Module 5: Clinical Outcomes by Disease Site - The Use of Proton Therapy in the Treatment of Cancers of the Connective Tissues and Bone
Sarcomas, from the Greek word for flesh, sarx, are cancers of connective tissue. They therefore represent a broad category of tumor types arising from tissues such as bone, muscle, fat, and blood vessel. Because these tissues course throughout the body, sarcomas can arise in a variety of locations. They also are rare cancers, comprising around one percent of adult tumors. Given these factors, conclusive guidelines on how best to manage sarcomas are more limited compared to other disease sites and treatment approaches vary widely. In general, surgery is the cornerstone of treatment of adult sarcomas. Radiation is offered as 1) neoadjuvant or adjuvant therapy in cases posing a high risk of local recurrence or 2) to decrease treatment morbidity by facilitating surgical resection. Radiation can also serve as definitive treatment (used without surgery) when tumors are unresectable or in inoperable patients.
An overarching theme among sarcoma treatment and one of the rationales for applying proton therapy to their treatment is their empirical radio-resistance relative to some other tumor types. Proton radiation allows for dose escalation within the tumor to a greater degree than what is achievable with photon radiation, given the ability to better spare normal tissue with proton therapy. This module will aim to provide an overview of the use of proton radiation in management of various subtypes of adult sarcomas. Many pediatric sarcomas exhibit different behavior and are treated under separate paradigms, so therefore will be discussed in a separate module.
Osteosarcoma is a tumor of bone that traditionally affects both teenage children as well as older adults above age 55. Often chemotherapy is used as an initial treatment in intermediate and high risk cases and all patients should be evaluated for subsequent local therapy. While a complete resection is typically feasible for tumors in the extremity, cancers arising in the axial (central) skeleton and skull can be difficult or impossible to remove surgically. Therefore, radiation is often used either as adjuvant or definitive treatment in such cases. Early experiences from the Cooperative Osteosarcoma Study Group reported on their experience using definitive radiation with photons for osteosarcoma. They demonstrated local control rates less than 20% in spinal and pelvic osteosarcomas treating to doses of 30-56 Gy and 56-68 Gy, respectively. By contrast, escalating radiation dose has shown some promise, and this has been attempted with both proton and photon radiation. Only one large report exists evaluating the role of proton therapy to treat osteosarcoma, from Massachusetts General Hospital (MGH). Ciernik and colleagues retrospectively reviewed records of 55 patients treated for osteosarcoma with proton only or combined photon-proton plans from 1983-2009. The mean dose was 6480 cGy and <5% of patients were treated to less than 60 Gy. 3 and 5 year local control was 82% and 72%, respectively. Long term Grade 3-4 toxicity was high, having occurred in 30.1% of patients. However, technological advances in radiation planning and delivery in the modern day would likely be able to improve on these toxicity outcomes.
Chordoma and Chondrosarcoma
Chordomas and chondrosarcomas are rare tumors that present and behave similarly, and therefore are often discussed together. Because they are so rare, clinical trials in these diseases are scarce, with literature consisting mostly of single institution experiences and meta-analyses. Chondrosarcomas are tumors of cartilage and chordomas are tumors that arise from residual cells of the notochord—the primitive cartilaginous spine in a developing embryo. They most often present at the skull base, sacrum, or mobile spine, all locations that present many challenges to achieving a complete resection given the anatomic complexities and importance of these locations. Proton radiation improves our ability to treat chordomas and chondrosarcomas by allowing safer dose escalation while limiting dose to critical structures. Often, in particularly intricate areas, combined proton/photon plans are used to take advantage of the sharp dose gradients achievable with protons with the conformality of VMAT or IMRT.
A large prospective experience in spinal chordomas and chondrosarcomas from MGH treating with combined proton/photon radiation reported safe treatment to a median dose of 7660 cGy. 5 and 8 year local control were 94% and 85% in primary tumors, respectively, and the 8 year risk of grade 3-4 late toxicity was only 13%. Similar to osteosarcoma, these results are in contrast to earlier experiences treating such patients to lower doses with photon radiation. For example, Princess Margaret Hospital reported on their experience of 48 patients from 1958-1992 treated with photon radiation to a median dose of 50 Gy, who experienced median time to progression of only 35 months with this regimen. Similar findings were demonstrated in a combined analysis by Amichetti and colleagues of over 400 patients treated at various institutions with proton and photon therapy for chordoma. Generally, better outcomes with proton therapy versus photon therapy were reported in their systematic review. Regarding safety of this approach, a recent analysis from Massachusetts General Hospital and Rochester by Chowdhry and colleagues was conducted consisting of 68 patients, 79% of whom diagnosed with chordoma or chondrosarcoma. All patients were identified as being treated to doses of ≥5900 cGy in the region of the spinal cord. Actuarial freedom from neurological injury from any cause at 5 years, including disease progression and toxic effects from chemotherapy, was 92.9%. These results suggest that such dose escalation for spinal chordomas or chondrosarcomas can be achieved safely given nearby anatomic constraints.
