Author's Accepted Manuscript
Palliative Radiotherapy: Current Status and Future Directions Sonam Sharma MD, Lauren Hertan MD, MBA, Joshua Jones MD, MA
www.elsevier.de/endend
PII: DOI: Reference:
S0093-7754(14)00241-3 http://dx.doi.org/10.1053/j.seminoncol.2014.09.021 YSONC51764
To appear in:
Semin Oncol
Cite this article as: Sonam Sharma MD, Lauren Hertan MD, MBA, Joshua Jones MD, MA, Palliative Radiotherapy: Current Status and Future Directions, Semin Oncol, http://dx.doi.org/10.1053/j.seminoncol.2014.09.021 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Palliative Radiotherapy: Current Status and Future Directions
Sonam Sharma, MD, Lauren Hertan, MD, MBA, Joshua Jones, MD, MA
Department of Radiation Oncology
Hospital of the University of Pennsylvania
Corresponding Author:
Joshua Jones, MD, MA
Assistant Professor
Department of Radiation Oncology
Hospital of the University of Pennsylvania
3400 Civic Center Boulevard, TRC 2 West
Philadelphia, PA 19104
[email protected]
Abstract:
For nearly 100 years, palliative radiotherapy has been a time-efficient, effective treatment for patients with metastatic or advanced cancer in any area where local tumors are causing symptoms. Short courses including a single fraction of radiotherapy may be effective for symptom relief with minimal side effects and maximization of convenience for patient and family. With recent advances in imaging, surgery and other local therapies as well as systemic cancer therapies, palliative radiotherapy has become more frequently utilized in patients who may not yet have symptoms of advanced or metastatic cancer. In this setting, more prolonged radiotherapy courses and advanced radiotherapy techniques including intensity modulated radiotherapy or stereotactic radiotherapy may be useful in obtaining local control and durable palliative responses. This review will explore the use of radiotherapy across the spectrum of patients with advanced and metastatic cancer and delineate an updated, rational approach for the utilization of palliative radiotherapy that incorporates symptoms, prognosis and other factors into the delivery of palliative radiotherapy.
Since shortly after the discovery of the x-ray, radiotherapy has been utilized to palliate symptoms 1
of advanced cancer. Radiotherapy utilized for palliation of symptoms is distinct from radiotherapy delivered as curative treatment. As described by Parker in a treatise on palliative radiotherapy in JAMA in 1964, the ground rules for delivering palliative radiotherapy are different from the rules for delivering curative radiotherapy: with palliative radiotherapy, treatment time must be short, convenience and cost 2
must be considered and side effects of radiotherapy must be minimized. These basic principles have underscored many years of research and practice in palliative radiotherapy exploring different dosefractionation schemes to palliate symptoms. However, with advances in imaging and systemic therapies for cancer over the past 30 years, it is now possible to detect metastases that are progressing before these metastases cause symptoms. As such, van Oorschot and colleagues defined a classification scheme for palliative radiotherapy that differentiates palliative radiotherapy utilized for treatment of symptoms versus palliative radiotherapy utilized for management of signs of progressive cancer in Seminars in Oncology in 2011. The authors argue that with radiotherapy delivered for symptoms of advanced cancer, the principles of Parker still hold, but for the treatment of signs of progressive cancer (ie. a growing bone metastasis that is not yet symptomatic but possesses imaging characteristics concerning for impending pathologic fracture), longer courses of radiotherapy with higher doses and more conformal techniques may be warranted for local tumor control and modest side effects may be 3
warranted. Such an approach advances an approach to palliative radiotherapy that distinguishes between indications for short-course radiotherapy versus more prolonged courses; this review will explore the recent literature to provide an update on palliative radiotherapy and suggest a prognosis-driven approach to the utilization of palliative radiotherapy that complements the signs versus symptoms approach of van Oorschot.
Decision-making in palliative radiotherapy is a complex process that must involve patient and any individuals who support the patient in decision-making (often the family) as well as other medical team members, including a radiation oncologist, a medical oncologist, a surgeon or interventionalist, a primary care physician, a palliative care or hospice physician. Decisions about radiotherapy must incorporate patient prognosis; patient performance status and quality of life; patient and family overall goals for care; patient and family understanding of radiotherapy including potential benefits such as likelihood and
timeliness of efficacy as well as potential burdens including trips to and from the radiotherapy center and radiotherapy side effects; previous and planned treatments including radiotherapy, surgery and systemic therapies, alternatives to radiotherapy that may have similar effect on symptoms or local tumor control.
3
Such factors are, by definition, complex and must be individualized to each patient in each clinical situation.
4
It has been well-documented that clinicians are poor predictors of patient prognosis. In palliative radiotherapy, clinicians have traditionally not been better at estimating prognosis than colleagues in other areas of oncology.
