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Too Much, Too Little, or Just the Right Amount: Finding the Balance in Palliative Radiotherapy
Too Much, Too Little, or Just the Right Amount: Finding the Balance in Palliative Radiotherapy ince shortly after the discovery of the X-ray in 1896, radiation therapy has been used effectively in the treatment of patients with cancer with two discrete rationales: to palliate symptoms and to eradicate disease. Early on, it was recognized that short courses, even single doses of radiation, could relieve pain, stop bleeding, and alleviate other symptoms of advanced cancer. In the 1930s, the discovery that dividing the dose into small daily fractions delivered over a period of weeks would exploit the differences between normal tissues and malignant cells, allowing high (tumoricidal) doses to be delivered to the tumor while sparing normal tissues from the late effects of radiation therapy, increasing the chance of tumor control in certain malignancies.1 More recently, advances in imaging (computed tomography-guided 3D planning, positron-emission tomography, magnetic resonance imaging) and in physics (intensity modulation) have allowed radiation oncologists to target malignant cells more precisely, sparing normal tissues in space as well as in time.2 It is now possible to deliver large doses of highly conformal radiation to malignant cells while sparing normal tissues and limiting acute and late side effects. In certain clinical circumstances in patients with advanced cancer, such as when a patient is young and has a single brain metastasis, good performance status, and no extracranial disease, these highly conformal radiation techniques have been shown to improve survival in patients with metastatic disease.3 Such advances have led to a new category of radiotherapy: palliative therapy that also has the opportunity to improve survival (sometimes referred to as “aggressive palliation”). In this setting, the overall trend for research into palliative radiotherapy presented at American Society of Radiation Oncology (ASTRO) over the past 10 years has been increasingly to focus on advanced techniques to deliver higher doses with more focus on local tumor control and overall survival.4
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When radiotherapy is used palliatively, even in this modern era and even if the patient may survive a few weeks longer, it is still understood that the patient will ultimately die of his or her disease. The goals of palliative radiation, therefore, must be optimal relief from burdensome symptoms with the fewest side effects possible, minimizing inconvenience and maximizing quality of life in these patients with limited life expectancy. With this goal in mind, there have been numerous attempts to tailor radiotherapy to life expectancy. When Gripp and colleagues adapted palliative radiotherapy treatments to anticipated life expectancy in a cohort of patients with anticipated short survival,5 their effort was a valiant attempt at moving the field of palliative radiotherapy forward. However, they, as with all previous researchers, were unable to predict life expectancy accurately. The science of prognostication in advanced cancer remains inexact.6 Often, physicians overestimate (sometimes dramatically) the survival of their patients with advanced cancer. Within radiation oncology, particularly with the recent technological advances, this may lead to overtreatment of patients. As Hartsell lamented in his editorial accompanying the Gripp study, we are still not able to prognosticate patient survival well enough to tailor the radiotherapy regimen to the individual patient.7 Traditional palliative radiotherapy approaches are effective in that they may use a single treatment or a few treatments with few acute side effects.8 As survival for patients with metastatic cancer increases, some are arguing for longer courses of initial palliative radiotherapy treatments in an attempt to avoid the challenges of retreating areas that could be subject to devastating late consequences from tumor recurrence or late radiation injury. For example, Rades et al. have conducted several retrospective and prospective studies in an attempt to optimize treatment for metastatic spinal cord compression. In the most recent prospective study, they compared short- and long-course palliative radiotherapy for metastatic spinal cord compression.9 Although short-term relief of symptoms and survival were similar, the long-course radiotherapy treatments had more durable local control, decreasing the necessity for retreatment and possible exposure to radiotherapy that exceeds spinal cord tolerance. On the other end of the spectrum, the decision about when to proceed with radiation therapy (vs palliative care without radiotherapy) is also complicated by questions of prognosis and the balance between potential benefits and risks to the patient.10 For example, when death is imminent, the beneficial effects of radiotherapy, which may take weeks to become manifest, are outweighed by the poor prognosis of the patient. As with all clinical situations, when the patient is alert and not actively dying, 326
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perhaps the most important tool at the disposal of the radiation oncologist and the entire treatment team is the critical conversation with the patient and the patient’s caregivers about the potential risks, benefits, and alternatives to palliative radiotherapy in the management of symptomatic advanced cancer. For example, a parent with young children may be apt to request aggressive care with a goal of spending more time with family, even knowing that there may be more side effects with treatment and that survival may not be impacted. The only way to understand these goals in the context of possible treatment regimens is to have these difficult conversations (communication in palliative care is reviewed in detail by Baumann in this issue of Current Problems in Cancer). Given its efficacy, safety, and efficiency, any patient with symptomatic malignant disease should be considered a candidate for palliative radiation therapy. There have been multiple reviews that detail specific indications for palliative radiotherapy.8,10 Table 1 lists the major indications for radiotherapy based on symptom and site of disease. Rather than attempting to review every indication for palliative radiotherapy, the remainder of this review clarifies some of the factors that may influence the decision to pursue aggressive palliative radiotherapy, short-course palliative radiotherapy, or palliative care without radiotherapy in a few common clinical scenarios. Table 2 describes some of the competing factors that influence the decisions regarding aggressive vs palliative vs no radiotherapy treatments.
