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Keywords:

  • bone metastases;
  • radiofrequency ablation;
  • pain palliation;
  • tumor ablation

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES

BACKGROUND:

The study was conducted to determine whether radiofrequency ablation (RFA) can safely reduce pain from osseous metastatic disease.

METHODS:

The single-arm prospective trial included patients with a single painful bone metastasis with unremitting pain with a score >50 on a pain scale of 0-100. Percutaneous computed tomography-guided RFA of the bone metastasis to temperatures >60°C was performed. Endpoints were the toxicity and pain effects of RFA before and at 2 weeks, 1 month, and 3 months after RFA.

RESULTS:

Fifty-five patients completed RFA. Grade 3 toxicities occurred in 3 of 55 (5%) patients. RFA reduced pain at 1 and 3 months for all pain assessment measures. The average increase in pain relief from pre-RFA to 1-month follow-up is 26.3 (95% confidence interval [CI], 17.7-34.9; P < .0001), and the increase from pre-RFA to 3-month follow-up is 16.38 (95% CI, 3.4-29.4; P = .02). The average decrease in pain intensity from pre-RFA to 1-month follow-up was 26.9 (P < .0001) and 14.2 for 3-month follow-up (P = .02). The odds of lower pain severity at 1-month follow-up were 14.0 (95% CI, 2.3-25.7; P < .0001) times higher than at pre-RFA, and the odds at 3-month follow-up were 8.0 (95% CI, 0.9-15.2; P < .001) times higher than at pre-RFA. The average increase in mood from pre-RFA to 1-month follow-up was 19.9 (P < .0001) and 14.9 to 3-month follow-up (P = .005).

CONCLUSIONS:

This cooperative group trial strongly suggests that RFA can safely palliate pain from bone metastases. Cancer 2010. © 2010 American Cancer Society

Metastatic cancer is the most common neoplasm involving the skeletal system.1 Pain from bone metastases can be related to mechanical or chemical factors. Pressure effects on the periosteum or adjacent neural structures can cause local or radiating pain.2 Primary treatment has relied on radiation therapy3 with or without systemic chemotherapy or hormonal therapy. Newer systemic treatments with radionuclides4, 5 and bisphosphonates6, 7 have also shown some success. Many prospective trials have been performed studying the ability of external beam radiation therapy to palliate pain or control progression of osseous metastatic disease.8-16 Meta-analysis of radiotherapy data has revealed that 1 month after treatment >40% of patients can expect a 50% reduction in pain, and <30% can expect complete pain relief.17 Despite the availability of effective treatments, many studies have documented the undertreatment of pain in cancer patients,18 and many patients live with inadequate analgesia requiring increasing doses of narcotics. Radiofrequency ablation (RFA) is an image-guided minimally invasive treatment for solid tumors. Patients who have not responded to conventional treatment, have a contraindication to initial or repeat radiation, or have limited disease may benefit from palliation with RFA. RFA has been used for patients who have persistent pain from a solitary focus of metastatic disease that has been previously treated or in localized disease where a more local ablative therapy can be performed as an alternative to external beam radiotherapy.19, 20 The hypothesis is that RFA can safely reduce pain as measured by multiple pain scale parameters. This multicenter trial was planned to determine the safety and toxicity of RFA as well as the palliative efficacy in patients with pain from a dominant site of osseous metastatic disease.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES

