. The median patient age was 59 years (range, 47-77 years). The median time to the start of compression changes was 14 months after CIRT (range, 4-23 months). All 7 patients who developed compression underwent fixation a median of 35 months after CIRT (range, 4-47 months). Although all patients underwent fixation, 1 patient retained weakness of the lower extremities, but the others had symptom improvement. Patients who received an irradiation dose of 70.4 GyE experienced significantly more compression fractures than those who received <70.4 GyE (P = .0331). There was no difference in the probability of compression between men and women.
There was 1 patient who presented with a grade 3 late reaction in the spinal cord. She was a woman aged 76 years who had a recurrent cervical level 6 (C6) chondrosarcoma after resection that revealed abnormal intensity at the spinal cord edge close to the tumor on T2-weighted MRI studies 16 months after irradiation without evidence of local recurrence. Her lower extremities gradually weakened, and she became dependent on a wheel chair 30 months after irradiation. A dose-volume histogram (DVH) of her spinal cord is provided in Figure 4 along with 2 other representative histograms from patients without myelopathy. The DVH from the woman with grade 3 myelopathy did not reveal more irradiated volume at a higher dose compared with the histograms from the patients without myelopathy. Aside from this patient, no others presented with severe adverse events.
With regard to ambulatory function, 22 of 28 patients who were alive at the last follow-up could walk without supportive devices. The median observed survival for those patients was between 5 months and 148 months (median: 35 months).
Radiotherapy has been used as either definitive or adjuvant therapy for patients with spinal and paraspinal sarcomas who are unsuitable candidates for curative resection. In most patients, the irradiation doses are constrained by the tolerable dose to the spinal cord. Although the dose constraint to the spinal cord is approximately 50 Gy using standard fractionation, Catton et al demonstrated that conventional radiotherapy with the delivery of 50 to 60 Gy did not provide long-term local control. Terezakis et al reported on 27 patients with partially resected/unresectable paraspinal sarcomas who received a median irradiation dose of 66 Gy in standard fractionation with IMRT. Their patients achieved 2-year local control and overall survival rates of 65% and 79%, respectively. Although the introduction of IMRT brought both a conformal dose distribution and slightly increased irradiation dosage, improvement of local control remained limited.
Charged particle therapies recently have attracted considerable attention, and some investigators have reported superior treatment outcomes and dose distribution compared with photon beam thearpy.[3, 6] However, there have been only a few reports on spinal tumors.[3, 4, 8] DeLaney et al reported on 50 patients with spinal sarcoma who received combined photon and proton radiotherapy. In that study, initial radical surgery was recommended with the intent of removing all gross tumors. Consequently, 25 patients underwent gross total resection, 12 underwent subtotal resection, and 13 only underwent biopsy. Preoperative and/or postoperative radiotherapy delivered up to a total of 77.4 Gy RBE. Those authors reported favorable 3-year and 5-year local control rates of 84% and 78%, respectively. There were no local failures among 8 patients (16%) who underwent complete (R0) resection. Of their patients, 34% received proton therapy for microscopic residual lesions, and 50% received proton therapy either for gross residual tumors after resection or for untreated tumors.
The results from our study, ie, a 5-year local control rate of 79%, demonstrated equivalent or superior outcomes to previously published data.[3, 4, 14] It is noteworthy that, compared with populations that underwent proton therapy as postoperative radiotherapy, irradiated tumor volumes were greater in our patients with unresectable disease. We conducted CIRT using mainly a dose of 4.0 GyE daily 4 days per week, for a total dose of 64 GyE, and a higher fraction dose was applied. Not considering the variety in the RBE of carbon ions, protons, and photon beams, when a linear-quadratic model is applied using α/β = 10 for tumor response and α/β = 3 for late toxicity, 64 Gy in 16 fractions could be equal to 74.7 Gy and 89.6 Gy using 2Gy daily fractions, respectively. All of the 5 marginal recurrences in our patients developed between the spinal cord and the tumor, as mentioned above. In those patients, the lesions were located <5 mm from the spinal cord, and the margins were reduced accordingly. It is possible that insufficient margins may be the cause of marginal recurrences, and this is a difficult problem in the treatment of spinal tumors. In patients with tumor-encircled spinal cord, we applied a patch-field technique to avoid high-dose spinal cord irradiation, which achieved a favorable local control rate equivalent to that of the other patients without severe adverse reactions (Table 2). Thus, for unresectable spinal sarcomas, our results indicate that CIRT represents a suitable curative treatment.