Palliative Radiotherapy to the Brain Brain metastases can present with headaches, seizures, mental status changes, focal weakness, or ataxia among other signs and symptoms. Treatment options for brain metastases may include any combination of best supportive care, whole brain radiotherapy (with or without systemic therapy and/or radiosensitizers), stereotactic radiosurgery, and surgical resection. The role of surgery followed by whole brain radiotherapy in improving both survival and functional independence and decreasing local recurrence compared with biopsy and whole brain radiotherapy was demonstrated by Patchell et al. in 1990.11 However, the standard of care for more than 1 symptomatic brain metastasis remained whole brain radiotherapy. The morbidity of severe neurologic compromise and mortality associated with newly diagnosed and recurrent brain metastases led the Radiation Therapy Oncology Group (RTOG) to conduct a series of trials to evaluate different dose/fractionation schedules for whole brain radioCurr Probl Cancer, November/December 2011
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TABLE 1. Indications for palliative radiotherapy by symptom type and site of disease Pain from: Bone metastases Visceral metastases Recurrent tumor at primary disease site Splenomegaly (hematologic malignancies) Neurologic symptoms (ie, headache, seizure, weakness, paresthesia, etc) from: Brain metastases Spinal cord compression Brachial or lumbosacral plexopathy from tumor involvement Bleeding from: Hemoptysis from malignancy within the lung Hematemesis from esophageal or gastric cancer Mucosal bleeding from head and neck or GYN malignancies Hematuria from cancer involving genitourinary malignancies Respiratory symptoms, including: Cough or shortness of breath from malignancy (primary or metastatic) within the lung Shortness of breath from head and neck malignancy Obstructive symptoms, including: Airway obstruction Biliary obstruction Dysphagia from esophageal obstruction (extrinsic or intrinsic) Rectal obstruction Superior vena cava syndrome Urinary outlet obstruction Status post other palliative intervention for metastatic disease Fixation of pathologic bone fracture Kyphoplasty or vertebroplasty Resection to relieve spinal cord compression Resection of brain metastases Laser treatment of intracavitary disease (bronchus, biliary tree) Stent placement (to maintain patency of airway, biliary tree, esophagus, etc)
therapy, radiosensitizers, and radiosurgery in an attempt to improve quality of life and survival for patients with brain metastases. These studies have shown improved neurologic outcomes and decreased death from brain metastases, without improvement in survival with different dose/fractionation schedules and radiosensitizers.12 However, improved local control and survival in subsets of patients from the early radiosurgery trials3 led the RTOG to analyze its data and generate the Recursive Partition Analysis (RPA) for brain metastases.13 This analysis of ⬎1000 patients led to the development of 3 RPA classes that divided patients based on age ⬍65, brain-only metastases, controlled primary tumor, and Karnofsky Performance Status (KPS) ⱖ70 for Class I (KPS ⬍70 with any other factors for Class III and Class II being any patient who did not fit Class I or Class III). Median survival based on RPA class varied significantly from 2.3 months for patients in Class III to 4.2 months for 328
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TABLE 2. Factors affecting choice of dose, fractionation, and technique in palliative radiotherapy Factors suggestive of a more aggressive approach (Highly Conformal or Stereotactic Treatment, Prolonged Fractionation)
Factors suggestive of a less aggressive approach (Less Conformal Treatment, Short Fractionation)
Good performance status Poor performance status (KPS ⬎80) (KPS ⬍50) Systemic disease controlled Large burden of systemic disease
Effective systemic treatments availablea
Few or no proven effective systemic treatments availablea Tumor that is not significantly radioresistant
Relatively radioresistant tumor (ie, melanoma, renal cell carcinoma) Large symptomatic tumor Small symptomatic tumor (less likely to respond to (more likely to respond to lower doses of lower doses of radiotherapy) radiotherapy) High likelihood of significant Low likelihood of significant late side effects late side effects High morbidity of possible recurrence High morbidity of retreatment
Low morbidity of possible recurrence Low morbidity of retreatment
Few or no effective alternative palliative therapies
Range of effective alternative palliative therapies
Factors suggestive of palliative care without radiotherapy intervention Very poor performance status/death imminent Overwhelming burden of symptoms—radiotherapy affecting 1 symptom among many No effective systemic treatments availablea
High likelihood of acute side effects that the patient may not outlive
Retreatment in an area that would exceed normal tissue tolerance If radiotherapy prohibits other effective palliative therapies (ie, delay of referral to hospice)
Note. Psychosocial issues (such as transportation issues, wanting to live to experience a specific event, wanting to spend time with family, etc) that emerge in conversations with patients and family may cross categories in either direction. KPS, Karnofsky Performance Status. a Effective systemic treatments may be based on the histology and biology of the primary cancer (ie, metastatic hormone receptor positive metastatic breast cancer vs metastatic squamous cell carcinoma of the lung) and number and effect of prior treatment regimens.
patients in Class II to 7.1 months for patients in Class I. This formed a basis for comparison for further studies of therapies for brain metastases to account for baseline differences in prognosis, although other investigators have also created prognostic indexes for brain metastases (notably score index for radiosurgery and basic score for brain metastases). In an attempt to refine the roles of surgery, radiosurgery, and whole brain radiotherapy, Sperduto and colleagues reevaluated the RTOG RPA Curr Probl Cancer, November/December 2011
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classification data to create the Graded Prognostic Assessment based on age, KPS, number of brain metastases, and presence vs control of extracranial metastatic disease, attempting to eliminate subjectivity from the score (ie, control of primary disease).14 The Graded Prognostic Assessment has been validated as a prognostic tool; however, much work is ongoing to define histopathology-specific prognostic indexes to refine prognostic estimates for different malignancies.15 As Videtic et al. describe in the American College of Radiology Appropriateness Criteria for brain metastases,12 different clinical scenarios require different palliative treatments. For example, a patient who is 72 years old, has 6 new symptomatic brain metastases from non-smallcell lung cancer, all smaller than 3 cm, a KPS of 60, and uncontrolled extracranial disease would have anticipated poor survival and is a good candidate for best supportive care vs a hypofractionated whole brain radiotherapy regimen. In contrast, a patient who is 48 years old, has a single new 2-cm brain metastasis from newly diagnosed metastatic hormone receptor positive breast cancer that presented with persistent headache, status post definitive therapy 10 years earlier, a KPS of 90, and no evidence of extracranial disease is a good candidate for more aggressive palliative therapy that might include a combination of surgical resection, radiosurgery, and/or whole brain radiotherapy. Details on the role of surgery, radiosurgery, and whole brain radiotherapy are described in the ASTRO Evidence-Based Guidelines on brain metastases (in press at the time of this writing).