5,6
However, over the past 10 years, a number of models to predict patient life
expectancy have been developed. Chow and colleagues examined a large cohort of patients referred for palliative radiotherapy and developed, then validated a predictive model that utilizes the number of risk 7
factors to determine prognosis. After collecting data on many variables including symptoms from the Edmonton Symptom Assessment Scale for 395 patients, the authors found that non-breast primary, metastases to sites other than bone, and Karnofsky Performance Status (KPS) 2.0 Gy per day, often 3 to 8 Gy per day), are commonly utilized in the treatment of patients with advanced cancer. The tradeoff is that hypofractionated radiotherapy allows patients to finish a course of radiotherapy more quickly, but based on the principles of radiobiology, carries a higher risk of long-term radiotherapy side effects. Higher doses per fraction can be utilized with highly conformal radiotherapy, including stereotactic radiotherapy (stereotactic radiosurgery or SRS – delivered in a single fraction, often to the brain, or fractionated stereotactic radiotherapy/stereotactic body radiotherapy or SBRT – delivered in multiple fractions). Such highly conformal radiotherapy requires extra time in planning and quality assurance and may lead to delays in the delivery of radiotherapy, but may improve local tumor control. See Table 3 for examples of radiotherapy doses commonly utilized in palliative radiotherapy.
Bone Metastases
Bone is a common site of metastatic disease in patients with cancer, with only liver and lung metastases being more common. The most common cancers (lung, breast and prostate) metastasize frequently to bone. Bone metastases can cause significant morbidity including significant pain, spinal cord compression, nerve root compression, hypercalcemia and bone metastases increase the risk of fracture. The ideal treatment requires multi-disciplinary coordination of care with medical oncologists, radiologists, radiation oncologists, orthopedic surgeons and palliative medicine specialists. The optimal treatment depends on the size and location of the metastasis, the burden of systemic disease, patient performance status, history of treatments and patient preference. Focal treatments may include some combination of surgical fixation, cryoablation, vertebroplasty/kyphoplasty for vertebral body metastases and external beam radiotherapy. Systemic treatment options for bone metastases include bone modifying agents including bisphosphonates and inhibitors of the RANK-ligand, opioid and non-opioid analgesics for pain, radiopharmaceuticals and histology-specific treatments, including chemotherapy, hormone therapies, targeted therapies and vaccine-based therapies.
16
Radiotherapy can provide successful palliation of
painful bone metastasis in up to 80% of patients treated with external beam radiation therapy (EBRT), with approximately 25%-35% of patients achieving complete pain relief at the treated site.
17
However,
international patterns of practice studies show significant variability in the dose and fractionation used for palliation.
18–22
Multiple studies have compared short course radiotherapy, often a single fraction of 8 Gy, with longer courses of radiation over several weeks for patients with uncomplicated bone metastases. Over the past 10 years, the evidence supporting the equivalence of a single 8 Gy fraction of radiotherapy to a multi-fraction course of radiotherapy for uncomplicated bone metastases has grown. Multiple high quality randomized controlled trials and systematic reviews (reviewed in detail by Chow and others) have demonstrated equivalence of single fraction with multi-fraction regimens with regard to pain response and without significant differences in acute or long-term toxicity, even among patients who live greater than one year after receipt of radiotherapy.
23
When controlled for size of the lytic component of the bone
metastasis, there was also no statistically significant difference between rates of pathologic fracture or
eventual spinal cord compression between single and multi-fraction treatments.
17
A re-analysis of the
RTOG 97-14 data demonstrated equivalence of pain relief between a single fraction of 8 Gy with 30 Gy in 10 fractions and no difference in spinal cord compression and the difference between the treatment modalities the retreatment rate (5% versus 15% with the majority of the retreatments over the lumbar spine).
24
The primary difference between single fraction and multi-fraction treatment for uncomplicated
bone metastases among all studies is retreatment rates, with approximately twice as many patients receiving retreatment in the single fraction arm as the multi-fraction arm.
17,25
The ASTRO guidelines
committee has concluded that regimens including 30 Gy in 10 fractions, 24 Gy in 6 fractions, 20 Gy in 5 fractions and 8 Gy in one fraction are equivalent in pain relief for uncomplicated bone metastases and that longer dose-fractionation schemes should not routinely be utilized for the management of uncomplicated bone metastases.
26
With similar pain responses between single and multi-fraction radiotherapy, several investigators have asked patients their preference for radiotherapy dose-fractionation in separate studies conducted in Australia, Singapore, and Canada. In Australia, Barton et al initially interviewed patients to understand which factors are important in decision-making and subsequently followed with surveys to patients pre and post treatment for bone metastases to see which factors they prioritize.
