International Journal of Radiation Oncology *
Biology * Physics
Volume 80, Issue 4 , Pages 1164-1170, 15 July 2011
Osteolymphoma (OL), or primary bone lymphoma, is a rare condition for which many features of the disease, including the optimal treatment, remain unknown. To improve our knowledge of this disease, a prospective study with four objectives was established.
The first objective was to set benchmark values for the clinical outcomes of standard treatment. There were no pre-existing prospective studies specifically addressing this disease, although there were retrospective reports These indicated that relatively poor results were achieved when patients were treated by radiotherapy alone. Improvements were associated with the addition of chemotherapy, but these did not reach statistical significance. Combined modality treatments were commonly claimed to be the preferred method of treatment for OL, based on improvements seen in nodal lymphomas. Studies indicating the role of monoclonal antibodies were not yet reported at the time that this study began.
The second objective was to identify significant prognostic factors. Only one previous study had been large enough to identify these, but the power to detect significant factors may have been limited by heterogeneity in the treatments that had been used. During the course of our trial, a second large retrospective study also produced results identifying prognostic factors
The third objective was to consider factors that might predispose patients to a higher risk of subsequent pathological fracture, and to try to minimize the risk by limiting specific features of the treatment. These included limiting the size of the biopsy, the exposure to corticosteroids in the chemotherapy schedule, the total radiation dose, the volume of the bone irradiated, and the radiation fraction size. Previous studies had highlighted the disability associated with subsequent fractures
The fourth objective was to look for evidence that OL may have specific features that would warrant its consideration as a separate clinical entity. It had been observed that OL may sometimes recur in bone exclusively, both in human beings and in dogs In some patients, multiple bony sites are affected in the absence of soft tissue disease, raising the possibility that a homing process was occurring. Clinical issues specific to OL include orthopaedic stabilization before treatment, fracture-related problems, and difficulties in assessing response to treatment, given that the changes in bone are often sufficient to mislead the clinician into thinking that local recurrence has occurred. Because of these characteristic features and because of the difficulties in literature searching based on the previous multitude of compound terms that had been used, the term “osteolymphoma” was proposed and is discussed in more detail elsewhere
In 1999, the Trans-Tasman Radiation Oncology Group (TROG) invited the Australasian Leukemia and Lymphoma Group (ALLG) to collab
The second objective was to identify prognostic factors, and the fourth objective was to identify features to suggest that OL was distinct from other NHLs. The small size of this study precluded the fulfilment of these goals.
The third objective was to address the high fracture rate that had been reported in two earlier studies These studies had noted the disability that fractures could cause and suggested that there were implications for the use of radiotherapy. In our study, the three pathological fractures after treatment were at the same site as the three fractures at presentation. No other factors were identified that predisposed to posttreatment fracture. At the doses and fraction size used, radiotherapy seems unlikely to have contributed to the fractures. On the contrary, it may have prevented other patients from developing fractures and disability by reducing the rate of local recurrence. Long-term toxicity from radiotherapy was not noted, possibly because the total doses used were lower than in these earlier studies and because a shrinking field technique was used. Pathological fractures may have also been avoided by limiting the exposure to corticosteroids by using only three cycles of chemotherapy. Contrary to these previous studies, we therefore conclude that with regard to pathological fractures, radiotherapy should continue to be given to prevent disability resulting from fractures associated with local recurrence.
Although the prospective study of rare cancers remains problematic, future studies in OL could consider several issues. These include the imaging requirements, as it is yet to be demonstrated that PET scanning is more useful than Gallium scanning, given that PET scanning often omits the limbs. A previous study of gallium scanning suggested a 75% sensitivity rate for OL. There should also be detailed pathological correlation to identify those pathological features that may predict for osseous homing, and assessment of the addition of monoclonal antibodies.
