ABSTRACT
Purpose/Objective(s)
Various radiation therapy (RT) dose/fractionation schedules are acceptable for palliation in Multiple Myeloma. Nine years of single Institution RT experience was reviewed to determine the influence of dose/fractionation and other factors pertinent to individualizing therapy.
Methods
152 items were identified from CPT codes for Multiple Myeloma treatment from 2012 through 6/30/2021. After exclusions, 204 sites of radiation in 94 patients were reviewed. Data were captured from treatment planning and clinical records. To statistically assess the association between biological effective dose (BED10) and variables of interest, BED was first dichotomized to <24 Gy vs. ≥24 Gy. Multivariate analysis used SAS software and a generalized estimating equation approach to account for multiple observations per patient.
Results
Fractions of 1.8 - 8Gy were used in one to 25 fractions. Most patients had no significant toxicity. Grade 1 toxicity was more likely with higher BED radiation courses, as expected [20% vs. 12% for BED <24 Gy]. Pain relief was complete or very good for most sites, with <3 % reporting no pain relief. Eleven sites in 9 patients required retreatment. All retreatment sites had palliation that was lasting, with median of 22 months to last follow-up or death after repeat course (range 0.5-106 months). There was a trend for better pain control and less risk of fracture retreatment with BED ≥24 Gy.
Conclusions
Most patients had good palliation without toxicity. BED ≥24 Gy caused 8% higher risk of grade 1 toxicity and trended towards better pain control plus reduced risk of fracture re-treatment.
INTRODUCTION
Multiple myeloma is a hematologic malignancy that frequently requires radiation therapy (RT) for palliation of painful bony metastases. Various dose/fractionation schedules are acceptable for palliation in Multiple Myeloma. [1], [2],[3] To further assess dose/fractionation efficacy/toxicity and seek other factors pertinent to individualizing therapy, we reviewed experience for patients identified in the past 9 years.
METHODS
Patient Data Acquisition
Institutional Review Board approval was granted for retrospective study. CPT codes for Multiple Myeloma treatments from 2012 through 6/30/2021 identified 152 items. Only patients treated for local myeloma sites were studied. Nine sites among those patients treated earlier than the capture date were included for a total of 205 sites in 94 patients. Treatment was individualized at the discretion of the care team. Toxicity attributed to radiotherapy was graded using CTCAE version 4.0. Data were captured from treatment planning software and electronic medical records. Statistical Analysis: To assess the association between Biological Effective Dose for early reacting tissue and tumors α/β =10 (BED) and the variables of interest, BED was first dichotomized into two distinct groups, having a BED scale less than 24, or BED scale of 24 or greater.
Statistical Analysis
Descriptive analyses consisted of summarizing variables of interest using measures of central tendency (sample medians), dispersion (interquartile range), and distribution (frequency, percentage). Missing data was assumed to be missing completely at random (MCAR) and was not included in descriptive summaries or models. Multivariate analysis of BED comprised of a generalized estimating equation (GEE) approach to account for multiple observations by participant. [4] Model specification included the logit link function and binomial distribution family, as well as a compound symmetric within-subject correlation structure. Although multiple variables were inspected for appropriateness to include in the longitudinal model, careful attention to the model convergence and factors that could reliably be estimated are included in the final model. All analyses were conducted using SAS software, version 9.4 of the SAS System for Windows.
RESULTS
Demographics are shown in Table 1 and information about concurrent systemic therapy, termed chemotherapy. Staging was coded as the most updated available. If a patient had data for both International Staging (ISS) and Durie Salmon, ISS was used, and revised ISS if known. Some of the Table 1 factors are known or possible prognostic indicators such as high risk cytogenetics, chromosome 1 abnormalities, race, stem cell transplant and family history of hematologic malignancies. [5, 6] [7] Components of bortezomib, lenalidomide and dexamethasone (VRD) were common 1st line systemic therapy. Most reported responses to initial systemic therapy ranged from good to complete while 8.6 % had stable or progressive disease. Response was unknown for 36 patients.
