Advanced-Technology Radiation Therapy for Bone Sarcomas

Samir Patel, MD; Thomas F. DeLaney, MD

Disclosures

Cancer Control. 2008;15(1):21-37. 

In This Article

Sarcomas of the Spine

Because of the proximity of the spinal cord, RT for treatment of sarcomas of the spine is constrained by the radiation tolerance of the spinal cord, which is well below that necessary to reliably control most sarcomas in the setting of close or positive margins[60] or gross residual disease.[61] The bone tumor histologies involving the spine include chondrosarcomas, chordomas, osteosarcomas,Ewing's sarcoma,malignant fibrous histiocytomas of bone, fibrosarcomas, and giant cell tumors.

Higher radiation doses to spine tumors and lower radiation doses to the spinal cord can now be delivered with the combination of intensity-modulated photon RT (IMRT), improved spine immobilization with body frames and/or spine tumor localization by in-treatmentroom image guidance, and fusion of computed tomographic and magnetic resonance images. The group at Memorial Sloan-Kettering reported their experience involving 14 patients with primary spine or paraspinal sarcomas treated with multifractionated stereotactic and image-guided IMRT coupled with noninvasive body frames.[62] In previously unirradiated patients, the median prescribed dose was 70 Gy (59.4 to 70 Gy) with a median planning target volume receiving the prescribed dose of 90%. The median dose maximum to the cord was 68% of the prescribed dose for previously unirradiated patients. Eighty-one percent of the primary lesions exhibited local control with 2 to 30 months of follow-up. No cases of radiation-induced myelopathy had been encountered to date. The investigators concluded that high-precision stereotactic and image-guided paraspinal IMRT allowed the delivery of high doses of radiation in multiple fractions to tumors within close proximity to the spinal cord while respecting cord tolerance. Although preliminary, the clinical results are encouraging.

Proton radiotherapy, with its ability to spare the spinal cord and/or cauda equina and adjacent normal tissues such as the kidney, lung, heart, esophagus, and bowel, offers advantages for treatment of tumors in this location. Isacsson et al[42] compared conformal RT treatment plans with photons and protons for a patient with a spinal Ewing's sarcoma. Even when only the final 20% of the treatment (the boost to the gross disease) was given with protons, the authors noted a 5% improvement in local control for a comparable predicted risk of spinal cord injury.

Hug et al[12] presented results on combined photon/ proton treatment of 47 patients with osteogenic and chondrogenic tumors of the axial skeleton. Radiation was delivered postoperatively in 23 patients, pre- and postoperatively in 17, and as sole treatment in 7 patients. Mean radiation doses of 73.9 (CGE), 69.8 CGE, and 61.8 CGE were delivered to group 1 (20 patients with recurrent/primary chordomas or chondrosarcomas), group 2 (15 patients with osteogenic sarcomas), and group 3 (12 patients with giant cell tumors, osteo- or chondroblastomas), respectively. The 5-year actuarial local control and survival rates for patients with chondrosarcomas were 100% and 100% and for those with chordomas were 53% and 50%, respectively. The actuarial 5-year local control rate for patients with osteosarcomas was 59%. The 5year actuarial local control and survival rates for the group 3 patients were 76% and 87%. Overall, improved local control was noted for primary vs recurrent tumors, gross total resection, and target doses >77 CGE.

The Massachusetts General Hospital (MGH) group recently reported on the results of treatment of 16 primary and 11 recurrent sacral chordoma patients managed with high-dose proton/photon treatment alone (6 patients) or combined with surgery (21 patients).[16] There was a large difference in local failure rate between patients treated for primary and recurrent chordomas. Local control results by surgery and radiation were 12 of 14 patients for primary vs 1 of 7 patients for recurrent lesions. Local control results in margin-negative patients were 2 of 3 in the primary group and 1 of 2 in the recurrent chordoma group. For the margin-positive patients, local control results were 10 of 11 and 0 of 5 in the primary and recurrent groups, respectively. Mean follow-up on these local control patients was 8.8 years (including 4 patients followed for 10.3, 12.8, 17, and 21 years). Radiation alone was used in 6 patients, 4 of whom received 73.0 CGE or more; local control was observed in 3 of these 4 patients for 2.9, 4.9, and 7.6 years. These data indicate a high local control rate for surgical and radiation treatment of primary (12 of 14) as distinct from recurrent (1 of 7) sacral chordomas. Three of 4 chordomas treated by 73.0 CGE or more of radiation without surgery had local control; 1 was at 91 months. This indicates that high-dose photon/proton therapy offers an effective treatment option for these patients (Fig 6A-B).