Palliative Radiotherapy to Bone Metastases External beam radiation therapy has been demonstrated to be effective in the palliation of painful bony metastases in a large number of randomized controlled trials designed to evaluate optimal dose and fractionation schedules going back to the 1960s. Multiple recent randomized controlled trials with more than 700 patients and at least 12 months of follow-up have found a single fraction of 8 Gy to be equivalent to longer courses of radiotherapy (ranging from 20 Gy divided in 5 fractions, 24 Gy in 6 fractions, or 30 Gy in 10 fractions).16-18 These studies, in conjunction with several smaller randomized trials, demonstrate pain relief rates ranging from 60% to 80% with complete pain responses in about one-third of all patients. Eight percent of patients required retreatment in the multiple fraction arm, whereas approximately 20% of patients required retreatment in the single fraction arm. Overall toxicity was minimal and similar in the groups. Thus, 8 Gy in 1 fraction is considered 330
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by many to be the standard of care for palliative radiotherapy for painful bony metastases.19 Even so, the most recent patterns of practice study of ASTRO, Canadian Association of Radiation Oncology (CARO), and Royal Australian and New Zealand College of Radiologists (RANCZR) members demonstrated wide variability in the treatment of painful bony metastases, with a median fractionation scheme of 30 Gy in 10 fractions and a range from 3 Gy in 1 fraction to 60 Gy in 20 fractions for different clinical scenarios among ASTRO members.20 The primary reasons cited for determining dose fractionation schedules included prognosis, risk of spinal cord compression, and performance status. In 2011, the ASTRO issued evidence-based guidelines for the palliative treatment of bone metastases.21 The task force reviewed the available literature and generated guidelines for different dose and fractionation schedules for palliation of bone metastases, supporting the findings that single fraction radiotherapy is often sufficient in the management of painful bone metastases. The task force reiterated that there are no long-term toxicities evident in the randomized clinical trials that would prohibit the use of single fraction radiotherapy in patients expected to have longer survival. The task force also indicated that, at present, highly conformal radiotherapy (or aggressive palliation), which allows steep dose gradients and high dose per fraction to lesions around the spine, should generally be used only in the setting of a clinical trial because of the complexities of target delineation and dose distribution and the lack of randomized studies comparing highly conformal radiotherapy to the known efficacy of standard external beam radiation. With that caveat, the question about aggressive palliation (long course or highly conformal radiotherapy) vs single fraction radiotherapy deserves further consideration in the case of metastatic epidural spinal cord compression as an illustrative example.
Metastatic Spinal Cord Compression Metastatic spinal cord compression can be a devastating consequence of metastatic disease that may lead to paralysis and significant loss of function in the affected individual. The excessive morbidity associated with metastatic spinal cord compression has led to many randomized clinical trials to evaluate the most effective treatments to prevent morbidity. Treatments have included surgical decompression followed by postoperative radiotherapy on the more aggressive end of the spectrum vs radiotherapy alone with dose and fractionation schedules ranging from 8 Gy in 1 fraction or 8 Gy in 2 fractions (8 Gy ⫻ 2) to 30 Gy in 10 fractions (3 Gy ⫻ 10) and even up to 50 Gy in 25 fractions (2 Gy ⫻ 25). In Patchell Curr Probl Cancer, November/December 2011
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et al.’s study of surgical decompression followed by radiotherapy vs radiotherapy for metastatic spinal cord compression, patients with displacement of the spinal cord with only a single site of spinal cord compression, good performance status, at least 1 neurologic symptom (including pain), and no evidence of other brain or visceral metastases were randomized to high-dose steroids with either surgical decompression followed by radiotherapy (3 Gy ⫻ 10 fractions) or radiation therapy alone (3 Gy ⫻ 10 fractions).22 The primary endpoint was the ability to walk. The study was stopped according to early stopping rules related to a significant difference in length of time able to ambulate (median 122 days vs 13 days). There was no statistically significant difference in overall survival, although the study was not powered for such differences. The conclusion many have drawn from this study is that, in a highly select group of patients with metastatic epidural spinal cord compression, surgical decompression followed by radiotherapy can provide improved palliation when compared with radiotherapy alone. In contrast to the Patchell study of surgical decompression and postoperative radiotherapy for spinal cord compression, Maranzano et al. have compared various short-course radiotherapy regimens for palliative treatment of spinal cord compression. In the most recent Phase III study, patients with metastatic spinal cord compression and expected poor survival (although how this was defined was unclear) were treated with either 8 Gy ⫻ 1 or 8 Gy ⫻ 2 one week apart and had similar functional and pain outcomes as well as similar overall survival.23 Similarly, Rades et al. found similar pain relief and neurologic function after short-course (8 Gy ⫻ 1 or 4 Gy ⫻ 5) vs long-course (3 Gy ⫻ 10, 2.5 Gy ⫻ 15, or 2 Gy ⫻ 20) radiotherapy for spinal cord compression.24 However, local control at 1 year was 61% vs 81% for short- and long-course radiotherapy, respectively. Given the potential devastating late effects in reirradiation of the spine, long-course radiotherapy is recommended for patients with longer expected survival. As with the groups developing prognostic scores for brain metastases, Rades and colleagues developed a prognostic score for survival for patients with metastatic spinal cord compression treated with radiation therapy but without surgery.24 The variables that impacted overall survival were primary tumor type, other bone metastases, visceral metastases, interval from diagnosis to spinal cord compression, ambulatory status before radiotherapy, and time to develop motor deficits. Tokuhashi et al. revised their prognostic scoring system for patients with metastatic spinal cord compression treated with surgical decompression and radiotherapy to incorporate KPS, number of extraspinal bone metastases, number of 332
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metastases in the vertebral body, visceral metastases, primary tumor site, and palsy.25 Although these data may be helpful in evaluating the utility of surgery and the appropriate radiotherapeutic fractionation scheme for patients with metastatic spinal cord compression, much work remains to be done to clarify the roles of surgery, highly conformal radiotherapy, and the various dose/fractionation schemes for patients with metastatic spinal cord compression.
