Combined-modality therapy for primary central nervous system lymphoma: long-term data from a Phase II multicenter study (Trans-Tasman Radiation Oncology Group).

PURPOSE: To assess, in a multicenter setting, the long-term outcomes of a brief course of high-dose methotrexate followed by radiotherapy for patients with primary central nervous system lymphoma (PCNSL). METHODS AND MATERIALS: Forty-six patients were entered in a Phase II protocol consisting of methotrexate (1 g/m(2) on Days 1 and 8), followed by whole-brain irradiation (45-50.4 Gy). The median follow-up time was 7 years, with a minimum follow-up of 5 years. RESULTS: The 5-year survival estimate was 37% (+/-14%, 95% confidence interval [CI]), with progression-free survival being 36% (+/-15%, 95% CI), and median survival 36 months. Of the original 46 patients, 10 were alive, all without evidence of disease recurrence. A total of 11 patients have developed neurotoxicity, with the actuarial risk being 30% (+/-18%, 95% CI) at 5 years but continuing to increase. For patients aged>60 years the risk of neurotoxicity at 7 years was 58% (+/-30%, 95% CI). CONCLUSION: Combined-modality therapy, based on high-dose methotrexate, results in improved survival outcomes in PCNSL. The risk of neurotoxicity for patients aged>60 years is unacceptable with this regimen, although survival outcomes for patients aged>60 years were higher than in many other series.

Radiotherapy in the management of solitary extramedullary plasmacytoma.

BACKGROUND: Solitary extramedullary plasmacytoma (SEP) is a rare tumour for which the standard treatment remains local radiotherapy (RT). We present a study of a multi-institutional experience, between 1980 and 1999, in an attempt to better understand the natural history of SEP and to identify possible prognostic factors. METHODS: The records at Radiation Oncology Victoria and Peter MacCallum Cancer Centre, Melbourne, were used for the identification of patients. The inclusion criteria were as follows: (i) histological confirmation of clonal plasma cells involving a single extramedullary site with or without lymph node involvement; (ii) no histological evidence of bone marrow involvement; (iii) no evidence of distant bone lesion on radiographic skeletal survey (bone erosions adjacent to the primary thought to be due to contiguous involvement were permitted) and (iv) no anaemia, hypercalcaemia or renal impairment due to plasma cell dyscrasia. RESULTS: A total of 16 patients was identified, with a median follow up of 66 months (range 12-211 months). The head and neck region accounted for the majority of presentations (88%). Among all patients, a serum mono-clonal paraprotein was found in three patients and bone erosion was identified in seven patients. All patients received local RT, although two patients also received elective nodal irradiation (ENI). The median RT dose was 45 Gy (range 40-50.4 Gy). Local control was achieved in all patients (100%), however, regional recurrence outside the RT fields occurred in 2/16. Multiple myeloma (MM) developed in five patients, all within 5 years. The predicted 10-year myeloma free survival is 75% and 10-year overall survival is 54%. CONCLUSION: RT can achieve excellent local control of SEP. The rate of conversion to MM is 31%. Moderate dose RT of at least 40 Gy using limited radiation fields is recommended, although ENI should be considered if toxicity is not increased.

Use of digitally reconstructed radiographs in radiotherapy treatment planning and verification.

The authors present 3 years of experience in using digitally reconstructed radiographs (DRR) for radiotherapy planning and verification. Comparison is made with simulation film (SF), to illustrate the advantages of DRR over SF. Emphasis is placed on using the appropriate equipment and applying the correct technique. A brief discourse on the principle of CT imaging is presented to illustrate the operation of CT software and optimization of image display for axial slices and DRR. Emphasis is placed on the application of clinical knowledge to enhance the usefulness, as well as the technical quality, of the DRR. Illustrative examples are given.

Acquired immunodeficiency syndrome-related primary cerebral lymphoma: response to irradiation.