27
They found that durability of
pain relief was more important than speed of pain relief, and short-term „convenience‟ factors were of lesser importance. Corresponding with this, treatment effectiveness was considered much more important than treatment brevity. The Singapore study utilized a decision board summarizing the difference between single and multi-fraction radiotherapy for bone metastases based on the Dutch Bone Metastases 28
study.
Specifically the decision board reviewed the number of visits, estimated cost to patient,
probability of repeat treatment and probability of fracture based and provided this information to patients to assist with decision-making. Of 62 patients enrolled, 85% chose the multi-fraction arm with re-treatment rate the most prominent factor in decision-making. The 15% of patients who chose single fraction did so mostly for convenience (89%) and less likely for cost (11%). The authors found the majority of patients (84%) expressed positive views about being involved in the decision making process.
29
In the Canadian
study, 101 patients were given a similar decision board comparing single versus multi-fraction treatment. Seventy six percent of patients chose to participate in the decision-making process with an active or
collaborative role and the majority of those patients (76%) chose single fraction radiotherapy. The most common rationale for choosing single fraction radiotherapy was convenience and the most common rationale for multiple fraction radiotherapy was the described decreased fracture risk.
30
Given the data on the equivalence of single fraction versus multi-fraction radiotherapy for uncomplicated bone metastases, some have argued that the ongoing variations in clinical practice with longer dose-fractionation schemes for palliative radiotherapy for uncomplicated bone metastases, represent a global reluctance to practice evidence-based medicine.
31
However, many institutions are
exploring the role of highly conformal radiotherapy in the management of bone metastases as a way to deliver higher doses to the target tumor in a short course of therapy while minimizing dose to surrounding tissues. The most common area of exploration is stereotactic body radiotherapy for spine metastases. The University of Pittsburgh experience with treating spinal metastases with SBRT included 500 patients 32
followed prospectively, all treated with SBRT. The group found a high rate (86%) of long term pain improvement with a median follow-up of 21 months as well as long term tumor control (90% treated as primary modality and 88% treated for radiographic progression). In a review of the current literature on SBRT for spinal lesions (both malignant and benign), Sahgal et al found overall high levels of local 33
control, with variable follow up. The authors examined local control rates in four different categories of patients. In previously unirradiated patients with spinal metastases there was an 87% local control rate. In patients undergoing reirradiation, a 96% local control rate was noted, while in post-operative patients there was a 94% local control rate. In primary studies that did not distinguish between patients in the previous three categories, an 87% local control rate was noted. The ASTRO guidelines on the management of bone metastases suggests that highly conformal radiotherapy (stereotactic body radiotherapy, SBRT and intensity modulated radiotherapy, IMRT) be utilized in the context of a clinical trial.
26
One ongoing trial, RTOG 0631, compares stereotactic body radiotherapy, 16 Gy in one fraction, to
conventional external beam radiotherapy, 8 Gy in one fraction. The trial may impact recommendations for palliative radiotherapy for uncomplicated spine metastases.
34
Nonetheless, goals for therapy (pain
relief, local tumor control, remineralization, etc.) must be explicitly delineated for clinicians and patients to make appropriate decisions regarding radiotherapy for bone metastases.
Patients who have previously received radiotherapy for bone metastases who have recurrent pain or other indications for re-irradiation (ie. development of cord compression) present a unique challenge. As previously described, re-irradiation with stereotactic radiotherapy may spare normal tissues, potentially allowing re-irradiation near sites at risk for radiation toxicity due to cumulative dose of radiation. However, re-irradiation is also possible with conventional external beam radiotherapy as long as normal tissue tolerance is accounted for. Chow and colleagues recently found that, in the setting of re-irradiation, a single fraction is non-inferior to multifraction radiotherapy. They randomized 850 patients with painful bone metastases that had previously received radiation to either receive a single fraction (8Gy x 1) or multiple fractions (20 Gy in either 5 or 8 fractions, depending on location of metastases and previous RT). There was no difference in overall response rate by either the intent to treat (28% SF v. 32% MF) or perprotocol (45% SF v 51% MF). However, there was higher acute toxicity at 14 days after therapy in multiple fraction group (lack of appetite 56% SF v. 66% MF [p=0.011]; diarrhea 23% SF v 31% MF [p=0.018]; vomiting 13% SF v. 23% MF [p=0.001]; skin reddening 14% SF v. 24% MF [p=0.002]). In addition, there was no difference in pathologic fracture (7% SF v. 5% MF) or spinal cord compression (2% SF v. 3
15-30 x 2-3 Gy
months
1-5 x 6-24 Gy
Stereotactic radiotherapy, requiring advanced technologies, advanced immobilization; generally reserved for
patients with good performance status (KPS>70) with expected long prognosis and/or with few metastases; also used in the setting of re-irradiation *Per ASTRO Guidelines for management of uncomplicated bone metastases **Per ASTOR Guidelines for management of brain metastases *** Per ASTRO lung metastases guidelines
61
46
26
Table 4. Brief summary of open research questions in palliative radiotherapy
Questions in general palliative radiotherapy
How can patients/families be optimally integrated in shared decision making regarding decision to utilize radiotherapy, type of radiotherapy utilized and selection of appropriate dose-fractionation scheme? What patient populations with poor prognosis are better palliated with supportive care alone without utilization of radiotherapy? How can palliative radiotherapy be optimally integrated into palliative care clinics and how can palliative care providers be integrated into radiotherapy clinics?