Patients

Patients were required to have pathologically confirmed malignant disease with a bone lesion that has the clinical and imaging features of metastatic disease. Patients with primary musculoskeletal malignancies, lymphoma, and leukemia were not eligible. Pain was required to be from a solitary site of metastatic disease to the bone, although patients may have had subclinical bone metastases in other areas, and the painful site had to be amenable to RFA using a percutaneous computed tomography (CT)-guided approach, defined as a location at which a radiofrequency electrode could be safely placed without significant harm to normal structures. To avoid damage to contiguous vital structures, certain criteria had to be met. Tumors within 3 cm of a major neurovascular bundle required continuous motor nerve testing during the ablation to reduce thermal nerve toxicity. The tumor mass could not come in contact with hollow viscera. Patients were not eligible if the tumor involved a weight-bearing long bone of the lower extremity. The site of the tumor could not have been previously surgically stabilized with metallic hardware. Patients with spinal tumors were eligible if they had an intact cortex between the mass and the spinal canal and exiting nerve roots. Patients were required to have intractable pain that resulted in a return visit to the oncologist. Intractable pain was defined as unremitting pain despite active treatment with narcotics by their medical oncologist. The measurable pain must be >50 on a 1-100 scale. The maximum size of the bone metastasis had to be ≤8 cm. Patients could not have a pacemaker. Patients were required to have a platelet count >70,000/μL and no uncontrolled coagulopathy or bleeding diatheses. Previous treatment with bisphosphonates or radiotherapy (radionuclide or external beam) was not an exclusion for this study. Patients could not have had previous radiation within 30 days. Chemotherapy was not allowed within 14 days before and within 14 days after RFA. All patients underwent a physical examination, laboratory assessment, and imaging of the bone metastases by CT or magnetic resonance imaging (MRI) within 2 weeks of RFA. Patients had to be cognitively intact. All patients signed informed written consent according to institutional and federal guidelines.

Methods

Aspirin and nonsteroidal anti-inflammatory medications, antiplatelet medications, and warfarin were discontinued before RFA for a time period that was appropriate to the drug half-life. Low molecular weight heparin preparations were discontinued 24 hours before procedure.

Radiofrequency ablation was performed using a Radionics CC-1 (Valley Lab, Boulder, Colo) radiofrequency generator and single 17-gauge or cluster Cool-tip electrode. RFA was performed under conscious sedation with midazolam (Abbott Laboratories, North Chicago, Ill) and fentanyl citrate (Abbott Laboratories), with monitoring by continuous pulse oximetry with blood pressure performed every 5 minutes. General endotracheal anesthesia or monitored anesthesia care was allowed in cases where tumors were not within 3 cm of a major neurovascular bundle when clinically appropriate as deemed by the site investigator. CT was used to localize the metastasis. Local anesthesia involved 1% lidocaine both intradermally and around the periosteum. A 14-gauge coaxial bone biopsy needle (Cook, Bloomington, Ind) was placed into the lesion if the cortical bone was intact. After the core was removed, the inner trephine needle was removed, and the radiofrequency electrode was placed through the outer cannula into the metastasis. For tumors that destroyed the bone cortex, the radiofrequency electrode was placed directly into the metastasis (Fig. 1). Tumors >4 cm were treated with a cluster radiofrequency electrode consisting of 3 17-gauge needles spaced 5 mm apart. A cluster electrode creates a spheroid ablation with diameters of thermocoagulation that range from 3 to 7 cm in diameter and 3.5 cm in length depending on tumor vascularity and tissue dielectric properties. Tumors <4 cm were treated with single radiofrequency electrodes (1-, 2-, or 3-cm active tips); tumors <2 cm were treated with a 1-cm active tip; tumors between 2 and 3 cm were treated with a 2-cm active tip; and tumors 3-4 cm were treated with a 3-cm active tip length. Single electrodes create elliptical ablations that range in diameter from 2 to 3 cm, with lengths approximately 1 cm greater than the active tip length. The initial ablation was performed for no longer than 4 minutes using the maximum allowable current given the impedance of the system (typical range, 1100-2000 mA). For larger lesions >4 cm, the goal of the ablation was to focus closer to the margins on the tumor-bone interface. For smaller lesions, less peripheral placement could achieve the therapeutic goal of treating the bone/tumor interface. Intratumoral temperature measurements after each ablation ensured adequate thermocoagulation of the metastasis.

thumbnail image

Figure 1. A 62-year old woman with T4 nonsmall cell lung cancer status after prior radiation and chemotherapy had persistent unremitting pain. (A) Supine computed tomography (CT) image shows the large lung mass involving the T4 vertebral body (arrow). (B) Radiofrequency ablation (RFA) of bone-tumor interface was performed under CT-guided fluoroscopy. The patient tolerated the procedure well, and her pain improved dramatically. Follow-up CT images 2 years later in (C) soft tissue and (D) bone windows show mass necrosis (arrow) and partial remineralization of the bone destruction (arrow). The patient remains pain free >2 years after RFA.

