Pain relief
Osteolytic lesions and bone pain is a common symptom in patients with multiple myeloma and present at the time of first diagnosis in 70% of cases [
5]. Larger osteolytic lesions are frequently associated with pain and the risk of fracture. Accordingly, radiotherapy in addition to systemic treatment is typically administered in these situations and is frequently associated with rapid pain relief. Bone disease remains complex and is caused by the production of the osteoclast stimulating enzymes [
15]. The inhibition of pain mediators and the shrinkage of the tumor are thought to be the main mechanisms of analgesic effects derived from irradiation. The often rapid analgesic effect of irradiation is not completely understood. Since ionizing irradiation induces apoptosis in myeloma cells within 72 h [
16], rapid death of myeloma cells resulting in decompression of nerves and pressure sensors following tumor shrinkage is probably the most important mechanism. Other proposed mechanisms include the obstruction of the secretion of mediators such as substance P and cytokines, at the interface of myeloma cells and the bone matrix [
17,
18]. Recalcification is achieved long term after a few months, while an analgesic effect is obtained during or immediately after radiotherapy.
The analgesic success rate of radiotherapy in our study was 85% of all irradiations. In the period of aftercare, 54% of our patients achieved partial analgesic effect and 31% achieved complete pain relief. Even partial pain relief is appropriate in view of the few side effects of radiotherapy. Uni- and multivariate logistic regression analysis revealed significant better pain relief at increased (2 Gy equivalence) total dose (α/β = 10 Gy, Figure
1) and with increasing age at time of radiotherapy (Figure
2). Using a α/β of 10 Gy to calculate 2 Gy equivalent total doses resulted in steeper dose response curves than using a α/β of 2 Gy for calculation indirectly indicating that pain relief behaves radiobiologically like an acute effect.
The high efficacy of radiotherapy that induces complete or partial pain relief in 75-95% of patients with painful myeloma bone lesions has been reported from several independent retrospective evaluations [
7,
19,
20]. The majority of the patients in these investigations were treated with total doses between 30 and 40 Gy, typically using fraction sizes between 2 and 3 Gy. Relatively few patients were treated with low doses like 1×8 Gy or 5×4 Gy. With a few exceptions, investigators did not test whether greater radiation doses are associated with improved pain control, either because of too small variation in the employed radiation schedules or because of too short variation in pain control. Stölting et al. found in a univariate analysis significantly better pain control for total doses between 40–49.9 Gy compared to total doses below 30 Gy as well as for doses per fraction of 2 Gy compared to doses per fraction of ≥4 Gy. In the multivariate analysis, only the use of 2 Gy per fraction compared to doses per fraction of ≥4 Gy remained significant. Since 2 Gy per fraction schedules were highly associated with total doses of 40 Gy or greater, the reported results can be interpreted as evidence for a significant dose response relationship. Unfortunately, the authors did not normalize their different fractionation schedule by using 2 Gy equivalent dose or normalized total doses, making a direct comparison to the data presented here difficult. Leigh et al. [
21] reported a slight trend to higher rates of pain relief at higher radiation doses, but did also not employ a normalization of the used fractionation schedule. In the work of Adamietz et al. [
8] the median total radiation doses (not normalized) of responding and not responding myeloma patients in terms of pain relief were identical, indirectly indicating no distinct dose response relationship. Whether the use of normalized total doses and more advanced statistical tools would have led to the detection of significant dose response relationships for pain control, however, remains unclear. In view of the retrospective nature of the data presented here and the relatively small number of patients treated with normalized total doses below 20 Gy, the question, which dose and fractionation is most appropriate for painful bone lesions from multiple myeloma remains unresolved. Additionally, all patients included in our analysis received anti-osteoclastic drugs such as bisphosphonates as well as analgetics, if necessary The associated effects of these treatments are difficult to account for given their universal use. In our investigation we found no correlation between pain relief and recalcification. Adamietz et al. [
8] reported a significantly longer duration of pain control at higher total radiation doses. No data in this regard are available from other authors.
An unexpected finding was that higher age at radiotherapy was associated with better pain control. This is in contradiction to the results of Stölting et al. [
7], who reported better outcome in patients <60 years compared to patients >70 years. Using the same dichotomous categories instead of age as continuous variable, we found no age effect in our cohort (data not shown). The considerably younger average age in the cohort presents here may explain the different findings that otherwise remain unexplained. Probably the analgesic effect is a summation of the previous treatment, which depends on the biology of the tumor and the prior chemotherapy.