Soft tissue sarcoma and retroperitoneal sarcoma
Soft tissue sarcomas are cancers arising from connective tissue excluding bone and cartilage. The term is a broad one, encompassing over one hundred distinct entities when categorized histologically. They commonly arise, in order of frequency, from the extremities (proximal leg more likely than arm), torso, retroperitoneum, and head and neck. The mainstay of treatment is surgical resection, often combined with radiation. As in other sarcomas, definitive radiation alone can be used to treat inoperable patients as well. In both cases, chemotherapy can play a role in the management as well in appropriate clinical contexts.
Regarding extremity (arm and leg) soft tissue sarcomas, to date there are no large reports specifically evaluating the use of proton therapy in its management. Given the high tolerance of structures in the extremity, photon radiation can often be safely administered and the dose-sparing effect of protons may not offer as much clinical benefit. However, for certain tumors of the proximal leg or torso, the sharp dose gradients of proton therapy may be of value. Fogliata and colleagues demonstrated a dosimetric benefit to protons compared to VMAT in terms of low dose spread to bone and soft tissues. The clinical consequence of this benefit is uncertain, but may be particularly relevant in the cases of reirradiation, in patients with known underlying disease of the blood vessels or bone within the treated limb, or when considering mitigating the possible risk of radiation-induced malignancy.
Retroperitoneal sarcomas are managed as a disease class of their own, given their unique anatomic considerations and differences in presentation compared to extremity of tissue sarcomas. The role of radiation in this disease is under investigation with conflicting results regarding its benefit on survival. Because of the proximity of retroperitoneal tumors to abdominal organs and kidneys, proponents of radiation have argued that adjuvant radiotherapy can enhance local control compared to surgery alone. Proton radiation may offer a unique benefit in this setting given the ability to deliver through posterior beams that limit dose to the anterior abdomen. This particular strategy may increase the therapeutic index of radiation in retroperitoneal sarcoma. The only published data available on proton radiation for retroperitoneal sarcoma is a dosimetric study that compared photon 3D conformal radiation, IMRT, and proton therapy in 8 patients with retroperitoneal sarcoma. Proton radiation compared to 3D conformal demonstrated lower doses to bowel (V15 16.4% vs. 66.1%) ipsilateral kidney (median dose 0 CGE versus 11 Gy), and contralateral kidney (median V5 0% versus 99.7%). All three modalities adequately spared meaningful doses to liver and spinal cord.
Evidence guiding treatment in sarcomas is limited by their low incidence in the population. Surgery and radiation are often used together for local control. This strategy is of particular importance in anatomically-intricate areas where a complete resection may not be feasible. Proton radiation offers the ability to escalate doses in relatively radio-resistant tumors, such as sarcomas, while limiting normal tissue toxicity, in some cases to a degree not previously achievable with photon-based radiation. We will await further prospective evaluation of proton radiation in the treatment of sarcomas.
1. Amichetti M, Cianchetti M, Amelio D, Enrici RM, Minniti G. Proton therapy in chordoma of the base of the skull: a systematic review. Neurosurg Rev. Oct 2009;32(4):403-416.
2. Catton C, O'Sullivan B, Bell R, et al. Chordoma: long-term follow-up after radical photon irradiation. Radiother Oncol. Oct 1996;41(1):67-72.
3. Chowdhry VK, Liu L, Goldberg S, et al. Thoracolumbar spinal cord tolerance to high dose conformal proton-photon radiation therapy. Radiother Oncol. Apr 2016;119(1):35-39.
4. Ciernik IF, Niemierko A, Harmon DC, et al. Proton-based radiotherapy for unresectable or incompletely resected osteosarcoma. Cancer. Oct 1 2011;117(19):4522-4530.
5. DeLaney TF, Liebsch NJ, Pedlow FX, et al. Long-term results of Phase II study of high dose photon/proton radiotherapy in the management of spine chordomas, chondrosarcomas, and other sarcomas. J Surg Oncol. Aug 2014;110(2):115-122.
6. DeLaney TF, Haas RL. Innovative radiotherapy of sarcoma: Proton beam radiation. Eur J Cancer. Jul 2016;62:112-123.
7. Fogliata A, Scorsetti M, Navarria P, et al. Dosimetric comparison between VMAT with different dose calculation algorithms and protons for soft-tissue sarcoma radiotherapy. Acta Oncol. Apr 2013;52(3):545-552.
8. Nussbaum DP, Rushing CN, Lane WO, et al. Preoperative or postoperative radiotherapy versus surgery alone for retroperitoneal sarcoma: a case-control, propensity score-matched analysis of a nationwide clinical oncology database. Lancet Oncol. Jul 2016;17(7):966-975.
9. Ozaki T, Flege S, Kevric M, et al. Osteosarcoma of the pelvis: experience of the Cooperative Osteosarcoma Study Group. J Clin Oncol. Jan 15 2003;21(2):334-341.
10. Ozaki T, Flege S, Liljenqvist U, et al. Osteosarcoma of the spine: experience of the Cooperative Osteosarcoma Study Group. Cancer. Feb 15 2002;94(4):1069-1077.
11. Swanson EL, Indelicato DJ, Louis D, et al. Comparison of three-dimensional (3D) conformal proton radiotherapy (RT), 3D conformal photon RT, and intensity-modulated RT for retroperitoneal and intra-abdominal sarcomas. International journal of radiation oncology, biology, physics. Aug 1 2012;83(5):1549-1557.