Questions related to palliative radiotherapy for bone metastases:
What should highly conformal radiotherapy be utilized in palliation of uncomplicated bone metastases? What is the optimal dose-fractionation scheme for palliation of uncomplicated bone metastases for patients from tumors generally considered to be “radio-resistant” such as melanoma, renal cell carcinoma, sarcoma? What is the optimal dose-fractionation for complicated bone metastases (ie. Spinal cord or nerve root compression, status post pathologic fracture, etc.)? When should conformal radiotherapy be utilized in the management of spinal cord compression, both without surgical decompression and after surgical decompression?
Questions related to palliative radiotherapy for brain metastases
What criteria should be utilized for selection of patients with brain metastases to be treated with stereotactic radiotherapy without whole brain radiotherapy? (prognosis, histology, number and size of brain metastases, volume of brain metastases, etc.)
What is the role of hippocampal sparing whole brain radiotherapy and whole brain radiotherapy with simultaneous boost in the management of multiple brain metastases?
Questions related to palliative radiotherapy for primary or metastatic tumors causing obstructive symptoms, bleeding, pain
How is use of palliative stents (tracheal/bronchial, esophageal, biliary, intestinal, ureteral) optimally integrated with palliative radiotherapy? How is the use of palliative surgery optimally integrated with palliative radiotherapy? How should brachytherapy be integrated into the management of patients with lesions causing symptomatic obstruction? What prognostic models can help optimize dose-fractionation schemes and/or stereotactic radiotherapy for patients with symptomatic tumors where local control is also likely to be important? Is there a role for concurrent chemoradiotherapy in the palliation of advanced and metastatic tumors and what factors should impact the use of concurrent chemoradiotherapy in patients with good performance status in need of palliative radiotherapy?
Table 5. Model for prognosis-driven approach to the utilization of palliative radiotherapy
Treatment Options Uncomplicated Estimated prognosis*
Bone Metastases
Primary or Spinal Cord
One to Three
Multiple Brain
symptomatic
Compression
Brain Metastases
Metastases (>3)
metastatic lung lesions
Supportive care alone Short course RT
Short course RT
Prognosis 4 cm and
WBRT alone
fraction or 17 Gy
fraction or 20 Gy fraction)
unresectable)
in 2 fractions one
in 5 fractions) week apart) Prognosis >3
Higher dose RT
Higher dose RT Surgery (if
months
(20-30 Gy in 510 fractions for large lytic lesions, soft tissue mass, neuropathic
Higher dose RT
(>30 Gy in 10 Surgery and
accessible,
post-op WBRT or
symptomatic
post-op
and lesion >4
radiosurgery or
cm) and post-op
both
WBRT or
(30 Gy in 10
fractions) with
fractions, 35 Gy
goal of
in 14 fractions,
moderately
40 Gy in 20
increased
fractions)
survival at cost of radiosurgery
pain)
side effects
Surgical Surgical
Intraluminal
stabilization with decompression post-op RT if
brachytherapy or Radiosurgery
Radiosurgery
and WBRT
and WBRT
and post-op RT high risk for
re-irradiation for
if surgical
locally recurrent
candidate
disease
pathologic fracture Radiosurgery alone or Radiosurgery fractionated alone stereotactic RT alone Systemic therapies including chemotherapy, targeted therapies, hormone therapies when appropriate; may be used with RT or in place of RT if further RT cannot be safely delivered Pain medication including NSAIDs, steroids, opioids, neuropathic adjuvants Opioids and Potential
Radiopharmaceuticals for
adjuvant
widespread painful and osteoblastic
therapies
bone metastases
Corticosteroids for edema, anti-
other
epileptics as indicated
medications for air hunger
Bisphosphonates or RANK-L
Endobronchial
inhibitors
stenting
Nerve root injection
* Prognosis based on prognostic models described in the text, including Chow model for patients referred for palliative radiotherapy, Rades model for patients with spinal cord compression and any of several models (RPA, GPA) for patients with brain metastases
Palliative Radiotherapy: Current Status and Future Directions Sonam Sharma MD, Lauren Hertan MD, MBA, Joshua Jones MD, MA
www.elsevier.de/endend
PII: DOI: Reference:
S0093-7754(14)00241-3 http://dx.doi.org/10.1053/j.seminoncol.2014.09.021 YSONC51764
To appear in:
Semin Oncol
Cite this article as: Sonam Sharma MD, Lauren Hertan MD, MBA, Joshua Jones MD, MA, Palliative Radiotherapy: Current Status and Future Directions, Semin Oncol, http://dx.doi.org/10.1053/j.seminoncol.2014.09.021 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Palliative Radiotherapy: Current Status and Future Directions
Sonam Sharma, MD, Lauren Hertan, MD, MBA, Joshua Jones, MD, MA
Department of Radiation Oncology