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The maximal intratumoral temperature was recorded, and a target intratumoral temperature >60°C was required to be obtained as an indicator of adequate thermocoagulation. If the temperature exceeded 60°C, the radiofrequency electrode was withdrawn in increments of 1 cm up to the length of the active tip (eg, 3 1-cm increments for a 3-cm active tip single electrode or 3 cm for a 2.5-cm active tip cluster electrode) while measuring the intratumoral temperature. If the temperature fell below 60°C and the radiofrequency electrode was still within the tumor, then another 4-minute treatment was performed at the new position. If after the first 4-minute treatment the maximum intratumoral temperature did not exceed 60°C, then an additional 4-minute treatment was performed at the same position. This could be repeated for a maximum time of 12 minutes (3 treatments) at any given electrode position. After the entire longitudinal dimension of the tumor was treated with a series of overlapping temperature-based treatments, the radiofrequency electrode was positioned into a new portion of the tumor such that the electrode shaft was 1.5-2 cm away from the longitudinal axis of the previous series of treatments. This was repeated until these cylinder-shaped treatment regions encompassed the volume of the tumor mass. After the RFA procedure, vital signs were monitored for a minimum of 2 hours.

Assessments

Pain assessment was measured before and after RFA using a modified Memorial Pain Assessment Card (MPAC).21 To eliminate a potential placebo effect and the regression-to-the mean phenomenon, daily pain scales were performed for 5 days before the procedure and 14 days after the procedure by giving the patient data sheets to record their responses. The initial 2-week postablation MPAC data were only accepted if recorded the same day as the scheduled reporting. The 1- and 3-month follow-up data were acquired in the clinic setting during the imaging follow-up. A 2-week window was allowed for these appointments. In a small number of cases where participants were unable to attend these appointments within the window, the assessment sheets were mailed. This system has been shown to be a valid, reliable, and sensitive measure of cancer pain. Four different measurement scales were used: pain relief (0: no relief; 100: complete relief), patient mood (0: worse; 100: best), pain intensity (0: least possible; 100: worst possible), and pain severity (1: no pain; 8: excruciating). To simplify statistical analysis, the pain severity scale was created by transforming the 8 pain descriptors into a number scale based on the severity of pain description. Patients underwent stabilization of narcotic usage 1 week before RFA. Narcotics usage, dosage, and frequency were recorded in a pain medication diary and recorded daily starting from 1 week pre-RFA to daily for 14 days post-treatment as well as at 1 month and 3 months. Patients were evaluated over a 3-month period of time.

Toxicities from RFA were graded according to the National Cancer Institute's Common Toxicity Criteria (version 3.0).

The follow-up contrast-enhanced CT and MRI examinations were evaluated for the size of the treated tumor and the size of the ablation defect in 3 dimensions. The volume of the treated tumor and ablation volume were calculated by using a prolate ellipse equation (height × width × length × 0.52), and the percentage of the tumor volume that was ablated was calculated.

Statistical Analysis

Measurements for pain intensity, pain, and mood were each modeled with a mixed effects model with time as the predictor of primary interest. A random patient effect was assumed to account for correlation between repeated observations from the same subject. The reduction in pain markers at 1 month and 3 months after RFA was estimated from these models along with 95% confidence intervals. To estimate the effect of RFA on pain severity reduction (an ordinal variable), cumulative logistic regression22 was fitted, which is the standard choice for ordinal response variables with multiple categories. To account for potential confounders, important covariates such as age, performance status, primary cancer site, anatomical location, narcotic score, tumor size, prior radiation therapy, and percentage of tumor volume ablated were included in the regression models. To calculate the number of patients who had increased pain after the RFA procedure, the mean MPAC Pain Scale assessment score for each patient for the 14 days immediately after the RFA treatment, the single score at 1 month, or the single score at 3 months, was subtracted from the mean pain score for each patient for the 5 days preceding the RFA treatment. A negative value was indicative of increased pain after the RFA procedure. To assess the effect of missing data on the outcome, several models were fitted according to different missing data mechanisms, and the results were compared. Specifically, the sensitivity of the model fitting was assessed to 3 missing data assumptions: 1) data missing completely at random, where missing data do not depend on covariates or outcomes; 2) data missing at random, where missing data may depend on covariates and observed outcomes but not on unobserved outcomes; and 3) data missing not at random, where missing data depend on unobserved outcomes.23 To account for data missing not at random, a pattern mixture model was fitted, where separate models corresponding to each missing data pattern were fit, and the results were combined statistically to form the final analysis result.24 All reported P-values are 2-sided. All computations were carried out with commercially available statistical software (SAS version 9.1, SAS Institute, Cary, NC).