Acquired immunodeficiency syndrome-related primary cerebral lymphoma (AIDS-PCL) is uncommon. Fourteen cases of presumed AIDS-PCL between 1986 and 1995 were reviewed retrospectively in order to characterize the natural history, and the response to radiotherapy. The median age was 38 years (range 24-65). The median interval between seropositive diagnosis of HIV and AIDS-PCL was 28 months (range 5-113). The median duration of symptoms was 2 weeks (range 0.2-12). At presentation, the Eastern Cooperative Oncology Group performance status (PS) was PS1 (2/14 patients), PS2 (6/14) and PS3 (6/14). The symptoms and signs were non-specific and depended on the site and extent of cerebral involvement. There was no characteristic pattern of brain imaging in terms of size, number, location or pattern of contrast enhancement of the cerebral lesions. Nine patients received various fractionation-dose schedules (range 8-50 Gy). Complete and partial responses were seen in 2/9 and 3/9 cases, respectively. Clinical stabilization of neurological symptoms was noted in 3/9 cases and disease progression in 1/9. The median survival times (MST) from presentation for irradiated and non-irradiated patients were 9.3 and 2.1 weeks, respectively (range 0.9-43.1). Although patient selection introduced bias, there appears to be a modest improvement in MST for treated patients. The MST with radiotherapy alone remains poor, but radiotherapy may provide palliation. For some selected patients, a prolonged response is possible.

Metacarpal and proximal phalangeal fractures--fixation with multiple intramedullary Kirschner wires.

The use of intramedullary wires for fixation of fractures of the metacarpal and proximal phalanx in our hospital was reviewed. Twenty-six patients with 26 metacarpal fractures and four proximal phalangeal fractures were treated using this technique from 1993 to 1998. After a minimal follow-up of nine months, all the patients were assessed clinically and radiologically. All fractures proceeded to bony union at an average of 5.7 weeks (range four to eight weeks). With this simple and minimally invasive technique, most of these patients required very short hospital stay and were able to start mobilisation relatively early. The general outcome was good hand function with few complications.

Radiation myelopathy following transplantation and radiotherapy for non-Hodgkin's lymphoma.

BACKGROUND: Combined modality therapy with chemotherapy and radiotherapy has become increasingly popular in the management of solid malignancies. However, unexpected toxicities may arise from their interactions. METHODS AND MATERIALS: We report the case of a young woman with a large mediastinal non-Hodgkin's lymphoma who underwent high-dose chemotherapy with autologous bone marrow transplantation and involved field radiotherapy, and who developed radiation myelopathy after a latent period of only 3 months. The spinal cord dose did not exceed 40.3 Gy in 22 fractions over 4.5 weeks, which is well within accepted tolerance limits. She had no other identifiable risk factors for radiation myelopathy, suggesting an adverse drug-radiation interaction as the most likely cause of her injury. RESULTS AND CONCLUSIONS: This represents the first report of radiation myelopathy at accepted safe radiation doses following high-dose chemotherapy with autologous bone marrow transplantation, and we recommend caution in the choice of radiotherapeutic dose in this setting.

Primary central nervous system lymphoma: age and performance status are more important than treatment modality.