Although large single institutions or networks such as the International Extranodal Lymphoma Study Group (IELSG) and the rare cancer network can productively amass large bodies of retrospective data, there are few that have demonstrated a capacity to run prospective clinical trials of rare cancers on a sufficiently large scale to draw firm conclusions. TROG and ALLG have successfully developed the infrastructure required to run trials relating to more common cancers, but attempts to run trials of rare cancers are likely to be among those trials that fail to achieve accrual of their intended sample size. Our previous retrospective review of nine institutions suggested an accrual rate of around 7 patients per year. Expanding this to approximately 45 institutions affiliated with TROG and ALLG, along with the increases in populations and increases in research infrastructure during the intervening time, would suggest that patients who were potentially eligible may not have been registered. To achieve success in this setting might require having a larger network of participating centers and having processes in place that would more strongly compel clinicians to at least offer patients the opportunity to enter trials that are available.
During the accrual period for this trial, a significant advance was made in the routine treatment of nodal NHL (17). The addition of rituximab to conventional chemotherapy was shown to increase survival and was funded for routine use in Australia in a way that did not distinguish between nodal and extranodal subtypes of disease. These improvements would have made it problematic for clinicians to manage patients with OL without including rituximab as a component of the treatment. However, as rituximab had not been shown to improve results in any trials of extranodal NHL, the protocol was not amended to include rituximab, but its use was noted as a minor treatment variation. In the final year of accrual, 3 patients received rituximab, and 6 patients received it over the whole accrual period. Of the 6 patients, 4 experienced Grade 3 toxicity attributable to rituximab, including 1 patient who was considered allergic to it.
orate on a prospective study of limited chemotherapy and radiotherapy for osteolymphoma. The treatment was designed to maintain efficacy but limit the risk of subsequent pathological fractures. Patient assessment included both functional imaging and isotope bone scanning. Treatment included three cycles of CHOP chemotherapy and radiation to a dose of 45 Gy in 25 fractions using a shrinking field technique.
The trial closed because of slow accrual after 33 patients had been entered. Accrual was noted to slow down after Rituximab became readily available in Australia. After a median follow-up of 4.3 years, the five-year overall survival and local control rates are estimated at 90% and 72% respectively. Three patients had fractures at presentation that persisted after treatment, one with recurrent lymphoma.
Relatively high rates of survival were achieved but the number of local failures suggests that the dose of radiotherapy should remain higher than it is for other types of lymphoma. Disability after treatment due to pathological fracture was not seen.
This was the only prospective trial specifically addressing the treatment of OL, and it had four objectives. The first objective was to establish benchmark results for standard treatment including limited chemotherapy and shrinking field radiotherapy. The survival results noted could be considered benchmark values; however the confidence intervals were wide, so any future improvements in treatment may be difficult to identify. The 5-year overall survival rate of 90% compares favorably with the results of our previous retrospective study , in which the corresponding figure was 59%, bearing in mind that the latter study included patients with more advanced disease and the proportion who received chemotherapy was only 56%. Although most studies addressing the effect of chemotherapy on survival for patients with OL have shown that it is of no statistically significant benefit, it is likely that the apparent improvement in results is due to chemotherapy, and it should remain part of the standard treatment. At the time that this study was designed, there was evidence to support the limitation of CHOP chemotherapy to three cycles,. However, since then, the use of six or eight cycles has become more common for nodal NHL. In this study, although the rate of overall survival was relatively high, the figure for failure-free survival suggests some room for improvement. Future prospective studies of OL could test the addition of a greater number of cycles of chemotherapy and the addition of rituximab. Comparison of this current study with our previous retrospective study shows a lower rate of local control (82% vs. 72%), although the CIs overlap. The assessment of local tumor response is problematic as there is often a persistent defect in the affected bone that could be misinterpreted as active disease. Consequently, the apparent reduction in local control might be due to more rigorous posttreatment assessment rather than being an indication of reduced treatment effectiveness. The use of functional assessment (PET scanning) posttreatment may warrant further study; however, as radiotherapy remains the principal method used to secure local control, it should remain a component of the treatment. Other authors have noted a growing trend toward the use of chemotherapy alone for early-stage DLBCL affecting other sites, but for OL it should be considered investigational. Although the radiation doses used in this study and most other studies of OL are higher than those used for other types of NHL, the toxicity is acceptable. Perhaps the next prospective study could test an incremental increase in the number of chemotherapy cycles, as well as the addition of rituximab, in combination with the same radiotherapy schedule that was used in this current trial.