Axial (A) and sagittal (B) dose displays for a high-dose combined photon (30.6 Gy)/proton (46.8 CGE) irradiation plan delivering 77.4 CGE in 43 fractions via shrinking field technique for a patient who declined surgery for a chordoma involving the S3 vertebral body. Note the rapid falloff of dose away from the tumor target. The patient is currently free of progressive tumor or treatment complications 4 years after the end of treatment.

Results of a prospective phase II study of high-dose proton/photon radiation treatment with or without surgical resection of sarcomas of the thoracic/lumbar spine/sacrum and paraspinal soft tissues have been recently reported that included 50 patients entered between December 1997 and March 2005.[63] Forty-seven of the 50 patients had primary spine sarcomas and 3 patients had paraspinal tumors. Treatment consisted of maximal resection and photon (<50.4 Gy photon component)/proton radiotherapy; selected patients with high-grade tumors received chemotherapy. Doxorubicin was not given concurrent with RT. Shrinking field technique was used to deliver 50.4 CGE to subclinical microscopic disease, 70.2 CGE to residual microscopic disease in tumor bed, and 77.4 CGE to gross disease at 1.8 CGE daily Doses were reduced by 8% to 10% if chemotherapy was given or if diabetes or connective tissue disorders were present. For giant cell tumors or Ewing's sarcomas, doses did not exceed 61.2 CGE. The spinal cord dose was limited to 63 CGE at the surface and 54 CGE at the center. No specific dose constraint was placed on the cauda equina, but dose was limited to nerve roots and the side of the cauda contralateral to the tumor if possible. If surgery was performed at MGH, preoperative RT of 19.8 Gy (sacrococcygeal) or 50.4 Gy (thoracolumbar) was given. When possible, intraoperative dural brachytherapy boost was given with a customized [90] Y plaque.[7] The most common histologies were chordomas (29) and chondrosarcomas (14); the sacrum (26) was the most common anatomic site. Thirty-six patients were treated at the time of primary presentation and 14 were treated for tumor locally recurrent after prior surgery. As part of their treatment on protocol, 25 patients underwent gross total resection of their tumor, with positive margins in 17 patients and negative margins in 8 patients. Tumor was subtotally excised in 12 patients and just biopsied in 13 patients. For patients undergoing biopsy only, the median size of the tumor was 7 cm (median 3 to 20 cm). One patient chose to not complete RT for social reasons. Otherwise, RT was given per the protocol within 3% of the specified dose, with the shortfall driven by the spinal cord dose constraint. The median radiation dose was 76.6 CGE (range 59.4 to 77.4 CGE). Three patients received a 10-Gy boost to the dural surface with a [90] Y dural plaque.

With a median follow-up after start of RT of 34 months, 6 patients have had local tumor recurrence (4 chondrosarcomas and 2 chordomas, P=.016) to yield a 3-year actuarial local control rate of 87%. Two of the chondrosarcoma patients who recurred after proton RT had suffered 4 to 5 prior recurrences after previous surgeries performed without adjuvant RT, and 1 patient who had a dedifferentiated chondrosarcoma had experienced gross tumor cut-through at the time a prior surgical procedure at another institution. Patients who were treated with locally recurrent tumors after prior surgery were more likely to suffer another local recurrence — 4 of 14 vs 2 of 36 patients treated at the time of initial presentation, P=.013. Local control was the highest among the patients treated after gross total resection with negative margins — 8 of 8 vs 36 of 42 among patients with positive margins or gross residual tumor, P=.028. Actuarial overall survival at 5 years was 90%. Two of the locally recurrent patients with chondrosarcomas also developed distant metastases as did 4 other patients whose tumors were locally controlled. Four patients died of progressive tumor and 2 patients died of unrelated causes (cardiac death,oral tongue cancer). One patient was lost to follow-up. Acute grade 3 toxicity consisted of acute pain from a sacral stress fracture after preoperative RT and surgery without late sequelae. Late grade 3 toxicity occurred in 4 patients. This included 1 neuropathy at 5.5 years (left foot drop, right lower extremity weakness, poor rectal tone, stress urinary incontinence); 1 erectile dysfunction at 4 years unresponsive to sildenafil following 77.4 CGE to unresected sacral chordomas; a sacral stress fracture following a fall 3 months after delivery of 77.4 CGE that was managed with sacral nail fixation; and 1 rectal bleeding requiring transfusion following surgery and 70.4 CGE of RT for a sacral chordoma.