PURPOSE: To assess prognostic factors and treatment modalities of patients with primary central nervous system lymphoma (PCNSL) in terms of response rates, patterns of failure and overall survival. METHODS AND MATERIALS: Sixty-two patients presenting with PCNSL between 1982 and 1994 at Peter MacCallum Cancer Institute with no evidence of human immunodeficiency virus infection were included in the study. Their median age was 60 years; World Health Organisation (WHO) performance status was > or = 2 in 85%. All patients were planned to receive whole brain irradiation; 7 also received spinal irradiation. The median planned dose to the target volume was 50.4 Gy. Twenty patients were planned to receive chemotherapy as well. Patients were followed up to June 20, 1995, giving a median follow-up for 14 surviving patients of 5.4 years, range 0.3 to 10.2 years. RESULTS: The clinical response rate to treatment was 77% [95% confidence interval (CI) 65 to 87%]. The estimated median overall survival was 20.6 months (CI 12.4 to 33.4 months). On univariate analysis male gender, age <60 years, WHO performance status < or = 1, treatment to the target volume > or = 45 Gy, and treatment with additional chemotherapy, were associated with a significantly better overall survival (p < 0.05). On multivariate analysis only age and performance status remained significant prognostic variables. Relapse involved the central nervous system or cerebrospinal fluid (CSF) in all patients with known sites of relapse except three who had ocular relapse only. There was a low incidence of relapse in the initial brain site (23% of known cases) and a high incidence (50%) of CSF/spinal cord relapse. Of 48 deaths, 15 were related to initial or subsequent treatment. CONCLUSIONS: Patient outcome is strongly influenced by age and performance status. Studies suggesting better survival for patients treated with chemoradiation may reflect patient selection rather than treatment variables. Optimal management remains to be defined. The high CSF/spinal relapse rate deserves particular attention.

Thyroid dysfunction after mantle irradiation of Hodgkin's disease patients.

Thyroid dysfunction can develop in patients with Hodgkin's disease who are treated with mantle irradiation. During the period 1970-89, the records of 320 patients who received mantle irradiation and who had thyroid function tests (TFT) were retrospectively reviewed. The median age was 30 years (range, 7-69 years). The median mantle and thyroid dose was 36 Gy (range, 30-40 Gy) and 39.8 Gy (range, 32-65 Gy), respectively. Overall thyroid dysfunction was present in 39% of the patients. Clinical hypothyroidism was seen in 10% and biochemical hypothyroidism was noted in 25%. Hyperthyroidism was found in 4% of patients. Thyroid nodules had developed in six patients (2%), of which those in four patients were malignant. Age, sex, histological subtype, stage of disease, dose, lymphangiogram and treatment with chemotherapy were not significant factors in the development of thyroid dysfunction. The narrow dose range prevented adequate analysis of dose effect. The results indicate that the incidence of thyroid abnormalities is high enough to warrant regular TFT assessment with pre-irradiation levels and follow-up testing for life because the development of abnormalities can occur many years later. Thyroid examination should form part of the routine follow-up examination and any abnormality should be promptly investigated.

Salvage radiotherapy for Hodgkin's disease following chemotherapy failure.

PURPOSE: This study aims to: 1) assess failure-free survival (FFS), overall survival (OS), and failure pattern after salvage radiotherapy (SRT) for patients with Hodgkin's disease (HD) who fail chemotherapy (CT); 2) identify patients suitable for SRT as an alternative to more aggressive salvage regimens. METHODS AND MATERIALS: Between 1978 and 1992, 52 patients with relapsed/refractory HD following 26 CT received SRT at the Peter MacCallum Cancer Institute. Patient characteristics at diagnosis were: median age (range 12-63); male-31, female-21; Stage I-4, II-16, III-25, or IV-7. Prior to SRT 27 patients had received the equivalent of both MOPP and ABV(D). The duration of initial complete response (CR) from CT was greater than 12 months in 22 patients. SRT (dose 34-42 Gy) was given to active disease sites. RESULTS: Five-year FFS and OS rates following SRT were 26 and 57%, respectively. Five-year FFS and OS rates of 36 and 75%, respectively, were achieved in patients who relapsed in supradiaphragmatic nodal sites without B symptoms; in a subset of patients with initial Stage I-II disease the FFS and OS rates were 50 and 86%, respectively. On multivariate analysis significant factors for FFS were B symptoms at the time of SRT (p = 0.003), extranodal involvement (p = 0.011) and histology (p = 0.018). For OS significant factors were B symptoms (p = 0.0007), age (p = 0.014) and number of prior CT regimens (p = 0.03). CONCLUSION: The relatively poor results of SRT in terms of FFS justify the use of alternative salvage strategies for most patients with Hodgkin's disease who fail CT. However, SRT offers a low morbidity, potentially curative option for a subset of patients. Our data suggest that patients most suitable for SRT are those with relapse in supradiaphragmatic nodal sites and no B symptoms.