The effect of systemic treatments on pain relief in patients with ostelytic bone lesion has not been well investigated. The shape of the dose response curve for radiotherapy (Figure
1) suggests that approximately 50% of patients may have the chance to experience pain relief without radiotherapy most likely as result of the effect of systemic treatments. Concurrent systemic therapy at the time of radiotherapy was associated with better pain control in some reports [
6]. This association was not confirmed in the present investigation. Since no details on concurrent and sequential systemic treatments were reported from any of the analyzed cohorts, potential interaction of radiotherapy with systemic treatments cannot be reliably performed. However, very few severe side effects have been reported, indicating that important interactions of radiotherapy and systemic treatments used for the treatment of multiple myelomas are probably rare.
Recalcification
Beside pain relief, a recalcification of bony lesions is desirable to reduce the bone fracture rate. Therapy of solitary plasmocytoma underline higher target volume doses are more effective. Total doses of 45 Gy or higher in 2.0-2.5 Gy per fraction seem to eradicate most tumors [
22,
23] and is re-emphasized by studies of solid tumors [
19]. But these clinical trials do not examine multiple myeloma osteolyses in particular.
The recalcification success rate of radiotherapy in our study was 48% of all irradiations. During follow up, 25% of our patients achieved partial recalcification and 23% reached complete recalcification. Uni- and multivariate logistic regression analysis revealed a significant better recalcification at increased (2 Gy equivalence) total dose (α/β = 10 Gy, Figure
3), whereas all other tested variables were not predictive for the likelihood of recalcification (Table
4). A limitation of our analysis is that it includes sole radiological reports and/or ROI and diameter measurement of the levels of recalcification, e.g. sclerosis, with the help of radiographs (CT, MRI or conventional X-ray imaging).
Recalcification after radiotherapy has been reported in 11-50% of patients with bone lesions of solid tumors from several independent retrospective evaluations [
6,
7]. The majority of the patients in these investigations were treated with total doses between 30 and 50 Gy typically using fraction sizes between 2 and 3 Gy. Relatively few patients were treated with low total doses like 1×8 Gy or 5×4 Gy, and most studies analyzed osteolyses of diverse solid tumors, not just multiple myeloma patients. There were only few significant results found whether higher radiation doses are associated with improved recalcification for patients with multiple myeloma.
Koswig et al. [
19] examined recalcification following radiation therapy with 2 different fractionation schedules (1 × 8 Gy vs 10 × 3 Gy) for bone metastasis of solid tumors. The recalcification showed a significant effect concerning patients in the fractionated group p <0.0001). In myeloma patients, Stölting et al. [
7] found in a univariate analysis significant better recalcification for total doses of 50–60 Gy compared to total doses below 30 Gy. This association remained significant in the multivariate analysis. Further significant parameters for recalcification in the multivariate analysis were concurrent chemotherapy vs no chemotherapy, and no fractures vs fractures. The reported results can be interpreted as evidence for a significant dose response relationship. Unfortunately, the authors did not normalize total doses, making a direct comparison to the data presented here difficult. Balducci et al. [
5] described recalcification in patients with osteolytic lesions due to diverse plasma cell neoplasm in 50% and identified as complete remission in 38%. Mose et al. [
6] also found a relevant effect in concurrent chemotherapy, but no difference in recalcification in terms of radiation dose probably due to the low variability in total doses (30–36 Gy) (Table
5). In summary, available data indicate that higher radiation doses result in improved recalcification.
Table 5
Remineralization of osteolysis at different radiation doses in literature
| 7 | 40-50 | 5X2Gy | 29 | 71 | - | - |
| 14 | 30-40 | 5X2Gy | 71 | 29 | - | - |
| 44 | 30-70 | 5X2Gy | 43 | - | - | - |
| 53 | 12-48 | - | 51 | - | - | 1943-1953 |
| 56 | 18-45 | 5X2Gy | 46 | 36 | 18 | 1988-1998 |
| 114 | 2-60 | 5X2Gy | 45 | 49 | 16 | 1970-2003 |
Current Data 2014
| 108 | 20-60 | diverse | 48 | 42 | 10 | 1989-2014 |
Side effects
Radiotherapy offers the advantage of few side effects and therefore is an appropriate palliative procedure for treating multiple myeloma [
24,
25]. Our analysis found 37% side effects with 50% grade 1, and 47.2% grade 2. One patient suffered from dysphagia (grade 3). A substantial increase in the side effects with simultaneous chemotherapy has not been reported. We found no correlation between radiotherapy-associated side effects and overall survival. Corresponding to us Foro and Arnalot [
20] reported acute side effects in 18% and Balducci et al. [
5] identified 44% of patients (n = 23) with side effects (grade 1–2): hematological toxicity in 11 (48%), gastroenteric toxicity in 6 (26%), pharyngeal toxicity in 2 (9%), and cutaneous toxicity in 4 (17%) patients. Mose et al. reported about 54% side effect mostly grade 1–2; in 4 % Grade 3 (hematopoietic changes, mucositis, creatinine level).
Median overall survival was 89.1 months for the whole cohort and radiation therapy statistically did not have an impact on survival.