Belinda A. Campbell

Involved-Nodal Radiation Therapy As a Component of Combination Therapy for Limited-Stage Hodgkin's Lymphoma: A Question of Field Size

PURPOSE Combined-modality therapy is the standard of care for limited-stage Hodgkins lymphoma (HL). Radiation therapy has evolved from extended-field radiation therapy (EFRT) to involved-field radiation therapy (IFRT), reducing toxicity while maintaining high cure rates. Recent publications recommend a further reduction to involved-nodal radiation therapy (INRT), however, this has not been clinically validated. PATIENTS AND METHODS We identified 325 patients with limited-stage HL, diagnosed between May 1, 1989 and April 1, 2005, and treated with chemotherapy and radiation therapy following era-specific guidelines: EFRT until 1996; IFRT from 1996 to 2001; INRT < or = 5 cm from 2001 to the present. INRT < or = 5 cm was defined as the prechemotherapy nodal volume with margins < or = 5 cm to account for physiological movement, set-up variation, and the limitations of conventional simulation and radiation therapy techniques. Exclusion criteria were age younger than 16, fluorine-18 fluorodeoxyglucose positron emission tomography, non-doxorubicin, bleomycin, vinblastine, and dacarbazine-like chemotherapy, and/or more than four chemotherapy cycles. RESULTS At diagnosis, median age was 35 years; 52% male; stage IA 29%; stage IIA 71%. Ninety-five percent of patients received two chemotherapy cycles. The three radiation therapy groups were: EFRT, 39%; IFRT, 30%; and INRT < or = 5 cm, 31%. Median follow-up of living patients was 80 months. Median time to relapse was 37 months. Twelve relapses occurred: four after EFRT (3%); five after IFRT (5%); and three after INRT < or = 5 cm (3%; P = .9). No marginal recurrences occurred after INRT < or = 5 cm. Locoregional relapse (LRR) occurred in five patients: three after EFRT; two with IFRT; and none with INRT < or = 5 cm. At 5 years, progression-free survival (PFS) was 97%, and overall survival (OS) was 95%. At 10 years, PFS and OS were 95% and 90%, respectively. CONCLUSION Reduction in field size appears to be safe, without an increased risk of LRR in patients receiving INRT < or = 5 cm.

Meningiomas in 2009: controversies and future challenges.

Meningiomas are the most common intracranial primary neoplasm in adults. Over recent years, interest in this clinically diverse group of tumors has intensified, bringing new questions and challenges to the fore, particularly in the fields of epidemiology, radiology, pathology, genetics, and treatment. Interest in modern meningioma research has been stimulated by the high tumor prevalence and the advances in technology. The incidence of meningiomas is climbing, and may indicate increased exposure to environmental risk factors or more sensitive diagnostic modalities. Technological advances have dramatically improved radiologic imaging and radiotherapy treatments, and further refinements are under investigation. Furthermore, the current era of tumor genetics and molecular biology is challenging translational researchers to discover new, targeted, therapeutic agents. This review is an update on the recent advances in the understanding of meningiomas and their management, and highlights pertinent research questions to be addressed in the future.

Long-term outcomes for patients with limited stage follicular lymphoma: involved regional radiotherapy versus involved node radiotherapy.

Given the indolent behavior of follicular lymphoma (FL), it is controversial whether limited stage FL can be cured using radiotherapy (RT). Furthermore, the optimal RT field size is unclear. The authors of this report investigated the long‐term outcomes of patients with limited stage FL who received RT alone and studied the impact of reducing the RT field size from involved regional RT (IRRT) to involved node RT with margins up to 5 cm (INRT≤5 cm).