This experience demonstrates that high-dose photon/proton RT can be given to tumors involving the spine and paraspinal tissues. To date,morbidity appears to be acceptable. Although follow-up to date is still relatively short, encouraging results have been achieved with this treatment approach in a patient population with tumors that historically have been difficult to control. The high-dose photon/proton RT treatment plan of an 18-year-old woman with an unresected osteosarcoma of the sacrum treated by chemoradiation is shown in Fig 7. This patient remains free of tumor or radiation-associated complications over 4 years after the end of RT.

Axial dose display for the radiation treatment of an 18-year-old female with an unresected, upper sacral osteosarcoma treated with induction chemotherapy with cisplatin/doxorubicin alternating with high-dose methotrexate followed by ifosfamide/etoposide. Chemoradiation was then given with concurrent ifosfamide/etoposide and 70.2 CGE photons (18 Gy)/proton(52.2 CGE) radiation delivered by shrinking field technique. The clinical target volume (magenta) was treated to 50.4 CGE, and gross tumor volume (red) received 70.2 CGE. The 45 (green), 50 (yellow), 60 (blue), and 70 (turquoise) CGE radiation isodose lines are shown. The patient remains free of disease and any radiation-related treatment complications over 4 years after treatment. Note excellent sparing of small bowel with protons. From DeLaney TD, Kirsch DG. Bone and soft tissue. In: DeLaney TF, Kooy HM, eds. Proton and Charged Particle Radiotherapy. Philadelphia, Pa: Lippincott Williams & Wilkins; 2007:172-185. Reprinted with permission.

Intensity modulation can also be applied to proton beams (IMPT), potentially further optimizing the dose distribution. The unresolved question is whether this optimized physical dose distribution will be accompanied by an important clinical advantage. This cannot be answered by physical analysis alone, and clinical trials are needed to definitively answer this question. Dosimetric comparisons, however, demonstrate reductions in doses to normal tissues with IMPT that may prove to have a clinically significant impact on toxicity for the patient.

Lomax et al[33] compared the merits and limitations of IMRT and IMPT. The comparison suggested that the use of IMRT, when compared to IMPT, resulted in similar levels of conformality of dose around the tumor. However, compared to IMRT, IMPT substantially reduces the integral (normal tissue) dose to organs at risk.[43] At our institute, we undertook a dosimetric optimization effort to compare IMRT to IMPT in the treatment of spinal and paraspinal sarcomas.[43] Gross tumor volume coverage was excellent with both IMRT and IMPT plans. The use of IMPT led to a substantial reduction of the integral dose in the low- to mid-dose level to organs at risk (Fig 4). Median heart, lung, kidney, stomach, and liver mean dose and dose at the 50% volume level were consistently reduced by a factor of 1.3 to 25 compared with IMRT. In addition,IMPT dose escalation (85.1 and 92.9 CGE) was possible in all patients, within the specified normal tissue dose constraints.

