Int. J. Radiation Oncology Biol. Phys., Vol. 80, No. 4, pp. 1164–1170, 2011Copyright � 2011 Elsevier Inc.

Printed in the USA. All rights reserved0360-3016/$–see front matter

jrobp.2010.03.036

doi:10.1016/j.i

CLINICAL INVESTIGATION Bone

LIMITED CHEMOTHERAPY AND SHRINKING FIELD RADIOTHERAPY FOROSTEOLYMPHOMA (PRIMARY BONE LYMPHOMA): RESULTS FROM THE

TRANS-TASMAN RADIATION ONCOLOGY GROUP 99.04 AND AUSTRALASIANLEUKAEMIA AND LYMPHOMA GROUP LY02 PROSPECTIVE TRIAL

DAVID CHRISTIE, F.R.A.N.Z.C.R.,* KEITH DEAR, M.STAT.,y THAI LE, B.H.B.,z

MICHAEL BARTON, F.R.A.N.Z.C.R.,x ANDREW WIRTH, F.R.A.N.Z.C.R.,k DAVID PORTER, F.R.A.C.P.,{

DANIEL ROOS, F.R.A.N.Z.C.R.,# AND GARY PRATT, F.R.A.N.Z.C.R.**

)Premion and Bond University, Gold Coast, Queensland, Australia; yDepartment of Epidemiology and Population Studies, AustralianNational University, Canberra, New South Wales, Australia; zBHB, Premion, Brisbane, Queensland, Australia; xCollaboration for

Cancer Outcomes and Research (CCORE) and University of NSW, Sydney, New South Wales, Australia; kPeter MacCallum CancerInstitute, Melbourne, Victoria, Australia; {Auckland Hospital, Auckland, New Zealand; #Royal Adelaide Hospital, Adelaide, South

Australia, Australia; and **Royal Brisbane Hospital, Brisbane, Queensland, Australia

Reprinand Bond0061 7christie@

FundinWesley Rthrough a

ConflicAcknowlebutions minstitutionSharon MOutcomesbra Norris

Purpose: To establish benchmark outcomes for combined modality treatment to be used in future prospective stud-ies of osteolymphoma (primary bone lymphoma).Methods and Materials: In 1999, the Trans-Tasman Radiation Oncology Group (TROG) invited the AustralasianLeukemia and Lymphoma Group (ALLG) to collaborate on a prospective study of limited chemotherapy andradiotherapy for osteolymphoma. The treatment was designed to maintain efficacy but limit the risk of subsequentpathological fractures. Patient assessment included both functional imaging and isotope bone scanning. Treatmentincluded three cycles of CHOP chemotherapy and radiation to a dose of 45 Gy in 25 fractions using a shrinkingfield technique.Results: The trial closed because of slow accrual after 33 patients had been entered. Accrual was noted to slowdown 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 frac-tures at presentation that persisted after treatment, one with recurrent lymphoma.Conclusions: Relatively high rates of survival were achieved but the number of local failures suggests that the doseof radiotherapy should remain higher than it is for other types of lymphoma. Disability after treatment due to path-ological fracture was not seen. � 2011 Elsevier Inc.

Bone, Lymphoma, Radiotherapy, Chemotherapy, Clinical trial.

INTRODUCTION

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 ob-

jectives was established.

t requests to: David Christie, F.R.A.N.Z.C.R., PremionUniversity, Gold Coast, Queensland, Australia. Tel:

55980366; Fax: 0061 7 55980377; E-mail: david.premion.com.aug for institutional data management was provided by theesearch Institute and from the Australian GovernmentStrengthening Cancer Care Grant.t of interest: none.dgments—The authors gratefully acknowledge the contri-ade by the clinicians and data managers at the contributings, as well the central data management provided byiles and Gabriel Gabriel from Collaboration for Cancerand Research (CCORE). The authors also thank Dr. De-for central pathology review. Participating institutions are