Table 1 statistics reported as Mean (Standard Deviation) for continuous factors, and Frequency (Column Percentage %) for categorical factorsUnknown values are reported and not included in summary statistics
Table 1Demographics by BED at First Course
| BED <24 Gy (N = 27) | BED +24 Gy (N = 67) | Total (N = 94) | |
|---|---|---|---|
| Age at Diagnosis (Years) | 62.0 (10.09) | 60.9 (12.59) | 61.3 (11.88) |
| Stage | |||
| 1 | 5 (26.3%) | 7 (15.9%) | 12 (19.0%) |
| 2 | 7 (36.8%) | 15 (34.1%) | 22 (34.9%) |
| 3 | 7 (36.8%) | 22 (50.0%) | 29 (46.0%) |
| Unknown | 8 | 23 | 31 |
| Sex (Male) | 18 (66.7%) | 37 (55.2%) | 55 (58.5%) |
| Stem Cell Transplant (Yes) | 12 (46.2%) | 35 (53.0%) | 47 (51.1%) |
| Unknown | 1 | 1 | 2 |
| Total Cytogenetics (Yes) | 4 (28.6%) | 11 (28.9%) | 15 (28.8%) |
| Unknown | 13 | 29 | 42 |
| Chromosome 1 Abnormality | |||
| Gain/amp | 3 (75.0%) | 13 (81.3%) | 16 (80.0%) |
| Del | 1 (25.0%) | 3 (18.8%) | 4 (20.0%) |
| Unknown | 23 | 51 | 74 |
| Race | |||
| White or Other | 15 (55.6%) | 42 (62.7%) | 57 (60.6%) |
| Black | 12 (44.4%) | 25 (37.3%) | 37 (39.4%) |
| Family History | |||
| Heme C | 3 (13.6%) | 4 (7.5%) | 7 (9.3%) |
| Other | 11 (50.0%) | 28 (52.8%) | 39 (52.0%) |
| None | 8 (36.4%) | 21 (39.6%) | 29 (38.7%) |
| Unknown | 5 | 14 | 19 |
| Death (Yes) | 13 (48.1%) | 35 (52.2%) | 48 (51.1%) |
| Response to first Chemo | |||
| CR | 6 (35.3%) | 9 (22.0%) | 15 (25.9%) |
| VGPR, Near CR | 7 (41.2%) | 18 (43.9%) | 25 (43.1%) |
| PR, Good | 3 (17.6%) | 10 (24.4%) | 13 (22.4%) |
| Stable | 1 (5.9%) | 1 (2.4%) | 2 (3.4%) |
| Progress | 0 (0.0%) | 3 (7.3%) | 3 (5.2%) |
| Unknown | 10 | 26 | 36 |
Abbreviations: CR = Complete Response, VGPR = Very Good Partial Response
The supplementary Table has details and radiation parameters that are not included in the Table 2 analysis, which was restricted to six radiation courses. Concurrent systemic therapy was used in the majority. For patients who had more than 3 radiation courses, all were beyond 1st line systemic therapy by then and they received a variety of salvage agents.
Table 2GEE model results
| Course 1 | Course 2 | Course 3 | Course 4 | Course 5 | Course 6 | Adjusted Odds Ratio (95% CI) | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| BED <24 Gy (N = 21) | BED +24 Gy (N = 78) | BED <24 Gy (N = 9) | BED +24 Gy (N = 29) | BED <24 Gy (N = 4) | BED +24 Gy (N = 13) | BED <24 Gy (N = 4) | BED +24 Gy (N = 5) | BED <24 Gy (N = 3) | BED +24 Gy (N = 7) | BED <24 Gy (N = 1) | BED +24 Gy (N = 1) | ||
| Stem Cell Transplant | |||||||||||||
| Yes | 7 (14.6%) | 41 (85.4%) | 7 (28.0%) | 18 (72.0%) | 2 (18.2%) | 9 (81.8%) | 4 (57.1%) | 3 (42.9%) | 1 (16.7%) | 5 (83.3%) | 1 (50.0%) | 1 (50.0%) | 1.26 (0.48, 3.33) |
| No | 14 (27.5%) | 37 (72.5%) | 2 (15.4%) | 11 (84.6%) | 2 (33.3%) | 4 (66.7%) | 0 (0.0%) | 2 (100.0%) | 2 (50.0%) | 2 (50.0%) | 0 (0.0%) | 0 (0.0%) | REF |
| Race | |||||||||||||
| White or Other | 16 (24.6%) | 49 (75.4%) | 6 (30.0%) | 14 (70.0%) | 2 (16.7%) | 10 (83.3%) | 3 (50.0%) | 3 (50.0%) | 1 (20.0%) | 4 (80.0%) | 1 (100.0%) | 0 (0.0%) | 0.99 (0.36, 2.72) |
| Black | 5 (14.7%) | 29 (85.3%) | 3 (16.7%) | 15 (83.3%) | 2 (40.0%) | 3 (60.0%) | 1 (33.3%) | 2 (66.7%) | 2 (40.0%) | 3 (60.0%) | 0 (0.0%) | 1 (100.0%) | REF |