IMPT with a spot scanning beam has been delivered for the boost component of treatment at the Paul Scherrer Institute in Switzerland.[56] Raster-scanned car-bon-ion RT is used to treat patients at GSI in Germany.[26]

Encouraging results have been achieved in 52 patients with tumors adjacent to and/or involving the cervical, thoracic, or lumbar spine who were treated between 1976 and 1987 with heavier-charged particle therapy at the University of California Lawrence Berkeley Laboratory.[64] Patients were treated with helium ions, which have physical dose-distribution advantages and biologic characteristics similar to protons; they were also treated with heavier neon ions, which are high LET particles that have excellent physical dose localization and also a higher RBE that might have additional biologic advantage against hypoxic or slowly proliferating tumors. The histologies included chordoma and chondrosarcomas in 24 patients, other bone and soft tissue sarcomas in 14, and metastatic or unusual histology tumors in 14. Radiation doses ranged from 29 to 80 CGE (median 70 CGE). Twenty-one patients received a portion of their treatment with photons. Median follow-up was 28 months. Local control was achieved in 21 (58%) of 36 previously untreated patients, and the 3-year actuarial survival rate was 61%. Seven of 16 patients treated for recurrent disease were locally controlled, and the 3-year actuarial survival was 51%. For patients treated for chordomas and chondrosarcomas, the probability of local control was influenced by tumor volume (less than 100 cc or greater than 150 cc) and whether disease was recurrent or previously untreated. Six of the 52 patients experienced complications including one spinal cord injury, 1 cauda equina, 1 brachial plexus injury, and 3 instances of skin or subcutaneous fibrosis.

Schoenthaler et al[55] from the same institute reported on 14 patients with sacral chordomas who were treated postoperatively; 10 had gross residual disease. The median dose was 75.65 CGE and the Kaplan-Meier survival rate at 5 years was 85%. The overall 5-year local control rate was 55%. A trend towards improved local control at 5 years was seen in patients treated with neon compared with patients treated with helium (62% vs 34%), in patients following complete resection compared with patients with gross residual tumor (75% vs 40%), and in patients who had treatment courses under 73 days (61% vs 21%). No patient developed neurologic sequelae or pain syndromes. One previously irradiated patient required a colostomy,1 had delayed wound healing following a negative postradiation biopsy, and 1 developed a second malignancy. There were no genitourinary complications. On the basis of that experience, the investigators concluded that additional evaluation of heavy charged particles was warranted.

Current interest in heavy charged particles is focused on carbon ions because of their excellent physical dose deposition and the higher RBE associated with their high LET. Kamada et al[25] reported the results of a phase I/II study evaluating the tolerance for and effectiveness of carbon-ion RT in patients with unresectable bone and soft tissue sarcomas treated on the Heavy Ion Medical Accelerator (HIMAC) at the National Institute of Radiological Sciences in Chiba, Japan. Fifty-seven patients with 64 sites of bone and soft tissue sarcomas not suited for resection were treated. Tumors involved the spine or paraspinous soft tissues in 19 patients, pelvis in 32 patients, and extremities in 6 patients. The total dose ranged from 52.8 to 73.6 carbon gray equivalent (GyE) and was administered in 16 fixed fractions over 4 weeks (3.3 to 4.6 CGE/fraction). Seven of 17 patients treated with the highest total dose of 73.6 CGE experienced Radiation Therapy Oncology Group grade 3 acute skin reactions. Dose escalation was then halted at this level. No other severe acute reactions (grade ≥3) were observed in this series. The overall local control rates were 88% at 1 year and 73% at 3 years of follow-up. The 1- and 3-year overall survival rates were 82% and 46%, respectively. A more recent report describes the successful treatment of a patient with a cervical osteosarcoma using carbon ions.[65]

Imai et al[66] reported a retrospective analysis of 30 patients with unresectable sacral chordomas treated with carbon-ion RT at HIMAC in Chiba, Japan. Twenty-three patients presented with no prior treatment, and the remaining 7 patients had locally recurrent disease following previous surgical resection. The median clinical target volume was 546 cm[3]. The applied carbon-ion dose ranged from 52.8 to 73.6 CGE (median 70.4) in 16 fractions over 4 weeks. At a median follow-up of 30 months (range 9 to 87 months), 26 patients were still alive and 24 patients remained continuously disease-free. Overall and cause-specific survival rates at 5 years were 52% and 94%, respectively. The overall local control rate at 5 years was 96%. Two patients experienced severe skin/soft tissue complications requiring skin grafts. No other treatment-related surgical interventions, including colostomy or urinary diversion, were carried out. All patients have remained ambulatory and able to stay at home after carbon-ion RT. These results suggest that carbon-ion RT is effective and safe in the management of patients with unresectable sacral chordomas and offers a promising alternative to surgery.