1164

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 dis-

ease, although there were retrospective reports (1–5). These

indicated that relatively poor results were achieved when

patients were treated by radiotherapy alone. Improvements

as follows: Auckland Hospital, Auckland, New Zealand; WaikatoHospital, Hamilton, New Zealand; Palmerston North Hospital, Pal-merston North, New Zealand; Liverpool Hospital, Sydney, Aus-tralia; Newcastle Mater Hospital, Newcastle, Australia; PrincessAlexander Hospital, Brisbane, Australia; Prince Alfred Hospital,Sydney, Australia; Peter MacCallum Cancer Institute, Melbourne,Australia; Royal Brisbane, Brisbane Mater, Australia; Royal Ade-laide Hospital, Adelaide, Australia; Royal Hobart Hospital, Hobart,Australia; Sir Charles Gairdner Hospital, Perth, Australia; West-mead Hospital, Sydney Australia; and Woolongong Hospital, Woo-longong, Australia.

Received Nov 6, 2009, and in revised form March 19, 2010.Accepted for publication March 26, 2010.

TROG 99.04 osteolymphoma trial d D. CHRISTIE et al. 1165

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 (4) 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 ret-

rospective study also produced results identifying prognostic

factors (6).

The third objective was to consider factors that might pre-

dispose 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 chemo-

therapy schedule, the total radiation dose, the volume of

the bone irradiated, and the radiation fraction size. Previous

studies had highlighted the disability associated with subse-

quent fractures (7, 8).

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

(1) and in dogs (9). 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 is-

sues 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 charac-

teristic 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 (10).

METHODS AND MATERIALS

Study designThe trial was a collaboration between the Trans-Tasman Radia-

tion Oncology Group (TROG) and the Australasian Leukemia and

Lymphoma Group (ALLG). The study was also promoted through

the Australasian Radiation Oncology Lymphoma Group (11) and

within the orthopedic specialist community (12).

The trial was registered on December 22, 2003, with the Austra-

lian and New Zealand Clinical Trials Registry (Reg. No.

ACTRN12607000111471) and on August 30, 2005, with the

Clinicaltrials.gov website (Reg. No. NCT00141648). TROG and

ALLG participating centers submitted the trial protocol to their

ethics committees. The processes involved in ethics committee re-

view for this trial were reviewed (13). Written informed consent

was obtained from each patient.

Patients were eligible for this trial if they had a biopsy-proven

non-Hodgkin’s lymphoma (NHL) primarily affecting bone and

demonstrable on computed tomography (CT) or magnetic resonance

imaging (MRI). All pathology subtypes were eligible except very

aggressive lymphoma (small noncleaved or lymphoblastic). Any

bony sites were considered, and patients with more than one lesion

in a single bone or lesions in adjacent bones were eligible, providing

that all of the macroscopic disease could be encompassed in a single

irradiated volume. Multiple separate sites of disease or those with

a soft-tissue component that was anatomically separate were

excluded. Tumors with an extraosseous component were allowed.

Patients were eligible if they were more than 17 years old, their East-

ern Cooperative Oncology Group (ECOG) performance was less

than 3, their predicted survival and accessibility for follow-up was

at least 6 months, and they were considered medically fit to receive

the trial treatments by the principal investigator at the treating insti-

tution (allowing substitution of doxorubin when indicated as

described below).

Assessment and stagingConventional measures for staging of NHL were used including

CT scanning and bone marrow assessment. Functional imaging

was also performed including gallium scanning initially, or positron

emission tomography (PET) scanning as it became more available.