Palliative Radiotherapy to Lung or Other Visceral Metastases In addition to being effective in the palliative treatment of brain metastases and bone metastases, radiotherapy can effectively palliate symptoms related to visceral metastases or local recurrences. Symptoms that can be effectively palliated are listed in Table 1. As an example that has been widely studied, symptomatic locally advanced and metastatic lung cancer that is not amenable to curative treatment has been extensively studied and possesses several illustrative characteristics similar to other visceral sites of disease. Advanced cancer in the lung can be highly symptomatic, presenting with cough, shortness of breath, hemoptysis, bronchial obstruction, and chest pain. Palliative radiotherapy may relieve many of these symptoms. Palliative radiotherapy may cause acute and late side effects that can have significant impact on quality of life. Fairchild’s systematic review of palliative radiotherapy for lung cancer evaluated the optimal dose fractionation scheme based on 13 randomized controlled trials.26 The findings indicate that shorter fractionation schemes (as short as a single fraction of 10 Gy) have similar rates of symptom palliation, but there was a trend toward improved survival and decreased retreatment in treatment schemes with biological equivalent dose of at least 35 Gy10, as calculated with a time adjusted model of equivalent dose with an alpha/beta ratio of 10. At the same time, the longer dose fractionation schemes had higher rates of esophagitis, while there was a risk of myelopathy in the short-course radiotherapy schemes. The recently published ASTRO Consensus Guidelines for Palliative Radiotherapy to the Lung confirm these findings, but add that, at present, the role of advanced treatment techniques, including intensity modulated radiotherapy, image-guided radiotherapy, and the incorporation of advanced imaging in radiotherapy treatment planning, remain unconfirmed.27 The ASTRO guidelines address another important question about palliative radiotherapy for lung cancer: at present, there is no clearly defined role for the combination of chemoradiotherapy in palliation of thoracic symptoms. The addition of chemotherapy to radiation therapy did not improve survival, but significantly increased acute toxicity for patients. Curr Probl Cancer, November/December 2011
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Conclusions Radiotherapy represents an effective, efficient, inexpensive treatment for the palliation of symptoms in advanced cancer. The goals of palliative radiotherapy should be to alleviate symptoms optimally with the least inconvenience to the patient and the fewest side effects. When treatments may impact survival, such as surgery or radiosurgery for brain metastases in patients with lengthy anticipated survival, validated prognostic indexes should be integrated into clinical practice and continually reevaluated to optimize treatments. The treatment for uncomplicated bone metastases should, as a general rule, use a single fraction of 8 Gy for optimal palliation. Certain clinical scenarios, such as long expected survival and areas where retreatment might exceed normal tissue tolerance, may warrant longer fractionation schemes or advanced radiotherapy techniques. Palliative radiotherapy to the lung can serve as a model for the palliation of other visceral disease: palliation can be achieved quickly and effectively with short-course radiotherapy, but duration of palliation may be enhanced with longer fractionation schemes. Advances in imaging and physics have enhanced the ability of the radiation oncologist to provide higher doses of radiation with more precision. However, the capability to treat more aggressively does not mean that all patients should receive highly conformal radiotherapy or protracted fractionation schemes. Rather, prognostic indexes (both those available and those in development with multidisciplinary input) must continually be refined to determine the appropriate use of advanced radiotherapy techniques to improve both palliation and survival for each individual. Above all, patient goals and wishes must be considered when generating the optimal treatment plan.
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Hall EJ, Giaccia AJ. Radiobiology for the Radiologist, 6th edition. Philadelphia, PA: Lippincott, Williams and Wilkins, 2006. Halperin EC, Perez CA, Brady LW, editors. Principles and Practice of Radiation Oncology, 5th edition. Philadelphia, PA: Lippincott, Williams and Wilkins, 2004. Andrews DW, Scott CB, Sperduto PW, et al. Whole brain radiation therapy with or without stereotactic radiosurgery boost for patients with one to three brain metastases: phase III results of the RTOG 9508 randomised trial. Lancet 2004;363:1665-72. Jones JA, Lutz S. Trends in Symptom Control and Palliative Care Abstract at ASTRO 2001-10. ASTRO Abstract 2907. Int J of Radiat Oncol Biol Phys. Suppl. 2011;81:S645. Gripp S, Mjartan S, Boelke E, et al. Palliative radiotherapy tailored to life expectancy in end-stage cancer patients: reality or myth? Cancer 2010;116:3251-6. Curr Probl Cancer, November/December 2011
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Lamont EB, Christakis NA. Complexities in prognostication in advanced cancer: “to help them live their lives the way they want to”. JAMA 2003;290:98-104. Hartsell WF. Myth: we can tailor palliative care to match life expectancy. Reality: no we can’t. Cancer 2010;116:3078-9. Konski A, Feigenberg S, Chow E. Palliative radiation therapy. Semin Oncol 2005;32:156-64. Rades D, Lange M, Veninga T, et al. Final results of a prospective study comparing the local control of short-course and long-course radiotherapy for metastatic spinal cord compression. Int J Radiat Oncol Biol Phys 2011;79:524-30. Lutz S, Korytko T, Nguyen J, et al. Palliative radiotherapy: when is it worth it and when is it not? Cancer J 2010;16(5):473-82. Patchell RA, Tibbs PA, Walsh JW, et al. A randomized trial of surgery in the treatment of single metastases to the brain. N. Engl. J. Med. 1990;322:494-500. Expert Panel on Radiation Oncology-Brain Metastases, Videtic GMM, Gaspar LE, Aref AM, et al. American College of Radiology appropriateness criteria on multiple brain metastases. Int J Radiat Oncol Biol Phys 2009;75:961-5. Gaspar L, Scott C, Rotman M, et al. Recursive partitioning analysis (RPA) of prognostic factors in three radiation therapy oncology group (RTOG) brain metastases trials. Int J Radiat Oncol Biol Phys 1997;37:745-51. Sperduto PW, Berkey B, Gaspar LE, et al. A new prognostic index and comparison to three other indices for patients with brain metastases: an analysis of 1,960 patients in the RTOG database. Int J Radiat Oncol Biol Phys 2008;70:510-4. Sperduto PW, Chao ST, Sneed PK, et al. Diagnosis-specific prognostic factors, indexes, and treatment outcomes for patients with newly diagnosed brain