Hospital of the University of Pennsylvania
Corresponding Author:
Joshua Jones, MD, MA
Assistant Professor
Department of Radiation Oncology
Hospital of the University of Pennsylvania
3400 Civic Center Boulevard, TRC 2 West
Philadelphia, PA 19104
[email protected]
Abstract:
For nearly 100 years, palliative radiotherapy has been a time-efficient, effective treatment for patients with metastatic or advanced cancer in any area where local tumors are causing symptoms. Short courses including a single fraction of radiotherapy may be effective for symptom relief with minimal side effects and maximization of convenience for patient and family. With recent advances in imaging, surgery and other local therapies as well as systemic cancer therapies, palliative radiotherapy has become more frequently utilized in patients who may not yet have symptoms of advanced or metastatic cancer. In this setting, more prolonged radiotherapy courses and advanced radiotherapy techniques including intensity modulated radiotherapy or stereotactic radiotherapy may be useful in obtaining local control and durable palliative responses. This review will explore the use of radiotherapy across the spectrum of patients with advanced and metastatic cancer and delineate an updated, rational approach for the utilization of palliative radiotherapy that incorporates symptoms, prognosis and other factors into the delivery of palliative radiotherapy.
Since shortly after the discovery of the x-ray, radiotherapy has been utilized to palliate symptoms 1
of advanced cancer. Radiotherapy utilized for palliation of symptoms is distinct from radiotherapy delivered as curative treatment. As described by Parker in a treatise on palliative radiotherapy in JAMA in 1964, the ground rules for delivering palliative radiotherapy are different from the rules for delivering curative radiotherapy: with palliative radiotherapy, treatment time must be short, convenience and cost 2
must be considered and side effects of radiotherapy must be minimized. These basic principles have underscored many years of research and practice in palliative radiotherapy exploring different dosefractionation schemes to palliate symptoms. However, with advances in imaging and systemic therapies for cancer over the past 30 years, it is now possible to detect metastases that are progressing before these metastases cause symptoms. As such, van Oorschot and colleagues defined a classification scheme for palliative radiotherapy that differentiates palliative radiotherapy utilized for treatment of symptoms versus palliative radiotherapy utilized for management of signs of progressive cancer in Seminars in Oncology in 2011. The authors argue that with radiotherapy delivered for symptoms of advanced cancer, the principles of Parker still hold, but for the treatment of signs of progressive cancer (ie. a growing bone metastasis that is not yet symptomatic but possesses imaging characteristics concerning for impending pathologic fracture), longer courses of radiotherapy with higher doses and more conformal techniques may be warranted for local tumor control and modest side effects may be 3
warranted. Such an approach advances an approach to palliative radiotherapy that distinguishes between indications for short-course radiotherapy versus more prolonged courses; this review will explore the recent literature to provide an update on palliative radiotherapy and suggest a prognosis-driven approach to the utilization of palliative radiotherapy that complements the signs versus symptoms approach of van Oorschot.
Decision-making in palliative radiotherapy is a complex process that must involve patient and any individuals who support the patient in decision-making (often the family) as well as other medical team members, including a radiation oncologist, a medical oncologist, a surgeon or interventionalist, a primary care physician, a palliative care or hospice physician. Decisions about radiotherapy must incorporate patient prognosis; patient performance status and quality of life; patient and family overall goals for care; patient and family understanding of radiotherapy including potential benefits such as likelihood and
timeliness of efficacy as well as potential burdens including trips to and from the radiotherapy center and radiotherapy side effects; previous and planned treatments including radiotherapy, surgery and systemic therapies, alternatives to radiotherapy that may have similar effect on symptoms or local tumor control.
3
Such factors are, by definition, complex and must be individualized to each patient in each clinical situation.
4
It has been well-documented that clinicians are poor predictors of patient prognosis. In palliative radiotherapy, clinicians have traditionally not been better at estimating prognosis than colleagues in other areas of oncology.