Isotope bone scanning was also performed in all patients. Labora-

tory studies included haematology, biochemistry, b2-microglobulin

(B2MG), and lactate dehydrogenase (LDH). Patients with tumors

involving the dura mater underwent lumbar puncture and cytologi-

cal assessment of cerebrospinal fluid (CSF). In an attempt to identify

a subgroup of ‘‘true’’ or more typical OL patients, a simple classifi-

cation system was proposed, and contributors were asked to nomi-

nate whether the tumors would fall into Type A (classical) or

Type B (locally extensive or multifocal) categories. Type A was

defined as tumors predominantly contained within the affected

bone (such that the extraosseous component was not greater than

the intraosseous component). Type B consisted of cases of multifo-

cal disease within a single bone or adjacent bones (able to be

included in a single radiation field), and cases in which the disease

may have arisen in lymph nodes adjacent to bone and invaded the

bone secondarily or patients with positive CSF serology. Patients

who otherwise had Stage II, III, or IV disease by the Ann Arbor sys-

tem were excluded. Factors considered to predispose to the develop-

ment of long-term pathological fracture after treatment were

assessed including presence of Paget’s disease or osteoporosis,

chronic steroid use, pathological fracture at presentation, or

advanced bone destruction.

TreatmentThe chemotherapy consisted of three cycles of cyclophosphamide

(750 mg/m2), doxorubicin (50 mg/m2), vincristine (1.4 mg/m2), and

prednisolone (50 mg/m2). Substitution of mitozantrone or epirubicin

was allowed for patients who were considered unable to tolerate

doxorubicin. Patients with positive CSF cytology also received in-

trathecal methotrexate (12 mg/m2) for three cycles or until the

CSF cleared. After chemotherapy, a CT or MRI scan was performed

to assess response and to assist in radiotherapy planning. Patients

proceeded to radiotherapy regardless of response to chemotherapy.

Radiotherapy consisted of two phases. In the first phase, 36 Gy in 20

fractions was given to the whole length of affected bones, prescribed

according to the International Commission on Radiation Units and

Measurements (ICRU) conventions (14). Thereafter a boost of 9

Gy in five fractions was delivered to the grossly involved areas

plus a margin of 2 cm as defined on the CT and MRI scanning

done at the time of diagnosis unless a marked response was noted

Table 1. Locations of tumors in study subjects

Location No. of patients

Skull (including mandible) 3Spine 4Upper limb 7Ribs 1Sacrum 1Pelvis 5Femur 8Other lower limb bones 2

Table 2. Patient characteristics

Male/female 19/12Age Median, 55 years

(range 20–83 years)Length of follow-up Median, 4.3 years

(range, 5–80 months)Pathological type

Diffuse large B-cell lymphoma 30 patientsFollicular B-cell lymphoma 1 patient

Tumor size Median, 6.5 cm(range 2.0–12.0 cm)

Classification (as definedin Methods and Materials)Type A 21 patients

B 10 patientsReason for B

Involved regional nodes 1 patientExtraosseous extension 8 patientsMultiple bones 1 patient

Extraosseous extension(8 patients)

Median , 1.5 cm(range 0–12 cm)

LDH level Median, 288 U/L(range 145–595 U/L)

b2-microglobulin level Median, 1.6 mg/L(range, 0.5–2.9 mg/L)

B-symptoms 1 patientCSF cytology performed 1 patientCSF positive 0 patientsPET scan performed 5 patients

Abbreviations: CSF = cerebrospinal fluid; LDH = lactate dehy-drogenase; PET = positron emission tomography;

1166 I. J. Radiation Oncology d Biology d Physics Volume 80, Number 4, 2011

on the postchemotherapy CT and MRI scans. The boost was omitted

if excisional surgery had been performed. Treatment on relapse was

at the discretion of the treating practitioner.

Assessments, follow-up, and analysisGiven the difficulties in assessing response early after treatment

of OL, only progression was recorded, defined as an increase of

50% or more in the product of the greatest diameters for solitary le-

sions and the sum thereof for multiple lesions. At 4 weeks and at 6

months after all treatment, this was repeated. Patients were seen

every 3 months for 18 months and every 6 months thereafter, with

investigation of any signs or symptoms suspicious for recurrence.

Common toxicity criteria were used to assess toxicity. Information

about the presence of long-term fractures and functional impairment

was specifically requested. The assessment of response was added

by protocol amendment when Cheson’s criteria (15) became avail-

able. Local and distant progression-free and disease-free survival

and overall survival were analyzed using the product-limit method.