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES

Study Population

Sixty-six participants were entered on the study. Six (9%) patients were ineligible because of primary bone cancer (n = 2), chemotherapy within 14 days (n = 2), ibuprofen within 24 hours (n = 1), and radiation to the RFA site within 30 days of the procedure (n = 1). Among the 60 eligible participants, 3 were medically unstable and did not undergo RFA. One patient did not complete the RFA procedure because of uncontrolled pain, and 1 patient had electrocardiographic changes that prevented completion of the procedure. Thus, a total of 55 participants underwent RFA and were included in the primary analysis.

Patient and tumor characteristics are shown in Table 1. The median age was 62 years (range, 34-85 years). The mean ± standard deviation treated tumor size was 5.2 ± 0.2 cm (range, 2.0-8.0 cm). Lung, renal, and colon cancer were the most common types of cancers treated. The anatomical regions treated were the pelvis, chest wall, spine, and extremities. Of all the tumors treated, 9 had an intact cortex requiring bone needle access before coaxially inserting the radiofrequency electrode.

Table 1. Patient Characteristics
CharacteristicValue
  1. SD indicates standard deviation.

Median age, y (range)62 (34-85)
Men:women29:26
Tumor size, cm ± SD (range)5.2 ± 0.23 (2-8)
Primary cancer, No. (%)
 Lung17 (30.9)
 Kidney10 (18.2)
 Colon10 (18.2)
 Breast4 (7.3)
 Prostate2 (3.6)
 Other12 (21.8)
Region, No. (%)
 Pelvis22 (40)
 Chest wall20 (36.4)
 Spine8 (14.5)
 Extremity5 (9.1)
Baseline pain values scale (0-100)
 Pain intensity
  No.54
  Minimum51
  Median54.0
  Maximum91
  Mean (SD)54.4 (18.5)
 Pain reduction
  No.54
  Minimum3
  Median41.70
  Maximum95
  Mean (SD)44.1 (17.3)
 Mood
  No.55
  Minimum51
  Median46.4
  Maximum84
  Mean (SD)47.0 (18.0)
 Pain severity, Tursky scale (1-8)
  No.53
  Minimum4
  Median6
  Maximum8
  Mean (SD)5.55 (1.0)

Of the 55 participants who completed RFA, 13 (23.6%) did not have the 1-month follow-up measurement, and 23 (41.8%) did not have the 3-month follow-up measurement. All 55 patients had completed at least 1 of the initial and follow-up pain and mood measures, so they were included in the statistical analysis. The reasons for missing follow-up data were: MPAC data returned beyond allowable time window (n = 2), patient could not be reached despite multiple attempts to acquire data (n = 7), participant too ill to continue because of admission to hospice, intensive care unit, or nursing home (n = 6), participant death (n = 4), and participant refusal (n = 4).

Toxicities

All toxicities grade ≥2 are shown in Table 2. Only 3 patients had grade 3 toxicities, including pain from RFA (n = 1), neuropathic pain (n = 1), and foot drop (n = 1). The grade 3 neuropathic pain was related to an ablation of a metastasis to the right pelvis, whereby a self-limited thermal injury to the pudendal nerve was observed, which resolved at the 1-month follow-up visit. The extensor weakness of the foot occurred secondary to an ablation in the acetabular region. The patient had an 8-cm mass that had been previously radiated and already had pre-existing leg weakness, avascular necrosis of the femoral head, and severe osteoarthritis. This patient reported increased leg weakness the second day after the ablation, which improved with physical therapy. The patient remained pain free for 2 years after the ablation and was ambulating with a cane. There were no episodes of significant infection or bleeding. There were no identifiable cardiac or pulmonary toxicities.