5,6
However, over the past 10 years, a number of models to predict patient life
expectancy have been developed. Chow and colleagues examined a large cohort of patients referred for palliative radiotherapy and developed, then validated a predictive model that utilizes the number of risk 7
factors to determine prognosis. After collecting data on many variables including symptoms from the Edmonton Symptom Assessment Scale for 395 patients, the authors found that non-breast primary, metastases to sites other than bone, and Karnofsky Performance Status (KPS) 2.0 Gy per day, often 3 to 8 Gy per day), are commonly utilized in the treatment of patients with advanced cancer. The tradeoff is that hypofractionated radiotherapy allows patients to finish a course of radiotherapy more quickly, but based on the principles of radiobiology, carries a higher risk of long-term radiotherapy side effects. Higher doses per fraction can be utilized with highly conformal radiotherapy, including stereotactic radiotherapy (stereotactic radiosurgery or SRS – delivered in a single fraction, often to the brain, or fractionated stereotactic radiotherapy/stereotactic body radiotherapy or SBRT – delivered in multiple fractions). Such highly conformal radiotherapy requires extra time in planning and quality assurance and may lead to delays in the delivery of radiotherapy, but may improve local tumor control. See Table 3 for examples of radiotherapy doses commonly utilized in palliative radiotherapy.
Bone Metastases
Bone is a common site of metastatic disease in patients with cancer, with only liver and lung metastases being more common. The most common cancers (lung, breast and prostate) metastasize frequently to bone. Bone metastases can cause significant morbidity including significant pain, spinal cord compression, nerve root compression, hypercalcemia and bone metastases increase the risk of fracture. The ideal treatment requires multi-disciplinary coordination of care with medical oncologists, radiologists, radiation oncologists, orthopedic surgeons and palliative medicine specialists. The optimal treatment depends on the size and location of the metastasis, the burden of systemic disease, patient performance status, history of treatments and patient preference. Focal treatments may include some combination of surgical fixation, cryoablation, vertebroplasty/kyphoplasty for vertebral body metastases and external beam radiotherapy. Systemic treatment options for bone metastases include bone modifying agents including bisphosphonates and inhibitors of the RANK-ligand, opioid and non-opioid analgesics for pain, radiopharmaceuticals and histology-specific treatments, including chemotherapy, hormone therapies, targeted therapies and vaccine-based therapies.
16
Radiotherapy can provide successful palliation of
painful bone metastasis in up to 80% of patients treated with external beam radiation therapy (EBRT), with approximately 25%-35% of patients achieving complete pain relief at the treated site.
17
However,
international patterns of practice studies show significant variability in the dose and fractionation used for palliation.
18–22
Multiple studies have compared short course radiotherapy, often a single fraction of 8 Gy, with longer courses of radiation over several weeks for patients with uncomplicated bone metastases. Over the past 10 years, the evidence supporting the equivalence of a single 8 Gy fraction of radiotherapy to a multi-fraction course of radiotherapy for uncomplicated bone metastases has grown. Multiple high quality randomized controlled trials and systematic reviews (reviewed in detail by Chow and others) have demonstrated equivalence of single fraction with multi-fraction regimens with regard to pain response and without significant differences in acute or long-term toxicity, even among patients who live greater than one year after receipt of radiotherapy.
23
When controlled for size of the lytic component of the bone
metastasis, there was also no statistically significant difference between rates of pathologic fracture or
eventual spinal cord compression between single and multi-fraction treatments.
17
A re-analysis of the
RTOG 97-14 data demonstrated equivalence of pain relief between a single fraction of 8 Gy with 30 Gy in 10 fractions and no difference in spinal cord compression and the difference between the treatment modalities the retreatment rate (5% versus 15% with the majority of the retreatments over the lumbar spine).
24
The primary difference between single fraction and multi-fraction treatment for uncomplicated
bone metastases among all studies is retreatment rates, with approximately twice as many patients receiving retreatment in the single fraction arm as the multi-fraction arm.
17,25
The ASTRO guidelines
committee has concluded that regimens including 30 Gy in 10 fractions, 24 Gy in 6 fractions, 20 Gy in 5 fractions and 8 Gy in one fraction are equivalent in pain relief for uncomplicated bone metastases and that longer dose-fractionation schemes should not routinely be utilized for the management of uncomplicated bone metastases.
26
With similar pain responses between single and multi-fraction radiotherapy, several investigators have asked patients their preference for radiotherapy dose-fractionation in separate studies conducted in Australia, Singapore, and Canada. In Australia, Barton et al initially interviewed patients to understand which factors are important in decision-making and subsequently followed with surveys to patients pre and post treatment for bone metastases to see which factors they prioritize.