Prognostic factors were assessed using multiple proportional

hazards regression analysis.

Quality assuranceAny serious adverse events (SAEs) were noted and submitted to

the trial chair for review. The TROG central operations office con-

ducted an independent assessment of quality assurance (QA). Con-

tributors submitted copies of source data including medical records

and films, which reviewers checked for variations in eligibility, ra-

diotherapy, and chemotherapy parameters.

Protocol amendmentsThere were four sets of amendments to the protocol that incorpo-

rated changes in the pathological classification of NHL, the adoption

of PET scanning, changes in the staff and location of the central of-

fice, substitution of chemotherapy agents where needed, and the

addition of intrathecal methotrexate.

RESULTS

Accrual and patient characteristicsA total of 33 patients were accrued between September 15,

2000, and February 28, 2007. One patient elected to with-

draw, and 1 patient was reclassified as having multiple mye-

loma on pathology review, leaving 31 analyzable patients.

Their median age at registration was 55 years (range, 20–

81 years). There were 19 men and 12 women. The median

length of follow-up was 4.3 years (range, 5–80 months).

No patients were lost to follow-up. The locations of the

tumors are shown in Table 1; other patient-related informa-

tion is listed in Table 2.

Treatment receivedThe QA review of protocol compliance was published

(16). It demonstrated high rates of protocol compliance for

both chemotherapy and radiotherapy, with an overall rate

of variation at 3.6% of the 1,165 variables reviewed. All pa-

tients completed chemotherapy. Three patients received six

cycles of chemotherapy, and 6 patients had rituximab in-

cluded in their chemotherapy. There were no patients for

whom variations were considered to result in the patient

becoming inevaluable. The protocol allowed substitution of

alternatives to doxorubicin if cardiac toxicity seemed likely

(2 patients) and the addition of methotrexate if there was sus-

picion of involvement of the dura mater (5 patients). Chemo-

therapy dose reductions were required in 4 patients and

delays in 2 patients because of acute toxicity.

Response after chemotherapy for OL is problematic and

was thus limited to evidence, or lack of evidence, of progres-

sive disease. One patient was considered to have progressive

disease radiologically, which was subsequently confirmed by

biopsy. All patients completed radiotherapy, although minor

variations in radiation dose and volume parameters were

noted, and 3 patients required an interruption of their radio-

therapy course.

Pattern of failure and survivalAt the time of analysis, 3 patients (all men) had died, all

because of recurrent disease. The 5-year survival was esti-

mated to be 90% (95% confidence interval [95% CI] 63–

Fig. 1. Overall survival in study patients.

TROG 99.04 osteolymphoma trial d D. CHRISTIE et al. 1167

97%; Fig. 1). There were nine local recurrences, seven within

the first 2 years. Two of these were confirmed to be in the

high radiation dose (boost) volume. The 5-year local control

rate was estimated as 72% (95% CI, 50–90%; Fig. 2). There

were four distant failures and the 5-year failure-free survival

rate (including death and local and distant failures) was esti-

mated to be 64% (95% CI, 43–79%). Individual details of the

patients with recurrence are listed in Table 3.

Multiple proportional hazards regression analysisThe following variables were tested for association with

survival time using stepwise regression: age, sex, tumor

size, the presence of an extraosseous component, OL type

A/B, hemoglobin level, white cell count, as well as serum

levels of g-glutamyl transferase, alanine aminotransferase,

aspartate aminotransferase, creatinine, LDH and B2MG.

Only white cell count was significant (hazard ratio, 1.27;

p = 0.028). Local recurrences were proportionally divided

between type A and B patients.

Toxicity, serious adverse events, and quality assuranceThe levels of toxicity were within the range expected for

these treatment modalities. In 7 patients toxicity reached

Grade 3, including nausea (3 patients), neutropaenia (2 pa-

tients), and diarrhea (2 patients). There were no Grade 4 tox-

icities or toxicity-related deaths. There were 13 SAEs among

10 patients. Central reviews of these showed that these were

Fig. 2. Local control in study patients.

expected complications of treatment and were transient in ex-

cept 1 patient who experienced a myocardial infarction.