At GSI, 87 patients with chordomas and low-grade chondrosarcomas of the skull base received raster-scanned carbon-ion RT alone (median dose 60 CGE). Seventeen patients with spinal (n = 9) and sacrococcygeal (n = 8) chordomas and chondrosarcomas were treated with combined photon and carbon-ion RT. Actuarial 3-year local control rates were 81% for chordomas and 100% for chondrosarcomas.[26] Of these 17 patients, local control was obtained in 15 patients (8 with spinal and 7 with sacral chordomas or chondrosarcomas). Common Toxicity Criteria grade 4 or grade 5 toxicity was not observed. The investigators concluded that carbon-ion therapy was safe with respect to toxicity and offers high local control rates for skull base tumors such as chordomas and low-grade chondrosarcomas. Because of concern about potential late normal tissue effects with the higher LET/RBE carbon ions, further follow-up is warranted on these interesting results.

Osteoblastic metastases and osteosarcomas can avidly concentrate bone-seeking radiopharmaceuticals. High-dose [153] Samarium-ethylenediaminetetramethylenephosphonate ([153] Sm-EDTMP, Quadramet) has been evaluated for its efficacy against osteosarcomas,both alone[67] and in conjunction with using a radiosensitizer, gemcitabine.[68] Anderson et al[67] initially treated 30 patients with locally recurrent or metastatic osteosarcomas or skeletal metastases avid on bone scan with escalating doses (1, 3, 4.5, 6, 12, 19, or 30 mCi/kg) of [153] Sm-EDTMP. Transient symptoms of hypocalcemia were seen at 30 mCi/kg. Cytopenias also occurred in all subjects and were dose-related. After peripheral blood progenitor cells (PBPCs) or marrow infusion on day +14 after [153] Sm-EDTMP, recovery of hematopoiesis was problematic in 2 patients at the 30 mCi/kg dose infused with less than 2 × 10[6] CD34+/kg on day +14 but not in other patients. Reduction or elimination of opiates for pain was seen in all patients. Patients had no adverse changes in appetite or performance status. The authors believed that [153] Sm-EDTMP with PBPC support could provide bone-specific therapeutic irradiation (estimates of 39 to 241 Gy). Hematologic toxicity at 30 mCi [153] Sm-EDTMP/kg required PBPC grafts with more than 2 × 10[6] CD34+/kg to overcome the myeloablative effects of skeletal irradiation. Nonhematologic side effects were minimal.

These investigators later evaluated the addition of gemcitabine to this approach.[67] They used 30 mCi/kg [153] Sm-EDTMP to treat 14 patients with osteoblastic lesions. Gemcitabine was administered 1 day after samarium ([153] Sm) infusion. All patients received autologous stem cell reinfusion 2 weeks after [153] Sm to correct expected grade 4 hematopoietic toxicity. PBPCs were infused in 11 patients, and 3 patients had marrow infused. Blood count recovery was uneventful after PBPCs in 11 of 11 patients. Toxicity from a single infusion of gemcitabine (1,500 mg/m[2] ) in combination with [153] Sm-EDTMP was minimal (pancytopenia). However, toxicity from a daily gemcitabine regimen (250 mg/m[2] per day × 4 to 5 days) was excessive (grade 3 mucositis) in 1 of 2 patients. There were no reported episodes of hemorrhagic cystitis (hematuria) or nephrotoxicity. At the 6- to 8-week follow-up, there were 6 partial remissions, 2 mixed responses, and 6 patients with progressive disease. The investigators believed that this strategy of radioactive drug binding to a target followed by a radiosensitizer may provide synergy and improved response rate. Nevertheless, in the 12 patients followed for more than 1 year, there were no durable responses. Thus, although high-dose [153] Sm-EDTMP plus gemcitabine had moderate palliative activity (improved pain, radiologic responses) in this poor-risk population,additional measures of local and systemic control were thought to be necessary for durable control of relapsed osteosarcomas with osteoblastic lesions.

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