Preliminary results of combined chemotherapy and radiotherapy for non-AIDS primary central nervous system lymphoma. Trans-Tasman Radiation Oncology Group (TROG).

OBJECTIVES: To assess the results and toxicity of a regimen of combined chemotherapy and radiotherapy for patients with non-AIDS-related primary central nervous system lymphoma. DESIGN: Prospective assessment of patients treated with intravenous methotrexate followed by cranial irradiation between 1 January 1991 and 31 July 1995. PATIENTS AND SETTING: Patients attending nine Australian and New Zealand centres who were eligible and gave informed consent. MAIN OUTCOME MEASURES: Probability of survival at two years, and acute toxicity. RESULTS: Twenty-four patients were treated. Their probability of survival at two years was 70% (95% confidence interval [CI], 45%-95%). The acute toxicity of the regimen was minimal in most cases, but one patient died of treatment-related neutropenia and subsequent sepsis. Two patients showed progression of pre-existing short term memory disturbance, without evidence of recurrent lymphoma. CONCLUSIONS: Combined-modality therapy improves survival in patients with non-AIDS-related primary central nervous system lymphoma, at least in the short term, relative to radiotherapy alone. The combined regimen resulted in only moderate treatment-related morbidity. Longer follow-up is required for a more accurate estimate of late effects and long-term survival prospects.

Radiotherapy for early infradiaphragmatic Hodgkin's disease: the Australasian experience.

PURPOSE: To review the Australasian results of Stage I and IIA Infradiaphragmatic Hodgkin's Disease (IHD) treated solely by irradiation. METHODS AND MATERIALS: Eligible patients had IHD only and were treated by irradiation with curative intent over the period of 1969 to 1988. Ten radiation oncology centres from within Australia and New Zealand were surveyed for patient, tumour and treatment variables. Disease free rates, survival and complications were analysed. RESULTS: 106 patients with IHD were studied. The average potential follow up was 9.4 years. The male to female ratio was 3.3:1. The median age was 37.5 years. Histological subgroups were as follows; lymphocyte predominant 43%, mixed cellularity 21%, lymphocyte depleted 5%, nodular sclerosing 27% and unclassifiable 4%. Fifty nine patients had laparotomy of which 22 (37%) were positive for tumour. Nine laparotomies were performed for diagnosis and the remainder for staging. One patient was up-staged by laparotomy and three were down-staged. Sixty-eight patients presented with inguinal disease alone, five with abdominal disease alone, 19 with two sites of involvement and 12 with inguinal, pelvic and abdominal disease. In two patients the site was unknown. There was no correlation between site of involvement, age, sex or histological subtype. Forty seven cases were clinically staged (CS) as follows: CS IA-23, CS IIA-24. The other 59 were pathologically staged (PS) as follows: PS IA-37, PS IB-1, PS IIA-21. Treatment consisted of involved field alone (16), inverted Y (68), inverted Y and spleen (13), para-aortic irradiation only (3), or total nodal irradiation (6). Mean dose was 37 Gy. There were 30 recurrences to give an acturial 10-year disease-free rate of 70%. In multivariate analysis lower number of tumour sites, lymphocyte predominant histology and higher dose were all significantly correlated with higher disease free rates. Eight patients died of Hodgkin's disease and 19 of other causes. The 10-year overall survival rate was 71%. Older age and higher number of disease sites were significantly correlated with shorter survival. Fourteen of 30 relapses may have been avoidable by the use of total nodal irradiation. In particular ten of 21 patients with abdominal disease relapsed in nodal sites which would have been covered by total nodal irradiation. CONCLUSIONS: The rate of control in IHD could perhaps be improved by avoiding involved field irradiation or by aggressive therapy with total nodal irradiation or combined modality chemo-irradiation in Stage II disease. Staging laparotomy does not appear to be indicated.