27
They found that durability of
pain relief was more important than speed of pain relief, and short-term „convenience‟ factors were of lesser importance. Corresponding with this, treatment effectiveness was considered much more important than treatment brevity. The Singapore study utilized a decision board summarizing the difference between single and multi-fraction radiotherapy for bone metastases based on the Dutch Bone Metastases 28
study.
Specifically the decision board reviewed the number of visits, estimated cost to patient,
probability of repeat treatment and probability of fracture based and provided this information to patients to assist with decision-making. Of 62 patients enrolled, 85% chose the multi-fraction arm with re-treatment rate the most prominent factor in decision-making. The 15% of patients who chose single fraction did so mostly for convenience (89%) and less likely for cost (11%). The authors found the majority of patients (84%) expressed positive views about being involved in the decision making process.
29
In the Canadian
study, 101 patients were given a similar decision board comparing single versus multi-fraction treatment. Seventy six percent of patients chose to participate in the decision-making process with an active or
collaborative role and the majority of those patients (76%) chose single fraction radiotherapy. The most common rationale for choosing single fraction radiotherapy was convenience and the most common rationale for multiple fraction radiotherapy was the described decreased fracture risk.
30
Given the data on the equivalence of single fraction versus multi-fraction radiotherapy for uncomplicated bone metastases, some have argued that the ongoing variations in clinical practice with longer dose-fractionation schemes for palliative radiotherapy for uncomplicated bone metastases, represent a global reluctance to practice evidence-based medicine.
31
However, many institutions are
exploring the role of highly conformal radiotherapy in the management of bone metastases as a way to deliver higher doses to the target tumor in a short course of therapy while minimizing dose to surrounding tissues. The most common area of exploration is stereotactic body radiotherapy for spine metastases. The University of Pittsburgh experience with treating spinal metastases with SBRT included 500 patients 32
followed prospectively, all treated with SBRT. The group found a high rate (86%) of long term pain improvement with a median follow-up of 21 months as well as long term tumor control (90% treated as primary modality and 88% treated for radiographic progression). In a review of the current literature on SBRT for spinal lesions (both malignant and benign), Sahgal et al found overall high levels of local 33
control, with variable follow up. The authors examined local control rates in four different categories of patients. In previously unirradiated patients with spinal metastases there was an 87% local control rate. In patients undergoing reirradiation, a 96% local control rate was noted, while in post-operative patients there was a 94% local control rate. In primary studies that did not distinguish between patients in the previous three categories, an 87% local control rate was noted. The ASTRO guidelines on the management of bone metastases suggests that highly conformal radiotherapy (stereotactic body radiotherapy, SBRT and intensity modulated radiotherapy, IMRT) be utilized in the context of a clinical trial.
26
One ongoing trial, RTOG 0631, compares stereotactic body radiotherapy, 16 Gy in one fraction, to
conventional external beam radiotherapy, 8 Gy in one fraction. The trial may impact recommendations for palliative radiotherapy for uncomplicated spine metastases.
34
Nonetheless, goals for therapy (pain
relief, local tumor control, remineralization, etc.) must be explicitly delineated for clinicians and patients to make appropriate decisions regarding radiotherapy for bone metastases.
Patients who have previously received radiotherapy for bone metastases who have recurrent pain or other indications for re-irradiation (ie. development of cord compression) present a unique challenge. As previously described, re-irradiation with stereotactic radiotherapy may spare normal tissues, potentially allowing re-irradiation near sites at risk for radiation toxicity due to cumulative dose of radiation. However, re-irradiation is also possible with conventional external beam radiotherapy as long as normal tissue tolerance is accounted for. Chow and colleagues recently found that, in the setting of re-irradiation, a single fraction is non-inferior to multifraction radiotherapy. They randomized 850 patients with painful bone metastases that had previously received radiation to either receive a single fraction (8Gy x 1) or multiple fractions (20 Gy in either 5 or 8 fractions, depending on location of metastases and previous RT). There was no difference in overall response rate by either the intent to treat (28% SF v. 32% MF) or perprotocol (45% SF v 51% MF). However, there was higher acute toxicity at 14 days after therapy in multiple fraction group (lack of appetite 56% SF v. 66% MF [p=0.011]; diarrhea 23% SF v 31% MF [p=0.018]; vomiting 13% SF v. 23% MF [p=0.001]; skin reddening 14% SF v. 24% MF [p=0.002]). In addition, there was no difference in pathologic fracture (7% SF v. 5% MF) or spinal cord compression (2% SF v. 3
15-30 x 2-3 Gy
months
1-5 x 6-24 Gy
Stereotactic radiotherapy, requiring advanced technologies, advanced immobilization; generally reserved for
patients with good performance status (KPS>70) with expected long prognosis and/or with few metastases; also used in the setting of re-irradiation *Per ASTRO Guidelines for management of uncomplicated bone metastases **Per ASTOR Guidelines for management of brain metastases *** Per ASTRO lung metastases guidelines
61
46
26
Table 4. Brief summary of open research questions in palliative radiotherapy
Questions in general palliative radiotherapy
How can patients/families be optimally integrated in shared decision making regarding decision to utilize radiotherapy, type of radiotherapy utilized and selection of appropriate dose-fractionation scheme? What patient populations with poor prognosis are better palliated with supportive care alone without utilization of radiotherapy? How can palliative radiotherapy be optimally integrated into palliative care clinics and how can palliative care providers be integrated into radiotherapy clinics?