Table 2. Table of All Adverse Events
Days since RFAGradeDescriptionRelated to RFA
1GRADE 3Neuropathic painDefinite
2GRADE 3Foot dropDefinite
17GRADE 2Skin groundingDefinite
6GRADE 2Neuropathic painProbable
106GRADE 2Bone fracturePossible
43GRADE 4Bone pain – disablingUnlikely
22GRADE 5Progressive Systemic tumorUnrelated
25GRADE 5Progressive Systemic tumorUnrelated
41GRADE 5Progressive Systemic tumorUnrelated
80GRADE 5Progressive Systemic tumorUnrelated
181GRADE 5Progressive Systemic tumorUnrelated
32GRADE 3Other neurologyUnrelated
83GRADE 3Pelvic painUnrelated
2GRADE 2GastrointestinalUnrelated
13GRADE 2ArrhythmiaUnknown
30GRADE 2Infection with neutropeniaUnknown
35GRADE 2Neuropathic painUnknown
35GRADE 2Pelvic painUnknown
72GRADE 2Bone painUnknown

Effect of RFA on Pain Reduction

Statistical analysis showed that the estimated effects of RFA in pain reduction were not sensitive to assumptions of the missing data mechanism. Therefore, we reported the analysis results based on the missing-at-random23 assumption for clarity and ease of interpretation. Pain scales are reported using a 100-point scale. RFA had a statistically significant effect in reducing pain at both 1- and 3-month follow-up for all 4 pain assessment measures (Fig. 2). The average increase in pain relief from pre-RFA to 1-month follow-up was 26.3 (95% confidence interval [CI], 17.7-34.9; P < .0001), and the increase from pre-RFA to 3-month follow-up was 16.4 (95% CI, 3.4-29.4; P = .02). The average increase in mood from pre-RFA to 1-month follow-up was 19.9 (95% CI, 11.9-27.9; P < .0001), and the increase from pre-RFA to 3-month follow-up was 14.9 (95% CI, 5.0-24.8; P = .005). The average decrease in pain intensity from pre-RFA to 1-month follow-up was 26.9 (95% CI, 17.7-36.2; P < .0001), and the decrease from pre-RFA to 3-month follow-up was 14.2 (95% CI, 2.9-25.4; P = .02). The odds of being in lower pain severity at 1-month follow-up were 14.0 (95% CI, 2.3-25.7; P < .0001) times higher than at pre-RFA, and the odds at 3-month follow-up were 8.0 (95% CI, 0.9-15.2; P < .001) times higher than at pre-RFA. These results are summarized in Table 3. Tumor size had a statistically significant effect on pain severity. Holding the other covariates as fixed, for every 1-mm increase in tumor size the odds of being in higher pain severity were on average 1.3 (95% CI, 1.1-1.7) times higher. The mean volume of ablated tumor was 17.5 mL, and the mean tumor volume was 29 mL for a mean percentage ablated tumor volume of 60%. The correlation of pain relief, mood, and pain intensity with the covariate of volume of ablated tumor was not statistically significant at 9.1 (95% CI, −11.0 to 29.2; P = .4), −12.3 (95% CI, −28.4 to 3.7; P = .14), and 10.6 (95% CI, −8.1 to 29.4; P = .27), respectively. Previous radiotherapy to the site (specific treatment to palliate the painful bone metastasis) did not statistically correlate with a reduction in pain intensity, improvement in mood, and increase in pain relief at 1.5 (95% CI, −12.1 to 15.0; P = .8), 4.5 (95% CI, −6.4 to 15.4; P = .42), and −6.4 (95% CI, −19.1 to −6.4; P = .32), respectively. Increased pain compared with pre-RFA levels during the 2 weeks after the RFA procedure and at 1 month and 3 months follow-up occurred in 27%, 17%, and 29% of patients, respectively.

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Figure 2. Summary box plots show the changes in (A) pain score, (B) pain relief, (C) mood, and (D) pain description. MPAC indicates Memorial Pain Assessment Card; RFA, radiofrequency ablation. *indicates the mean.

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Table 3. Statistical Analysis
MeasurementPre-RFA to 1-Month Follow-up (SE)Pre-RFA to 3-Month Follow-up (SE)
  1. RFA indicates radiofrequency ablation; SE, standard error; MPAC, Memorial Pain Assessment Card.