Radiation therapy for early stage Hodgkin's disease: Australasian patterns of care. Australasian Radiation Oncology Lymphoma Group.

PURPOSE: Analysis of treatment outcome for Stage I-IIA supradiaphragmatic Hodgkin's disease treated solely by irradiation in Australia and New Zealand. METHODS AND MATERIALS: Patients with supradiaphragmatic Hodgkin's disease only who were treated by irradiation alone with curative intent between 1969 to 1988 were retrospectively reviewed. Ten radiation oncology departments in Australia and New Zealand contributed patient data to the study. Patient, tumor, and treatment variables were recorded. Disease-free interval, survival, and complications were analyzed. RESULTS: Eight hundred and twenty patients were reviewed. The median age was 29 years. There were 437 men and 383 women. The distribution of 310 clinically staged patients was 170 stage IA, 5 IB, and 135 IIA. Five hundred and ten patients received laparotomies, and pathologic staging was as follows: IA 214, IB 13, IIA 283. The 10-year actuarial disease-free rate was 69% and overall survival rate was 79%. Increasing age, male sex, higher number of involved sites, the use of involved field irradiation, no staging laparotomy, and earlier year of treatment were significantly associated with an increased risk of relapse and lower survival. Actuarial 10-year survival following recurrence was 48%. Acute complications requiring interruption to treatment occurred in 46 patients (6%), but < 1% had their treatment permanently suspended. Actuarial complication rates at 10 years were: cardiac 2%, pulmonary 3% and thyroid 5%. There were 44 second malignancies including 10 non-Hodgkin's lymphomas, 3 leukemias, 7 lung, and 6 breast cancers. Mean delay to the development of a second cancer was 6 years. The 10-year actuarial rate of second malignancy was 5%. CONCLUSIONS: The Australasian experience of early stage Hodgkin's disease is consistent with the results in the published literature and confirms that irradiation produces a high cure rate with minimal toxicity.

Lymphocyte predominant Hodgkin's disease: a clinicopathologic comparative study of histologic and immunophenotypic subtypes.

PURPOSE: To compare the clinicopathologic features of the histologic and immunophenotypic subgroups of lymphocyte predominant Hodgkin's disease. METHODS AND MATERIALS: A retrospective review of 64 patients with lymphocyte predominant Hodgkin's disease treated at the Peter MacCallum Cancer Institute, Melbourne, was performed. Nodular and diffuse histological subtypes were confirmed by review of hematoxylin and eosin paraffin sections. Immunophenotyping with monoclonal antibodies L26 (B-cell origin) and Leu M1 (Hodgkin's phenotype) were available in 36 patients. RESULTS: The estimated freedom from progression and estimated overall survival at 10 years was 74% standard error (SE 5.8%) and 85% (SE 5.2%), non-Hodgkin's respectively. There were no significant differences in freedom from progression or overall survival when nodular and diffuse histology were compared. Similarly the presence of B-cell markers did not influence prognosis. There was only one case of secondary non-Hodgkin's lymphoma. CONCLUSION: Our results are consistent with major reported series displaying no differences between any of the subgroups of lymphocyte predominant Hodgkin's disease.

Infradiaphragmatic Hodgkin's disease, long term follow-up of a rare presentation.

Hodgkin's disease limited to the infradiaphragmatic region was seen in 30 of 306 (9.8%) of all Stage I and II patients referred to the Peter MacCallum Cancer Institute between 1968 and 1980. The male:female ratio was 2.3:1 with median age of 43.5 years at presentation. Of the seven patients with clinical stage (CS) IA-IIA disease who had staging laparotomy and splenectomy only one CSIIA patient had splenic involvement. The patients were staged as pathological stage (PS) IA 2, PSIIA 5, CSIA 4, CSIIA 10, CSIIB 9. Primary treatment was by radiation in 24 patients, combination chemotherapy in five and surgical excision in one. Twenty-five patients achieved complete response. Relapse free survival (RFS) at five and ten years was 59% and the five and ten-year survival was 75% and 67% respectively. On univariate analysis the significant prognostic factors for RFS and survival were stage, constitutional symptoms and presence of bulky disease. Using Cox regression analysis the only significant variable for RFS and survival was bulky disease (p = 0.01, 0.02). A treatment policy for patients with infradiaphragmatic Hodgkin's disease is recommended.