Minimising critical organ irradiation in limited stage Hodgkin lymphoma: a dosimetric study of the benefit of involved node radiotherapy

BACKGROUND Chemotherapy plus radiotherapy is the standard of care for patients with limited stage Hodgkin lymphoma (HL). Radiotherapy is evolving from involved field radiotherapy (IFRT) to involved node radiotherapy (INRT) to decrease radiotherapy-related morbidity. In the absence of long-term toxicity data, dose-volume metrics of organs at risk (OAR) provide a surrogate measure of toxicity risk. PATIENTS AND METHODS Ten female patients with stage I-IIA supradiaphragmatic HL were randomly selected. All patients had pre-chemotherapy computerised tomography (CT) and CT-positron emission tomography staging. Using CT planning, three radiotherapy plans were produced per patient: (i) IFRT, (ii) INRT using parallel-opposed beams and (iii) INRT using volumetric modulated arc therapy (VMAT). Radiotherapy dose was 30.6 Gy in 1.8 Gy fractions. OAR evaluated were lungs, breasts, thyroid, heart and coronary arteries. RESULTS Compared with IFRT, INRT significantly reduced mean doses to lungs (P < 0.01), breasts (P < 0.01), thyroid (P < 0.01) and heart (P < 0.01), on Wilcoxon testing. Compared with conventional INRT, VMAT improved dose conformality but increased low-dose radiation exposure to lungs and breasts. VMAT reduced the heart volume receiving 30 Gy (V30) by 85%. CONCLUSIONS Reduction from IFRT to INRT decreased the volumes of lungs, breasts and thyroid receiving high-dose radiation, suggesting the potential to reduce long-term second malignancy risks. VMAT may be useful for patients with pre-existing heart disease by minimising further cardiac toxicity risks.BACKGROUND Chemotherapy plus radiotherapy is the standard of care for patients with limited stage Hodgkin lymphoma (HL). Radiotherapy is evolving from involved field radiotherapy (IFRT) to involved node radiotherapy (INRT) to decrease radiotherapy-related morbidity. In the absence of long-term toxicity data, dose-volume metrics of organs at risk (OAR) provide a surrogate measure of toxicity risk. PATIENTS AND METHODS Ten female patients with stage I-IIA supradiaphragmatic HL were randomly selected. All patients had pre-chemotherapy computerised tomography (CT) and CT-positron emission tomography staging. Using CT planning, three radiotherapy plans were produced per patient: (i) IFRT, (ii) INRT using parallel-opposed beams and (iii) INRT using volumetric modulated arc therapy (VMAT). Radiotherapy dose was 30.6 Gy in 1.8 Gy fractions. OAR evaluated were lungs, breasts, thyroid, heart and coronary arteries. RESULTS Compared with IFRT, INRT significantly reduced mean doses to lungs (P < 0.01), breasts (P < 0.01), thyroid (P < 0.01) and heart (P < 0.01), on Wilcoxon testing. Compared with conventional INRT, VMAT improved dose conformality but increased low-dose radiation exposure to lungs and breasts. VMAT reduced the heart volume receiving 30 Gy (V30) by 85%. CONCLUSIONS Reduction from IFRT to INRT decreased the volumes of lungs, breasts and thyroid receiving high-dose radiation, suggesting the potential to reduce long-term second malignancy risks. VMAT may be useful for patients with pre-existing heart disease by minimising further cardiac toxicity risks.

Primary breast lymphoma.

Primary breast lymphoma is a rare form of extranodal lymphoma, defined by the presence of a primary lesion within the breast with or without regional nodal involvement but no other extra-mammary sites of involvement. It comprises diverse histologic subtypes, but diffuse large B-cell lymphoma is the most common. In this review, we describe in detail the clinical features, diagnosis and staging, pathogenesis, risk factors and therapy of primary breast diffuse large B-cell lymphoma. We consider choice and number of cycles of chemotherapy, the indications for radiotherapy and discuss the need for central nervous system prophylaxis. We also provide a brief overview of the less commonly encountered histologic subtypes including marginal zone, follicular, Burkitt and breast implant associated anaplastic large cell lymphoma. We conclude with a suggested treatment approach and potential areas of future research.