metastases: a multi-institutional analysis of 4,259 patients. Int J Radiat Oncol Biol Phys 2010;77:655-61. Gy single fraction radiotherapy for the treatment of metastatic skeletal pain: randomised comparison with a multifraction schedule over 12 months of patient follow-up. Bone Pain Trial Working Party. Radiother Oncol 1999;52:111-21. Hartsell WF, Scott C, Bruner DW, et al. Randomized trial of short- versus long-course radiotherapy for palliation of painful bone metastases. J Natl Cancer Inst 2005;97:798-804. Steenland E, Leer JW, van Houwelingen H, et al. The effect of a single fraction compared to multiple fractions on painful bone metastases: a global analysis of the Dutch Bone Metastasis Study. Radiother Oncol 1999;52:101-9. Chow E, Harris K, Fan G, et al. Palliative radiotherapy trials for bone metastases: A systematic review. J Clin Oncol 2007;25:1423-36. Fairchild A, Barnes E, Ghosh S, et al. International patterns of practice in palliative radiotherapy for painful bone metastases: Evidence-based practice? Int J Radiat Oncol Biol Phys 2009;75:1281-628. Lutz S, Berk L, Chang E, et al. Palliative Radiotherapy for Bone metastases: an ASTRO evidence-based guideline. Int J Radiat Oncol Biol Phys 2011;79:965-76. Patchell RA, Tibbs PA, Regine WF, et al. Direct decompressive surgical resection in the treatment of spinal cord compression caused by metastatic cancer: a randomised trial. Lancet 2005;366:643-8. Maranzano E, Trippa F, Casale M, et al. 8 Gy single-dose radiotherapy is effective in metastatic spinal cord compression: results of a phase III randomized multicenter Italian trial. Radiother Oncol 2009;92:174-9.
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Rades D, Dunst J, Schild SE. The first score predicting overall survival in patients with metastatic spinal cord compression. Cancer 2008;112:157-61. Tokuhashi Y, Matsuzaki H, Oda H, et al. A revised scoring system for preoperative evaluation of metastatic spine tumor prognosis. Spine 2005;30:2186-91. Fairchild A, Harris K, Barnes E, et al. Palliative thoracic radiotherapy for lung cancer: a systematic review. J Clin Oncol 2008;26:4001-11. Rodrigues G, Videtic GMM, Sur R, et al. Palliative thoracic radiotherapy in lung cancer: an American Society for Radiation Oncology evidence-based clinical practice guideline. Pract Radiat Oncol 2011;1:60-71.
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When radiotherapy is used palliatively, even in this modern era and even if the patient may survive a few weeks longer, it is still understood that the patient will ultimately die of his or her disease. The goals of palliative radiation, therefore, must be optimal relief from burdensome symptoms with the fewest side effects possible, minimizing inconvenience and maximizing quality of life in these patients with limited life expectancy. With this goal in mind, there have been numerous attempts to tailor radiotherapy to life expectancy. When Gripp and colleagues adapted palliative radiotherapy treatments to anticipated life expectancy in a cohort of patients with anticipated short survival,5 their effort was a valiant attempt at moving the field of palliative radiotherapy forward. However, they, as with all previous researchers, were unable to predict life expectancy accurately. The science of prognostication in advanced cancer remains inexact.6 Often, physicians overestimate (sometimes dramatically) the survival of their patients with advanced cancer. Within radiation oncology, particularly with the recent technological advances, this may lead to overtreatment of patients. As Hartsell lamented in his editorial accompanying the Gripp study, we are still not able to prognosticate patient survival well enough to tailor the radiotherapy regimen to the individual patient.7 Traditional palliative radiotherapy approaches are effective in that they may use a single treatment or a few treatments with few acute side effects.8 As survival for patients with metastatic cancer increases, some are arguing for longer courses of initial palliative radiotherapy treatments in an attempt to avoid the challenges of retreating areas that could be subject to devastating late consequences from tumor recurrence or late radiation injury. For example, Rades et al. have conducted several retrospective and prospective studies in an attempt to optimize treatment for metastatic spinal cord compression. In the most recent prospective study, they compared short- and long-course palliative radiotherapy for metastatic spinal cord compression.9 Although short-term relief of symptoms and survival were similar, the long-course radiotherapy treatments had more durable local control, decreasing the necessity for retreatment and possible exposure to radiotherapy that exceeds spinal cord tolerance. On the other end of the spectrum, the decision about when to proceed with radiation therapy (vs palliative care without radiotherapy) is also complicated by questions of prognosis and the balance between potential benefits and risks to the patient.10 For example, when death is imminent, the beneficial effects of radiotherapy, which may take weeks to become manifest, are outweighed by the poor prognosis of the patient. As with all clinical situations, when the patient is alert and not actively dying, 326
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perhaps the most important tool at the disposal of the radiation oncologist and the entire treatment team is the critical conversation with the patient and the patient’s caregivers about the potential risks, benefits, and alternatives to palliative radiotherapy in the management of symptomatic advanced cancer. For example, a parent with young children may be apt to request aggressive care with a goal of spending more time with family, even knowing that there may be more side effects with treatment and that survival may not be impacted. The only way to understand these goals in the context of possible treatment regimens is to have these difficult conversations (communication in palliative care is reviewed in detail by Baumann in this issue of Current Problems in Cancer). Given its efficacy, safety, and efficiency, any patient with symptomatic malignant disease should be considered a candidate for palliative radiation therapy. There have been multiple reviews that detail specific indications for palliative radiotherapy.8,10 Table 1 lists the major indications for radiotherapy based on symptom and site of disease. Rather than attempting to review every indication for palliative radiotherapy, the remainder of this review clarifies some of the factors that may influence the decision to pursue aggressive palliative radiotherapy, short-course palliative radiotherapy, or palliative care without radiotherapy in a few common clinical scenarios. Table 2 describes some of the competing factors that influence the decisions regarding aggressive vs palliative vs no radiotherapy treatments.