Pain MPAC (0-100)−26.9 (4.7) [n = 41]−14.16 (5.73) [n = 31]
Pain relief26.3 (4.4) [n = 42]16.4 (6.6) [n = 32]
Mood19.9 (4.1) [n = 43]14.9 (5.1) [n = 33]
Pain severity14.0 (6.0) [n = 42]8.0 (3.7) [n = 32]

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES

Of approximately 965,000 new cancer cases each year in the United States, approximately 30% to 70% will develop skeletal metastases. Given the high prevalence of carcinomas of the breast, lung, and prostate, these cancers account for >80% of cases of metastatic bone disease. Bone metastases lead to significant morbidity because of pain, pathologic fracture, and neural compression.

Apart from narcotic administration, external beam radiotherapy is the primary modality for palliation of painful osseous metastases. The Radiation Therapy Oncology Group study by Tong et al8 measured cancer patients' response to radiation therapy with a pain scale and narcotic requirement scale of 1-4. Two hundred sixty-six of the 1016 patients studied had a solitary metastasis. The study showed a complete response rate of 54% and a partial response rate of 90%. There was a 30% relapse rate within the patients who survived at least 12 weeks, and patients in the study with lung cancer or with severe constant pain at the outset tended not to improve after radiation. Madsen reported a response rate of only 48% when measuring a patient's pain using a visual analog scale.9 As pointed out by a review of all published reports by Ratanatharathorn et al,16 the relapse after initial response is frequent, the pain relief in all studies is poor, and the practices of radiation therapy need to be improved.

Surgical therapy is applied in certain instances where mechanical strengthening is necessary, such as an impending fracture. These therapies are often unsuccessful in pain reduction, and patients may require significant doses of narcotics. Therefore, a more effective modality of local treatment for bone metastases could substantially improve quality of life. The life expectancy of patients with osseous metastatic disease is limited, with an average median survival of between 3 and 6 months. Therefore, finding an effective local therapy that can be done at a single outpatient sitting would be beneficial.

Percutaneous image-guided procedures for providing local tumor ablative therapy such as ethanol injection,24 vertebroplasty,25 and RFA26, 27 have shown some promise in the treatment of metastatic bone lesions. Percutaneous RFA is a technique that was originally pioneered decades ago for the treatment of trigeminal neuralgia.28 For the treatment of bone lesions, the technique involves placing an electrode under CT guidance directly into the metastasis. The electrode is coupled to a radiofrequency generator and causes tissue necrosis by heating of adjacent tissues. The potential advantages of RFA versus other destructive methods are multifold; cell death is immediate, lesion size can be accurately controlled, lesion temperature can be monitored, electrode placement can be achieved with a percutaneous image-guided procedure, and radiofrequency lesions can be performed under local anesthesia and conscious sedation.

Today RFA is commonly used in the musculoskeletal system for treatment of intractable back pain because of failed back syndrome29 and chronic back pain because of facet joint osteoarthritis.30 In addition, CT-guided RFA has been shown to be a cost-effective surgical alternative in the treatment of osteoid osteomas.27 Several early studies specifically looked at RFA's ability to reduce pain from osseous metastatic disease. Callstrom et al19 published a single-arm, paired comparison, observational study involving 12 patients with a single painful osteolytic metastasis; each patient served as their own control. Radiation therapy or chemotherapy had failed to provide pain relief. All treated lesions were osteolytic, with a combination of bone destruction and soft tissue mass. A single lesion was treated in all 12 patients. The size of the treated lesion ranged from 1 to 11 cm. One patient with a large lesion was treated in 2 separate sessions 6 weeks apart, and the remaining 11 patients were treated in a single RFA session. Before RFA, the mean worst pain score in a 24-hour period in the 12 patients was 8.0 (range, 6-10). At 4 weeks post–RFA treatment, the recorded mean worst pain had decreased to 3.1 (P < .001). No major complications from RFA were observed in these 12 patients. The American College of Radiology Imaging Network trial is consistent with a study by Goetz et al,20 which is a follow-up of Callstrom et al's study19 that demonstrated pain reduction in 41 of 43 (95%) patients after RFA. In that trial, a preprocedural pain score of 7.9 was reported, followed by mean worst pain scores decreasing to 4.5 (P < .0001) at week 4, 3.0 (P < .0001) at week 12, and 1.4 (P = .0005) at week 24 after RFA treatment. This industry-sponsored study reports highly significant and rapid reductions in pain scores as well as improvements in the quality of life for patients after RFA of painful bone metastases. In the American College of Radiology Imaging Network trial, we collected but did not analyze the brief pain inventory scale. The mean worst pain before RFA was 7.9, and the mean worst pain at 2 weeks, 1 month, and 3 months after RFA was 6.6, 4.9, and 5.0, respectively.