Questions related to palliative radiotherapy for bone metastases:
What should highly conformal radiotherapy be utilized in palliation of uncomplicated bone metastases? What is the optimal dose-fractionation scheme for palliation of uncomplicated bone metastases for patients from tumors generally considered to be “radio-resistant” such as melanoma, renal cell carcinoma, sarcoma? What is the optimal dose-fractionation for complicated bone metastases (ie. Spinal cord or nerve root compression, status post pathologic fracture, etc.)? When should conformal radiotherapy be utilized in the management of spinal cord compression, both without surgical decompression and after surgical decompression?
Questions related to palliative radiotherapy for brain metastases
What criteria should be utilized for selection of patients with brain metastases to be treated with stereotactic radiotherapy without whole brain radiotherapy? (prognosis, histology, number and size of brain metastases, volume of brain metastases, etc.)
What is the role of hippocampal sparing whole brain radiotherapy and whole brain radiotherapy with simultaneous boost in the management of multiple brain metastases?
Questions related to palliative radiotherapy for primary or metastatic tumors causing obstructive symptoms, bleeding, pain
How is use of palliative stents (tracheal/bronchial, esophageal, biliary, intestinal, ureteral) optimally integrated with palliative radiotherapy? How is the use of palliative surgery optimally integrated with palliative radiotherapy? How should brachytherapy be integrated into the management of patients with lesions causing symptomatic obstruction? What prognostic models can help optimize dose-fractionation schemes and/or stereotactic radiotherapy for patients with symptomatic tumors where local control is also likely to be important? Is there a role for concurrent chemoradiotherapy in the palliation of advanced and metastatic tumors and what factors should impact the use of concurrent chemoradiotherapy in patients with good performance status in need of palliative radiotherapy?
Table 5. Model for prognosis-driven approach to the utilization of palliative radiotherapy
Treatment Options Uncomplicated Estimated prognosis*
Bone Metastases
Primary or Spinal Cord
One to Three
Multiple Brain
symptomatic
Compression
Brain Metastases
Metastases (>3)
metastatic lung lesions
Supportive care alone Short course RT
Short course RT
Prognosis 4 cm and
WBRT alone
fraction or 17 Gy
fraction or 20 Gy fraction)
unresectable)
in 2 fractions one
in 5 fractions) week apart) Prognosis >3
Higher dose RT
Higher dose RT Surgery (if
months
(20-30 Gy in 510 fractions for large lytic lesions, soft tissue mass, neuropathic
Higher dose RT
(>30 Gy in 10 Surgery and
accessible,
post-op WBRT or
symptomatic
post-op
and lesion >4
radiosurgery or
cm) and post-op
both
WBRT or
(30 Gy in 10
fractions) with
fractions, 35 Gy
goal of
in 14 fractions,
moderately
40 Gy in 20
increased
fractions)
survival at cost of radiosurgery
pain)
side effects
Surgical Surgical
Intraluminal
stabilization with decompression post-op RT if
brachytherapy or Radiosurgery
Radiosurgery
and WBRT
and WBRT
and post-op RT high risk for
re-irradiation for
if surgical
locally recurrent
candidate
disease
pathologic fracture Radiosurgery alone or Radiosurgery fractionated alone stereotactic RT alone Systemic therapies including chemotherapy, targeted therapies, hormone therapies when appropriate; may be used with RT or in place of RT if further RT cannot be safely delivered Pain medication including NSAIDs, steroids, opioids, neuropathic adjuvants Opioids and Potential
Radiopharmaceuticals for
adjuvant
widespread painful and osteoblastic
therapies
bone metastases
Corticosteroids for edema, anti-
other
epileptics as indicated
medications for air hunger
Bisphosphonates or RANK-L
Endobronchial
inhibitors
stenting
Nerve root injection
* Prognosis based on prognostic models described in the text, including Chow model for patients referred for palliative radiotherapy, Rades model for patients with spinal cord compression and any of several models (RPA, GPA) for patients with brain metastases