Palliative Radiotherapy to the Brain Brain metastases can present with headaches, seizures, mental status changes, focal weakness, or ataxia among other signs and symptoms. Treatment options for brain metastases may include any combination of best supportive care, whole brain radiotherapy (with or without systemic therapy and/or radiosensitizers), stereotactic radiosurgery, and surgical resection. The role of surgery followed by whole brain radiotherapy in improving both survival and functional independence and decreasing local recurrence compared with biopsy and whole brain radiotherapy was demonstrated by Patchell et al. in 1990.11 However, the standard of care for more than 1 symptomatic brain metastasis remained whole brain radiotherapy. The morbidity of severe neurologic compromise and mortality associated with newly diagnosed and recurrent brain metastases led the Radiation Therapy Oncology Group (RTOG) to conduct a series of trials to evaluate different dose/fractionation schedules for whole brain radioCurr Probl Cancer, November/December 2011
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TABLE 1. Indications for palliative radiotherapy by symptom type and site of disease Pain from: Bone metastases Visceral metastases Recurrent tumor at primary disease site Splenomegaly (hematologic malignancies) Neurologic symptoms (ie, headache, seizure, weakness, paresthesia, etc) from: Brain metastases Spinal cord compression Brachial or lumbosacral plexopathy from tumor involvement Bleeding from: Hemoptysis from malignancy within the lung Hematemesis from esophageal or gastric cancer Mucosal bleeding from head and neck or GYN malignancies Hematuria from cancer involving genitourinary malignancies Respiratory symptoms, including: Cough or shortness of breath from malignancy (primary or metastatic) within the lung Shortness of breath from head and neck malignancy Obstructive symptoms, including: Airway obstruction Biliary obstruction Dysphagia from esophageal obstruction (extrinsic or intrinsic) Rectal obstruction Superior vena cava syndrome Urinary outlet obstruction Status post other palliative intervention for metastatic disease Fixation of pathologic bone fracture Kyphoplasty or vertebroplasty Resection to relieve spinal cord compression Resection of brain metastases Laser treatment of intracavitary disease (bronchus, biliary tree) Stent placement (to maintain patency of airway, biliary tree, esophagus, etc)
therapy, radiosensitizers, and radiosurgery in an attempt to improve quality of life and survival for patients with brain metastases. These studies have shown improved neurologic outcomes and decreased death from brain metastases, without improvement in survival with different dose/fractionation schedules and radiosensitizers.12 However, improved local control and survival in subsets of patients from the early radiosurgery trials3 led the RTOG to analyze its data and generate the Recursive Partition Analysis (RPA) for brain metastases.13 This analysis of ⬎1000 patients led to the development of 3 RPA classes that divided patients based on age ⬍65, brain-only metastases, controlled primary tumor, and Karnofsky Performance Status (KPS) ⱖ70 for Class I (KPS ⬍70 with any other factors for Class III and Class II being any patient who did not fit Class I or Class III). Median survival based on RPA class varied significantly from 2.3 months for patients in Class III to 4.2 months for 328
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TABLE 2. Factors affecting choice of dose, fractionation, and technique in palliative radiotherapy Factors suggestive of a more aggressive approach (Highly Conformal or Stereotactic Treatment, Prolonged Fractionation)
Factors suggestive of a less aggressive approach (Less Conformal Treatment, Short Fractionation)
Good performance status Poor performance status (KPS ⬎80) (KPS ⬍50) Systemic disease controlled Large burden of systemic disease
Effective systemic treatments availablea
Few or no proven effective systemic treatments availablea Tumor that is not significantly radioresistant
Relatively radioresistant tumor (ie, melanoma, renal cell carcinoma) Large symptomatic tumor Small symptomatic tumor (less likely to respond to (more likely to respond to lower doses of lower doses of radiotherapy) radiotherapy) High likelihood of significant Low likelihood of significant late side effects late side effects High morbidity of possible recurrence High morbidity of retreatment
Low morbidity of possible recurrence Low morbidity of retreatment
Few or no effective alternative palliative therapies
Range of effective alternative palliative therapies
Factors suggestive of palliative care without radiotherapy intervention Very poor performance status/death imminent Overwhelming burden of symptoms—radiotherapy affecting 1 symptom among many No effective systemic treatments availablea
High likelihood of acute side effects that the patient may not outlive
Retreatment in an area that would exceed normal tissue tolerance If radiotherapy prohibits other effective palliative therapies (ie, delay of referral to hospice)
Note. Psychosocial issues (such as transportation issues, wanting to live to experience a specific event, wanting to spend time with family, etc) that emerge in conversations with patients and family may cross categories in either direction. KPS, Karnofsky Performance Status. a Effective systemic treatments may be based on the histology and biology of the primary cancer (ie, metastatic hormone receptor positive metastatic breast cancer vs metastatic squamous cell carcinoma of the lung) and number and effect of prior treatment regimens.