Fractures and orthopedic stabilizationFactors predisposing to the subsequent development of

fractures were noted before treatment; these included osteo-

porosis (4 patients) and fracture at presentation (3 patients).

Clinicians indicated that advanced age (8 patients) and an un-

usually large bone biopsy (1 patient) may also have contrib-

uted. One patient had three of these predisposing factors.

There were 3 patients who had orthopedic stabilization

before treatment, including 1 patient who had a fracture of

the right olecranon and 2 patients who had vertebral lesions

without fractures.

After treatment, there were 3 patients who had pathologi-

cal fractures. Their ages were 34, 45, and 55 years at diagno-

sis. Their tumors were in the right olecranon, fourth lumbar

vertebra, and right lower pelvis, respectively. The last of

these was associated with biopsy-proven local recurrence.

All 3 patients had fractures that persisted from the time of

presentation (with advanced bone destruction in the vertebral

case). No significant functional impairment was noted during

continuous follow-up of 6.0, 5.5, and 3.5 years, respectively.

DISCUSSION

This was the only prospective trial specifically addressing

the treatment of OL, and it had four objectives. The first ob-

jective was to establish benchmark results for standard treat-

ment 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 diffi-

cult to identify. The 5-year overall survival rate of 90% com-

pares favorably with the results of our previous retrospective

study (1), in which the corresponding figure was 59%, bear-

ing in mind that the latter study included patients with more

advanced disease and the proportion who received chemo-

therapy 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 treat-

ment. At the time that this study was designed, there was ev-

idence to support the limitation of CHOP chemotherapy to

three cycles (18, 19). 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.

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Fig. 3. Failure-free survival in study patients.

1168 I. J. Radiation Oncology d Biology d Physics Volume 80, Number 4, 2011

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) posttreat-

ment may warrant further study; however, as radiotherapy re-

mains 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 radia-

tion 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 cy-

cles, as well as the addition of rituximab, in combination

with the same radiotherapy schedule that was used in this cur-

rent trial.

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 (7, 8). 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 be-

cause 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 limit-

ing 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.

TROG 99.04 osteolymphoma trial d D. CHRISTIE et al. 1169

Although the prospective study of rare cancers remains

problematic, future studies in OL could consider several is-

sues. These include the imaging requirements, as it is yet to

be demonstrated that PET scanning is more useful than Gal-

lium scanning, given that PET scanning often omits the

limbs. A previous study of gallium scanning suggested

a 75% sensitivity rate for OL (20). There should also be

detailed pathological correlation to identify those pathologi-

cal features that may predict for osseous homing, and assess-

ment 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 bod-

ies 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 re-

quired to run trials relating to more common cancers, but at-

tempts 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. Ex-

panding 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 eligi-

ble 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 oppor-

tunity to enter trials that are available.

During the accrual period for this trial, a significant ad-

vance was made in the routine treatment of nodal NHL

(17). The addition of rituximab to conventional chemother-

apy was shown to increase survival and was funded for rou-

tine use in Australia in a way that did not distinguish between

nodal and extranodal subtypes of disease. These improve-

ments would have made it problematic for clinicians to man-

age 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.

CONCLUSION

In summary, we conclude the following. First, the results

of conventional treatment for OL are relatively favorable,

suggesting that more intensive styles of chemotherapy are

unlikely to significantly improve survival. Second, local con-

trol remains an issue in OL, and doses of radiotherapy (40–45

Gy) that are higher than are used for other types of NHL

should continue to be used. If given with due regard for frac-

tionation and volume, then pathological fractures and subse-

quent disability are unlikely. When fractures do occur, they

are more likely to be associated with pre-existing fracture.

Finally, better methods of undertaking clinical trials in rare

cancers are required, possibly involving larger networks of

treatment centers than currently exist and using systematic

methods of ensuring that all suitable patients presenting are

offered the opportunity to participate

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