| Site | |||||||||||||
| Pelvis | 6 (15.8%) | 32 (84.2%) | 1 (20.0%) | 4 (80.0%) | 0 (0.0%) | 5 (100.0%) | 0 (0.0%) | 0 (0.0%) | 1 (50.0%) | 1 (50.0%) | 0 (0.0%) | 0 (0.0%) | 1.71 (0.74, 3.93) |
| Spine | 4 (13.3%) | 26 (86.7%) | 5 (26.3%) | 14 (73.7%) | 1 (25.0%) | 3 (75.0%) | 1 (50.0%) | 1 (50.0%) | 0 (0.0%) | 2 (100.0%) | 0 (0.0%) | 0 (0.0%) | 1.76 (0.66, 4.71) |
| Other | 11 (35.5%) | 20 (64.5%) | 3 (21.4%) | 11 (78.6%) | 3 (37.5%) | 5 (62.5%) | 3 (42.9%) | 4 (57.1%) | 2 (33.3%) | 4 (66.7%) | 1 (50.0%) | 1 (50.0%) | REF |
| Known fracture at time of treatment | |||||||||||||
| Yes | 6 (17.1%) | 29 (82.9%) | 1 (50.0%) | 1 (50.0%) | 0 (0.0%) | 5 (100.0%) | 1 (100.0%) | 0 (0.0%) | 0 (0.0%) | 1 (100.0%) | 1 (100.0%) | 0 (0.0%) | 1.44 (0.55, 3.75) |
| No | 15 (23.4%) | 49 (76.6%) | 8 (22.2%) | 28 (77.8%) | 4 (33.3%) | 8 (66.7%) | 3 (37.5%) | 5 (62.5%) | 3 (33.3%) | 6 (66.7%) | 0 (0.0%) | 1 (100.0%) | REF |
| Toxicity | |||||||||||||
| 1 or 2 | 5 (26.3%) | 14 (73.7%) | 0 (0.0%) | 6 (100.0%) | 0 (0.0%) | 4 (100.0%) | 0 (0.0%) | 2 (100.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 1.31 (0.14, 12.56) |
| 0 | 16 (20.0%) | 64 (80.0%) | 9 (28.1%) | 23 (71.9%) | 4 (30.8%) | 9 (69.2%) | 4 (57.1%) | 3 (42.9%) | 3 (30.0%) | 7 (70.0%) | 1 (50.0%) | 1 (50.0%) | REF |
| Pain Scale Category | |||||||||||||
| Complete or Very Good Relief | 11 (16.9%) | 54 (83.1%) | 5 (18.5%) | 22 (81.5%) | 4 (44.4%) | 5 (55.6%) | 0 (0.0%) | 3 (100.0%) | 2 (22.2%) | 7 (77.8%) | 0 (0.0%) | 1 (100.0%) | - |
| Partial or No Relief | 10 (29.4%) | 24 (70.6%) | 4 (36.4%) | 7 (63.6%) | 0 (0.0%) | 8 (100.0%) | 4 (66.7%) | 2 (33.3%) | 1 (100.0%) | 0 (0.0%) | 1 (100.0%) | 0 (0.0%) | - |
Table 2 statistics reported as Frequency (Row Percentage %) for all categorical factors
Total of 175 observations used in model, or 85.4% of all available observations (175/205) from 85 of the available 94 patients
† Odds are based on the probability that BED +24
‡ Odds ratio and CI are stratified by Pain Scale (Complete of Very Good Relief)
Radiation dose per fraction varied from 1.8 - to 8 Gy while the number of fractions varied from one to 25 with delivery in one to 36 days. Some sites with unusual fractionations, such as 3 Gy x 6, were planned for more but the full course was not delivered. Two patients were treated with 1.8 Gy to 45 Gy based on good prognostic factors; one had last follow-up at 105 months and the other died at 57.7 months. The most frequent schedule was 2 Gy x 10 fractions (EQD2 of 20 Gy) and corresponds to the Biologically Effective Dose for early reacting tissue with an α/β of 10 (BED) of 24 Gy. Table 2 provides Odds Ratios for six parameters using radiation with BED 24 Gy or higher compared to lower dose. With limitations of the statistical model, selection of factors for comparison was influenced by the frequency.
The majority of patients had no reported toxicity (87.8% for BED <24 Gy and 79.5% for ≥24 Gy). As expected, the risk of toxicity was greater for higher BED radiation and the only Grade 2 was gastrointestinal complaint after 3 Gy x 10 fractions to the pelvis. Since most patients continued with systemic therapy, this may also have contributed to toxicity attributed to radiation.