patients in Class II to 7.1 months for patients in Class I. This formed a basis for comparison for further studies of therapies for brain metastases to account for baseline differences in prognosis, although other investigators have also created prognostic indexes for brain metastases (notably score index for radiosurgery and basic score for brain metastases). In an attempt to refine the roles of surgery, radiosurgery, and whole brain radiotherapy, Sperduto and colleagues reevaluated the RTOG RPA Curr Probl Cancer, November/December 2011
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classification data to create the Graded Prognostic Assessment based on age, KPS, number of brain metastases, and presence vs control of extracranial metastatic disease, attempting to eliminate subjectivity from the score (ie, control of primary disease).14 The Graded Prognostic Assessment has been validated as a prognostic tool; however, much work is ongoing to define histopathology-specific prognostic indexes to refine prognostic estimates for different malignancies.15 As Videtic et al. describe in the American College of Radiology Appropriateness Criteria for brain metastases,12 different clinical scenarios require different palliative treatments. For example, a patient who is 72 years old, has 6 new symptomatic brain metastases from non-smallcell lung cancer, all smaller than 3 cm, a KPS of 60, and uncontrolled extracranial disease would have anticipated poor survival and is a good candidate for best supportive care vs a hypofractionated whole brain radiotherapy regimen. In contrast, a patient who is 48 years old, has a single new 2-cm brain metastasis from newly diagnosed metastatic hormone receptor positive breast cancer that presented with persistent headache, status post definitive therapy 10 years earlier, a KPS of 90, and no evidence of extracranial disease is a good candidate for more aggressive palliative therapy that might include a combination of surgical resection, radiosurgery, and/or whole brain radiotherapy. Details on the role of surgery, radiosurgery, and whole brain radiotherapy are described in the ASTRO Evidence-Based Guidelines on brain metastases (in press at the time of this writing).
Palliative Radiotherapy to Bone Metastases External beam radiation therapy has been demonstrated to be effective in the palliation of painful bony metastases in a large number of randomized controlled trials designed to evaluate optimal dose and fractionation schedules going back to the 1960s. Multiple recent randomized controlled trials with more than 700 patients and at least 12 months of follow-up have found a single fraction of 8 Gy to be equivalent to longer courses of radiotherapy (ranging from 20 Gy divided in 5 fractions, 24 Gy in 6 fractions, or 30 Gy in 10 fractions).16-18 These studies, in conjunction with several smaller randomized trials, demonstrate pain relief rates ranging from 60% to 80% with complete pain responses in about one-third of all patients. Eight percent of patients required retreatment in the multiple fraction arm, whereas approximately 20% of patients required retreatment in the single fraction arm. Overall toxicity was minimal and similar in the groups. Thus, 8 Gy in 1 fraction is considered 330
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by many to be the standard of care for palliative radiotherapy for painful bony metastases.19 Even so, the most recent patterns of practice study of ASTRO, Canadian Association of Radiation Oncology (CARO), and Royal Australian and New Zealand College of Radiologists (RANCZR) members demonstrated wide variability in the treatment of painful bony metastases, with a median fractionation scheme of 30 Gy in 10 fractions and a range from 3 Gy in 1 fraction to 60 Gy in 20 fractions for different clinical scenarios among ASTRO members.20 The primary reasons cited for determining dose fractionation schedules included prognosis, risk of spinal cord compression, and performance status. In 2011, the ASTRO issued evidence-based guidelines for the palliative treatment of bone metastases.21 The task force reviewed the available literature and generated guidelines for different dose and fractionation schedules for palliation of bone metastases, supporting the findings that single fraction radiotherapy is often sufficient in the management of painful bone metastases. The task force reiterated that there are no long-term toxicities evident in the randomized clinical trials that would prohibit the use of single fraction radiotherapy in patients expected to have longer survival. The task force also indicated that, at present, highly conformal radiotherapy (or aggressive palliation), which allows steep dose gradients and high dose per fraction to lesions around the spine, should generally be used only in the setting of a clinical trial because of the complexities of target delineation and dose distribution and the lack of randomized studies comparing highly conformal radiotherapy to the known efficacy of standard external beam radiation. With that caveat, the question about aggressive palliation (long course or highly conformal radiotherapy) vs single fraction radiotherapy deserves further consideration in the case of metastatic epidural spinal cord compression as an illustrative example.