|Variable||No. With LR /Total No.||P|
|Tumor volume, cm3||.0194|
|Vertical tumor size, mm||.0064|
|Level of spine||NS|
|Distance between tumor and cord, mm||.1927 (NS)|
|Primary vs recurrent tumor||.1567 (NS)|
|Total irradiated dose, GyE||.0252|
There are a few reports concerning tolerance of the spinal cord to radiotherapy. DeLaney et al reported that the central spinal cord dose was limited to 54 Gy RBE at 1.8 RBE daily, and the cord surface dose was limited to 63 Gy RBE over a length of ≤5 cm. Regarding hypofractionated radiotherapy, Kirkpatrick et al reported that myelopathy was rare (<1%) when the maximum spinal cord dose was limited to the equivalent of 13 Gy in a single fraction or 20 Gy in 3 fractions. Applying a linear-quadratic model, those dosages could converted to 41.6 Gy and 38.7 Gy using 2Gy daily fractions and α/β = 3, respectively. Based on spinal cord DVHs from 3 patients (see Fig. 4), D0.1cc and D1cc of the spinal cord in the patient with grade 3 myelopathy were 24 GyE and 17 GyE, which could be converted to only 21.6 Gy and 13.8 Gy using 2Gy daily fractions, respectively. Conversely, D0.1cc and D1cc of the spinal cord in the 2 patients without spinal cord toxicity were 21 GyE and 9 GyE, respectively, in 1 patient and 29 GyE and 17 GyE, respectively, in the other. Actually, in the patient who had myelopathy, the DVH did not indicate that the spinal cord had been irradiated more than in the patients without myelopathy. Radiation-induced myelopathy is quite rare, and insufficient data are available to recommend a threshold for safety, as mentioned by Sahgal et al.
There were some technical problems related to applying precise doses to spinal sarcomas, especially for tumors with large vertical sizes along the spine. In such patients, physiologic spinal curves made a precise and steep dose distribution difficult along the close boundary between the tumor and the spinal cord. We had a 6-mm square multileaf collimator, which may be one of the reasons why the precise dose distribution was reduced. The cervical spine and upper thoracic spine have anatomic complexity close to both the scapula and the clavicular bones. These bones consist of joints with large range of motion, which would influence the reproducibility of irradiated fields. The anatomic instability may cause less reproducibility and may result in more irradiation to the spinal cord than expected. Another possible cause of the myelopathy is that the patient may have undergone prior surgery, with the result that the epidural space and thecal sac may have been adhesive. This adhesion could make blood circulation worse than that under normal conditions. This may be related to the cause of the myelopathy.
The challenges related to preserving the quality of life after CIRT remain important. In our study, as noted previously, 22 of 28 patients who were alive at the last follow-up could walk without supportive devices. The observed median survival for those patients was between 5 months and 148 months (median, 35 months). This result indicates that CIRT is both safe and feasible, although 88% of patients had tumors located <5 mm distance from the spinal cord.
In conclusion, although longer follow-up is still needed, the results from this study demonstrate that CIRT appears to be both effective and safe as a treatment for patients who have unresectable spinal sarcoma. In particular it will be useful for small tumors and tumors separated from the spinal cord.
This study was supported by the Heavy Ions Research Project at the National Institute of Radiological Sciences-Heavy Ion Medical Accelerator in Chiba (NIRS-HIMAC).
The authors made no disclosures.