Pain relief was complete or very good for the majority of sites. There was variation of pain response between sites of treatment that were not radiation- or patient dependent. For instance, an individual might have complete pain relief at one site while another site receiving the same radiation had less response.
Good palliation (Complete or Very Good pain relief) was more likely with BED ≥ 24 Gy than less radiation (51% vs. 68.75% when confounding factors were not assessed). Pain response was usually durable with <10% of patients having a site retreatment with monitoring up to 133 months from initial radiation to death or last follow-up. Most patients in the category of partial, or no pain response, had modest relief. Only 4 patients had no significant pain relief at 6 sites (2.9%), and 2 of the patients had relief at other sites. Three sites given 8Gy fractions had worse pain the next day, consistent with flare response. Confounding factors of no pain relief reports include incomplete radiation course and pain at other sites or medical conditions that interfered with assessment.
Objective measures were helpful in assessing the efficacy of radiation. Images confirmed that a single 4 Gy treatment was adequate to allow fracture healing and complete pain relief although the area remained weak and another fracture in that lesion occurred after trauma at 31 months. Two others with low BED at fractures had short survival and a third patient had no problem during 72-month follow-up but that fracture had rod stabilization. In concern for higher dose impedance of bone healing, no problem was noted of fractures treated at higher dose. No indication was found that BED ≥30 Gy at 7 fracture sites interfered with healing. Most sites had control until death or last follow-up; the retreatment rate was 5.3% as discussed below.
Positron emission tomography (PET) imaging was helpful for assessing efficacy of radiation and was available for 76 sites (37.0%). PET demonstrated efficacy of low dose RT in some patients, whereas 46% at higher radiation lacked complete resolution. Factors other than radiation dose, such as resistant disease, inflammation not definitively distinguishable from active disease, or larger masses not controlled by usual palliative doses of radiation, were not analyzed.
Most patients who had PET resolution had complete pain relief as shown in Table 3. The observation that a few patients who still had pain at PET resolution suggests other factors contributing to pain such as continued mass effect or other etiologies. There are myeloma patients whose disease does not always appear PET avid, but none were found in this series. PET resolution was more likely with BED ≥24 (53.9%) than BED <24 Gy (38.4%). Each group had one PET progression within 6 mo. and partial pain relief in those sites.
5 lesions with PET images were excluded due to unknown pain response
Table 3PET Resolution Compared to Pain Relief
| PET Result | |||
|---|---|---|---|
| Resolution | Residual | Progression | |
| Pain Relief | Number | Number | Number |
| Complete | 16 | 5 | 0 |
| Partial | 20 | 28 | 2 |
Overall, fracture sites were treated with nearly the whole range of BED (3.9-31.25 Gy). However, fracture sites requiring retreatment tended to received lower initial BED (5.6-31.25 Gy, mean 16.9 Gy, median 14.8 Gy); while fracture associated sites not requiring retreatment received BED of 3.9-31.25 Gy, (mean 22.9 Gy, median 24 Gy). Initial fracture sites treated at 4 Gy x 1 and 2 Gy X 10 (ID31 and 79, respectively) had healing but experienced 2nd fracture after trauma and were retreated (Table 4).
Months from 1st to 2nd RT and Months to last follow-up or death are rounded to nearest month. Pain and PET response CR = complete, PR = Partial, na = not available
Table 4Comparison of features associated with initial RT and retreatment
| ID | Fracture | BED | Pain | Toxicity | PET Response | Months 1st-2nd RT | Months to Last FU/dod | ||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| 1st RT | 2nd RT | 1st RT | 2nd RT | 1st RT | 2nd RT | 1st RT | 2nd RT | ||||
| 31 | yes | 5.6 | 5.6 | CR | PR | 0 | 0 | na | na | 32 | 22 |
| 31 | yes | 5.6 | 5.6 | CR | PR | 0 | 0 | na | na | 16 | 22 |
| 31 | yes | 5.6 | 5.6 | CR | PR | 0 | 0 | na | na | 15 | 22 |
| 42 | - | 9.6 | 9.6 | PR | PR | 0 | 0 | na | Low residual | 11 | 23 |
| 46 | yes | 24 | 24 | Near CR | PR | 0 | 1 | na | na | 27 | 31 |
| 53 | yes | 31.25 | 43.75 | CR | CR | na | na | na | CR | 18 | 106 |
| 79 | yes | 24 | 24 | PR | PR | 0 | 0 | na | na | 7 | 94 |
| 146 | yes | unk | 37.5 | CR | PR | na | 1 | na | Low residual | 90 | 11 |
| 172 | - | 8.49 | 31.25 | PR | PR | 1 | 1 | na | na | 16 | 12 |
| 184 | - | 30 | 28 | CR | CR | 0 | 0 | residual | residual | 2 | 1 |
| 229 | yes | 14.4 | 24 | PR | PR | 1 | 0 | progress | na | 7 | 3 |
Eleven sites in 9 patients required retreatment, with at least partial overlap of the initial field. No patient had 3 treatments to the same site. Factors are compared in Table 4. Initial dose/fractionations included 1.8 Gy x 4, 2 Gy x 4, 2 Gy x 10, 3 Gy x10, 4 Gy x1, 8 Gy x 1 and one site with 10 fractions of unknown Gy delivered at another institution. The need for retreatment was considered in field progression in 6 and overlap with other lesions in 3. All sites treated at our institution had palliative benefit from both 1st and 2nd courses that was lasting with median of 22 months to latest follow up or death after retreatment.