This National Cancer Institute-sponsored Clinical Trials Cooperative Group phase 2 study demonstrates that RFA can effectively palliate pain from bone metastases in patients with advanced solid tumors 1 and 3 months after the procedure. Pain was assessed by the MPAC before RFA. Statistically significant improvement was seen in all 4 measures of the MPAC: pain relief, patient mood, patient intensity, and pain severity. The MPAC was chosen over other pain assessment instruments because it is simple, takes <30 seconds to complete, and is an efficient means of quantifying pain.31-33 Evaluating not only pain severity, but improvement in pain and mood, makes it more suitable for medically ill patients undergoing treatment.

Of the 55 patients completing RFA, 13 (23.2%) did not have the 1-month follow-up measurement, and 23 (41.1%) did not have the 3-month follow-up measurement. This data loss is typical for a follow-up study and is a limitation of this study and other studies of its kind. The inability to obtain more complete 3-month follow-up was because of general patient deterioration caused by widespread metastatic disease. This is not uncommon for palliative studies and similar to a published drop-out rate of 32% in a recent randomized trial looking at short versus long course radiotherapy and its effects on bone pain from metastatic disease.34 In the study by Goetz et al, the drop-out rate was 47%.20 The majority of patients in this study had progressive, refractory solid tumors that had progressed after multiple chemotherapy and radiation regimens. Despite this limitation, we were able to demonstrate statistically significant pain relief. To assess the effect of missing data on the outcome, we considered all possible missing data mechanisms, and corresponding models were fitted. Our statistical analyses showed that the estimated effects of RFA in pain reduction were not sensitive to assumptions of the missing data mechanism.35 Hence, statistical analyses indicated that missing data did not have a systematic effect on the estimates of pain reduction.

RFA was well tolerated, and the observed toxicity rate was low. Only 3 of 55 (5.4%) participants experienced grade 3 adverse events related to RFA (95% CI, 1.9%-17.0%). The upper confidence limit is lower than the 30% rate defined prestudy as being unacceptable, which was used to determine the study sample size. Two factors may have contributed to the low toxicity. General endotracheal anesthesia or deep sedation with monitored anesthesia care was not used when treating tumors close to major motor nerves. This allowed sensorimotor testing during ablations where tumors were in close proximity to a major neurovascular bundle. In fact, 27 of the patients had tumors within 3 cm of a major neurovascular bundle, yet there was only 1 motor nerve deficit. Neuropathic pain can occur when treating tumors near sensory nerves because of the direct toxic effect of the heat on the nerve and may occur later because of periablational inflammatory tissue that extends adjacent to a nerve. This occurred as a grade 2 in 2 patients (Day 6 and Day 35 after RFA) and a grade 3 in 1 patient (Day 1 after RFA). In our experience, the neuropathic pain is self-limited, can be treated with gabapentin, and usually resolves or improves, as was the case in all 3 patients. Pain immediately after RFA that was greater than the baseline pre-RFA pain was observed in 27% of patients. Four patients had worse pain at either the 1- or 3-month follow-up period. No re-treatment with RFA was allowed as part of this trial. Despite allowing patients to have chemotherapy 2 weeks after RFA, the mood and pain control data were statistically significant. A total of 14 patients had chemotherapy >14 days after RFA, with a mean start date of 1 month after RFA. The 1-month pain relief was greater than the 3-month pain relief, and allowing chemotherapy administration after RFA may partially account for less pain relief at the 3-month follow-up period. In comparison to the Goetz et al trial, our pain relief was not as pronounced. This can be explained by several factors, including eligibility criteria and differences in tumor types. In the Goetz et al trial, the patients had to have a life expectancy of >2 months and had to have had previous treatment to the tumor site; 74% had previous radiotherapy to the tumor site. In our trial, we did not have these 2 eligibility criteria, and the number of patients who had previous radiotherapy to the site for bone pain palliation was only 13 of 55 (23.6%). When we specifically looked at the small subset of patients who did have previous radiotherapy, we did not see a statistically significant difference in pain relief, mood, or pain intensity compared with those patients who did not initially receive radiotherapy to their painful bone metastasis. Combination radiotherapy and ablation has been reported to be more efficacious than 1 modality alone36 as applied to palliation of chest wall masses. This difference in the number of painful sites previously irradiated could explain the differences in pain relief. In the Goetz et al trial, there were a large majority of other tumors (19 of 42), some of which have more favorable biology (eg, desmoid, paraganglioma, meningioma, thyroid, prostate, breast) and very few lung cancer metastases (4 of 42) treated, whereas in the American College of Radiology Imaging Network trial, there were 3 times more lung metastases (17 of 55) treated, which are known to be more aggressive and difficult to treat. If we combine the percentage of lung, colon, and renal metastases treated, the American College of Radiology Imaging Network trial had 68% versus 53% in the Goetz et al trial. Based on these differences, it is not surprising that the magnitude of pain relief was less in the American College of Radiology Imaging Network trial.