Metastatic Spinal Cord Compression Metastatic spinal cord compression can be a devastating consequence of metastatic disease that may lead to paralysis and significant loss of function in the affected individual. The excessive morbidity associated with metastatic spinal cord compression has led to many randomized clinical trials to evaluate the most effective treatments to prevent morbidity. Treatments have included surgical decompression followed by postoperative radiotherapy on the more aggressive end of the spectrum vs radiotherapy alone with dose and fractionation schedules ranging from 8 Gy in 1 fraction or 8 Gy in 2 fractions (8 Gy ⫻ 2) to 30 Gy in 10 fractions (3 Gy ⫻ 10) and even up to 50 Gy in 25 fractions (2 Gy ⫻ 25). In Patchell Curr Probl Cancer, November/December 2011
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et al.’s study of surgical decompression followed by radiotherapy vs radiotherapy for metastatic spinal cord compression, patients with displacement of the spinal cord with only a single site of spinal cord compression, good performance status, at least 1 neurologic symptom (including pain), and no evidence of other brain or visceral metastases were randomized to high-dose steroids with either surgical decompression followed by radiotherapy (3 Gy ⫻ 10 fractions) or radiation therapy alone (3 Gy ⫻ 10 fractions).22 The primary endpoint was the ability to walk. The study was stopped according to early stopping rules related to a significant difference in length of time able to ambulate (median 122 days vs 13 days). There was no statistically significant difference in overall survival, although the study was not powered for such differences. The conclusion many have drawn from this study is that, in a highly select group of patients with metastatic epidural spinal cord compression, surgical decompression followed by radiotherapy can provide improved palliation when compared with radiotherapy alone. In contrast to the Patchell study of surgical decompression and postoperative radiotherapy for spinal cord compression, Maranzano et al. have compared various short-course radiotherapy regimens for palliative treatment of spinal cord compression. In the most recent Phase III study, patients with metastatic spinal cord compression and expected poor survival (although how this was defined was unclear) were treated with either 8 Gy ⫻ 1 or 8 Gy ⫻ 2 one week apart and had similar functional and pain outcomes as well as similar overall survival.23 Similarly, Rades et al. found similar pain relief and neurologic function after short-course (8 Gy ⫻ 1 or 4 Gy ⫻ 5) vs long-course (3 Gy ⫻ 10, 2.5 Gy ⫻ 15, or 2 Gy ⫻ 20) radiotherapy for spinal cord compression.24 However, local control at 1 year was 61% vs 81% for short- and long-course radiotherapy, respectively. Given the potential devastating late effects in reirradiation of the spine, long-course radiotherapy is recommended for patients with longer expected survival. As with the groups developing prognostic scores for brain metastases, Rades and colleagues developed a prognostic score for survival for patients with metastatic spinal cord compression treated with radiation therapy but without surgery.24 The variables that impacted overall survival were primary tumor type, other bone metastases, visceral metastases, interval from diagnosis to spinal cord compression, ambulatory status before radiotherapy, and time to develop motor deficits. Tokuhashi et al. revised their prognostic scoring system for patients with metastatic spinal cord compression treated with surgical decompression and radiotherapy to incorporate KPS, number of extraspinal bone metastases, number of 332
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metastases in the vertebral body, visceral metastases, primary tumor site, and palsy.25 Although these data may be helpful in evaluating the utility of surgery and the appropriate radiotherapeutic fractionation scheme for patients with metastatic spinal cord compression, much work remains to be done to clarify the roles of surgery, highly conformal radiotherapy, and the various dose/fractionation schemes for patients with metastatic spinal cord compression.
Palliative Radiotherapy to Lung or Other Visceral Metastases In addition to being effective in the palliative treatment of brain metastases and bone metastases, radiotherapy can effectively palliate symptoms related to visceral metastases or local recurrences. Symptoms that can be effectively palliated are listed in Table 1. As an example that has been widely studied, symptomatic locally advanced and metastatic lung cancer that is not amenable to curative treatment has been extensively studied and possesses several illustrative characteristics similar to other visceral sites of disease. Advanced cancer in the lung can be highly symptomatic, presenting with cough, shortness of breath, hemoptysis, bronchial obstruction, and chest pain. Palliative radiotherapy may relieve many of these symptoms. Palliative radiotherapy may cause acute and late side effects that can have significant impact on quality of life. Fairchild’s systematic review of palliative radiotherapy for lung cancer evaluated the optimal dose fractionation scheme based on 13 randomized controlled trials.26 The findings indicate that shorter fractionation schemes (as short as a single fraction of 10 Gy) have similar rates of symptom palliation, but there was a trend toward improved survival and decreased retreatment in treatment schemes with biological equivalent dose of at least 35 Gy10, as calculated with a time adjusted model of equivalent dose with an alpha/beta ratio of 10. At the same time, the longer dose fractionation schemes had higher rates of esophagitis, while there was a risk of myelopathy in the short-course radiotherapy schemes. The recently published ASTRO Consensus Guidelines for Palliative Radiotherapy to the Lung confirm these findings, but add that, at present, the role of advanced treatment techniques, including intensity modulated radiotherapy, image-guided radiotherapy, and the incorporation of advanced imaging in radiotherapy treatment planning, remain unconfirmed.27 The ASTRO guidelines address another important question about palliative radiotherapy for lung cancer: at present, there is no clearly defined role for the combination of chemoradiotherapy in palliation of thoracic symptoms. The addition of chemotherapy to radiation therapy did not improve survival, but significantly increased acute toxicity for patients. Curr Probl Cancer, November/December 2011
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Conclusions Radiotherapy represents an effective, efficient, inexpensive treatment for the palliation of symptoms in advanced cancer. The goals of palliative radiotherapy should be to alleviate symptoms optimally with the least inconvenience to the patient and the fewest side effects. When treatments may impact survival, such as surgery or radiosurgery for brain metastases in patients with lengthy anticipated survival, validated prognostic indexes should be integrated into clinical practice and continually reevaluated to optimize treatments. The treatment for uncomplicated bone metastases should, as a general rule, use a single fraction of 8 Gy for optimal palliation. Certain clinical scenarios, such as long expected survival and areas where retreatment might exceed normal tissue tolerance, may warrant longer fractionation schemes or advanced radiotherapy techniques. Palliative radiotherapy to the lung can serve as a model for the palliation of other visceral disease: palliation can be achieved quickly and effectively with short-course radiotherapy, but duration of palliation may be enhanced with longer fractionation schemes. Advances in imaging and physics have enhanced the ability of the radiation oncologist to provide higher doses of radiation with more precision. However, the capability to treat more aggressively does not mean that all patients should receive highly conformal radiotherapy or protracted fractionation schemes. Rather, prognostic indexes (both those available and those in development with multidisciplinary input) must continually be refined to determine the appropriate use of advanced radiotherapy techniques to improve both palliation and survival for each individual. Above all, patient goals and wishes must be considered when generating the optimal treatment plan.
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