DISCUSSION
Historically a variety of dose/fractionation schedules have been successfully used for palliation of predominantly bone lesions in multiple myeloma patients [2] [1] [8] [9, 10] [11] [2] [12] Since myeloma is usually more radiosensitive than most solid tumors, lower doses have frequently been satisfactory. ASTRO guidelines for bone metastasis provides a review of outcome with various “practices” and the tradeoff of quicker relief plus convenience for short course radiation versus reduced rate of retreatment for longer courses. [1], [9] One more recent analysis of 87 lesions had less need for re-treatment with Equivalent dose in 2 Gy fractions (EQD2 = 23.33 Gyα/β =10) or above. [12] Others found satisfactory results with yet a lower dose range for more selected patients. [12, 13] Price et, al. found that radiation schedules with EQD2 <12 Gy was effective for pain control in 95% of uncomplicated bone lesions. [13] Although the number of lesions was limited to 48 for the high dose and 22 for the low dose, the duration of pain relief and rate of pain recurrence was not statistically different. Retreatment was used for 9.5% of the low dose group and 6.3% of the higher dose group. This rate of retreatment is similar to that in other reports using a variety of dose/fractionation courses. [1, 10] [2] [14] In keeping with the desire to provide appropriate treatment, that study excluded patients who had epidural lesions and fractures since a prior report found short course radiation to be suboptimal for spinal cord compression in myeloma patient.[15] [10]
The choices of dose/fractionation schedules of this experience showed good outcomes and provide data for efforts to improve radiation guidelines. No toxicity was reported for the majority of sites treated regardless of the radiation dose/fractionation schedule and whether or not the radiation was given alone or with systemic agents; mild toxicity was more frequent with higher BED. Similar to other studies, most of our patients received systemic therapy that was not interrupted for radiation. [16]
With individualization, the minority of patients treated with large single fractions had circumstances such as limited life expectancy, other medical conditions and social difficulties. Only 4 had 8 Gy x 1 to the spine, with most patients having multi-fraction courses to the spine in following published guidelines. [1, 17, 18]
Most patients had good palliative benefit; some may have had better pain relief than reported due to early evaluation but limited follow-up. Except for 2.9% of sites, at least modest pain relief was achieved. Consistent with earlier reports, low BED radiation to selected patients had acceptable rates of palliation and risk of retreatment although less than BED ≥24 Gy [13]. Single and hypo-fractionated regimens are appropriate for many patients but are not recommended for all sites, such as multi-level spine, cord compression, areas of fracture and large masses.[18] In general, relief was durable. Outcome from retreatment was improved over that reported for bone metastasis from more diverse histologies. [19]
Although treatment courses were based on non-financial factors, the risk of retreatment was cost effective. The billing charges for two single fraction courses versus a single course of 10 fractions, was 9% more. The fact that only 11 of 205 total sites required retreatment reduces health care spending compared to longer courses for all sites.
PET and other imaging was helpful for assessing efficacy of radiation but suggest that there are multiple factors involved in individual site responses. [20]
Conclusions
Most patients had good palliation without toxicity. BED ≥24 Gy caused 8% higher risk of grade 1 toxicity and trended towards better pain control plus reduced risk of fracture re-treatment.
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Supported by Department of Radiation Oncology and the UAB Center for Clinical and Translational Science Award UL1TR003096.
All pertinent data generated and analyzed during this study are included in this published article.
Declaration of Competing Interest
No authors have a conflict of interest.
Acknowledgments
The authors wish to thank Roleah Hill for assistance.
Appendix. Supplementary materials
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Accepted:
February 28,
2023
Received:
December 13,
2022
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