In conclusion, this study demonstrates that RFA for bone metastases can be safely performed and achieves palliation for bone pain metastases in a cooperative group setting. It represents a novel treatment option for patients with solid tumors that have metastasized to the bone, and further analysis in a randomized controlled trial is warranted.

Acknowledgements

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES

We thank the many people at the headquarters of the American College of Radiology Imaging Network and at the recruiting sites for their important contributions to the study as well as the oncologists at the clinical sites; Gary Dorfman, MD, Cornell Medical Center, for protocol development; Valley Lab/Covidien for technical assistance; Sujaya Rao, M. D. Anderson Cancer Center, for data collection; Lisa Nelson, University of Alabama Medical Center, for data collection; S. Nahum Goldberg, MD, Beth Israel Deaconess Medical Center, for data collection; Ronald J. Zagoria, MD, Wake Forest University Baptist Medical Center, for data collection; Daniel B. Brown, MD, Thomas Jefferson University Hospital, for data collection; Adam C. Zoga, MD, Thomas Jefferson University Hospital, for data collection; Sridhar Shankar, MD, University of Massachusetts Memorial Medical Center, for data collection; Wendy Smith, RT(R)(CV), Rhode Island Hospital, for data collection; Cynthia Cobb, RT(R)(CT), Rhode Island Hospital, for data collection; Evelyn Stainthorpe, Abrams Cancer Center of the University of Pennsylvania, for data collection; Bruce Hillman, MD, American College of Radiology Imaging Network (ACRIN), for administrative assistance; Mitchell Schnall, MD, PhD, ACRIN, for administrative assistance; Steven King, MS, CHE, ACRIN, for administrative assistance; Charles Apgar, MBA, ACRIN, for administrative assistance; Anthony Levering, RT(R)(CT)(MR), ACRIN, for data collection; Robert Sole, RT(RCTC), ACRIN, for data collection; Nancy Fredericks, MBA, ACRIN, for administrative assistance; Maria Oh, ACRIN, for administrative assistance; C. Rex Welsh, MA, ACRIN, for data collection; Timothy Welsh, ACRIN, for data collection; Fraser Wilton, CET, ACRIN, for data collection; Cheryl Crozier, RN, ACRIN for data collection; Mary Kelly-Truran, RN, ACRIN, for data collection; Chris Steward, BS, RT (R)(CV), ACRIN, for data collection; and the following members of the American College of Radiology Biostatistics Center: Constantine Gatsonis, PhD for editorial assistance and Meredith Blevins for statistical assistance.

CONFLICT OF INTEREST DISCLOSURES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES

The trial was conducted by the American College of Radiology Imaging Network and funded by the National Cancer Institute. The American College of Radiology Imaging Network receives funding from the National Cancer Institute through the grants U01 CA079778 and U01 CA080098. Drs. Dupuy and Ahrar receive speaking honoraria from Covidien.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES
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