A study of splenic irradiation in chronic lymphocytic leukemia.

A retrospective study was performed to assess the effect of splenic irradiation (SI) on splenomegaly, splenic pain, anemia, and thrombocytopenia in patients with chronic lymphocytic leukemia. Twenty-two patients received 32 courses of SI. Of 31 courses of SI given for splenomegaly there were 19 responders (61%). Ten courses of SI were given for splenic pain resulting in partial relief of pain in 4 courses and complete relief in 4 courses. Only 4 of 16 courses given for anemia resulted in elevations of hemaglobin of 2 g/dL or more. Of the 14 courses of SI given for thrombocytopenia there were only 2 responses with platelet counts decreasing further in another 9 courses. The median duration of response was 14 months (range: 3-116 months). There was no dose-response relationship detected for SI in CLL. Treatment related toxicity was hematologic and secondary to leucopenia and thrombocytopenia. We recommend the use of small fraction sizes of 25 cGy to 50 cGy and close monitoring of hematological parameters. Splenic irradiation effectively palliates splenomegaly and reduces spleen size in CLL. It was of limited value in correcting anemia and thrombocytopenia in this patient population.

An analysis of prognostic factors in early stage Hodgkin's disease.

An analysis of prognostic factors has been carried out in 398 patients presenting with clinical Stage I and II Hodgkin's disease treated between 1963 and 1979. By life table analysis older age, lymphocyte depletion histology, systemic symptoms, mediastinal node bulk, and erythrocyte sedimentation rate (ESR) greater than 40 mm/h were associated with a significantly worse survival probability. On multiple factor regression analysis only age and stage were independent prognostic variables for survival, with systemic symptoms having borderline significance. Using this information, together with other analyses of prognosis in early Hodgkin's disease three groups of patients are defined. The first with a predicted 5-year survival of 78% would include patients possessing at least one of the following features; age greater than 60, lymphocyte depletion, greater than 3 sites involved, systemic symptoms, mediastinal/thoracic ratio of greater than 1/3. The second groups present with at least two of the following factors; ESR greater than 40 mm/h, male sex, 3 involved sites, or mixed cellularity histology, and the 5 year survival probability is 84%. The remaining Stage I and II patients would constitute a good prognosis group with a predicted 5-year survival of 92%.

Non-Hodgkin's lymphoma involving the central nervous system.

In 44 out of 758 patients (5.8%) with non-Hodgkin's lymphoma presenting between 1971 and 1982, the central nervous system (CNS) was involved. Patients with a diffuse histology had a 7.6% (34/449) incidence of CNS involvement compared to 3.9% (10/257) for patients with nodular lymphoma. In 63% of patients there was evidence of progressive systemic lymphoma at the time of diagnosis of CNS disease and in 23% CNS relapse occurred in clinical remission. Bone marrow was involved in 34% of patients at diagnosis and in 52% at some time prior to the onset of CNS complications. Cerebrospinal fluid cytology was positive in 63% and an elevated protein level was found in 95% of patients. The median length of survival of the 44 patients was only 3.2 months, but patients who responded to treatment of CNS lymphoma survived significantly longer than those who showed no response or progressed on therapy. Complete response to CNS treatment was achieved in five patients, of whom none relapsed in the CNS and two are long-term disease-free survivors. CNS prophylaxis appears justified for patients with lymphoblastic lymphoma, Burkitt's tumour, and diffuse undifferentiated lymphoma, who are at high risk of developing CNS complications. Patients with diffuse histiocytic, and diffuse poorly differentiated lymphocytic, lymphoma who have bone marrow involvement may also benefit from CNS prophylaxis.