Incidence of transformation to aggressive lymphoma in limited-stage follicular lymphoma treated with radiotherapy

BACKGROUND The established treatment of limited-stage follicular lymphoma is radiotherapy (RT). There is an inherent risk of transformation of follicular lymphoma to aggressive lymphoma; however, the frequency and impact on the outcome are unknown in limited-stage patients. MATERIALS AND METHODS We identified 237 patients with limited-stage follicular lymphoma treated with curative intent RT. Cases were reviewed to determine the frequency of transformation and subsequent survival. RESULTS With a median follow-up of 7.4 years, the 10-year risk of transformation was 18.5%. With a median follow-up after transformation of 4.7 years, the 3-year post-transformation progression-free survival (PFS) and overall survival (OS) were 42% and 44%, respectively. The addition of rituximab improved the 3-year post-transformation PFS and OS compared with combination chemotherapy alone (78% versus 15%, P < 0.00001) and (87% versus 38.5%, P < 0.00001), respectively. In multivariate analysis, only rituximab was associated with OS [HR 0.07 (95% CI 0.015-0.312, P = 0.001)] and PFS [HR 0.19 (95% CI 0.55-0.626, P = 0.007)] following transformation. CONCLUSIONS There is a moderate risk of transformation in limited-stage follicular lymphoma treated with curative intent RT, and it substantially impacts outcome in these patients. Treatment with rituximab at the time of transformation appears to improve survival in this otherwise poor-risk population.BACKGROUND The established treatment of limited-stage follicular lymphoma is radiotherapy (RT). There is an inherent risk of transformation of follicular lymphoma to aggressive lymphoma; however, the frequency and impact on the outcome are unknown in limited-stage patients. MATERIALS AND METHODS We identified 237 patients with limited-stage follicular lymphoma treated with curative intent RT. Cases were reviewed to determine the frequency of transformation and subsequent survival. RESULTS With a median follow-up of 7.4 years, the 10-year risk of transformation was 18.5%. With a median follow-up after transformation of 4.7 years, the 3-year post-transformation progression-free survival (PFS) and overall survival (OS) were 42% and 44%, respectively. The addition of rituximab improved the 3-year post-transformation PFS and OS compared with combination chemotherapy alone (78% versus 15%, P < 0.00001) and (87% versus 38.5%, P < 0.00001), respectively. In multivariate analysis, only rituximab was associated with OS [HR 0.07 (95% CI 0.015-0.312, P = 0.001)] and PFS [HR 0.19 (95% CI 0.55-0.626, P = 0.007)] following transformation. CONCLUSIONS There is a moderate risk of transformation in limited-stage follicular lymphoma treated with curative intent RT, and it substantially impacts outcome in these patients. Treatment with rituximab at the time of transformation appears to improve survival in this otherwise poor-risk population.

Efficacy of low dose radiotherapy for primary orbital marginal zone lymphoma

Abstract Marginal zone lymphoma (MZL) is a radiosensitive tumor, with high local control (LC) rates with moderate dose radiotherapy (RT). This retrospective study, performed at the Peter MacCallum Cancer Centre, evaluated the efficacy and toxicity of patients with orbital MZL treated to 24–25 Gy. Twenty-four patients (27 orbits) were identified, with median follow-up of 41 months. Disease was conjunctival in 16 orbits (59%), lacrimal in seven (26%), in the eyelid in one (4%) and elsewhere in three (11%). All patients attained a complete response. Three patients had treatment failures: one local relapse, one contralateral and one distant relapse. Freedom from local failure, freedom from progression, progression-free survival and overall survival were 100%, 90%, 90% and 100% at 2 years and 92%, 81%, 81% and 100% at 5 years, respectively. Aside from cataractogenesis, there was no significant late toxicity. Our study shows that RT doses of 24–25 Gy provide high rates of LC for orbital MZL with acceptable morbidity.

Limited-stage diffuse large B-cell lymphoma treated with abbreviated systemic therapy and consolidation radiotherapy: involved-field versus involved-node radiotherapy.

For limited‐stage diffuse large B‐cell lymphoma (DLBCL), treatment decisions are often influenced by toxicity profiles. One strategy that minimizes chemotherapy‐induced toxicities is abbreviated chemotherapy plus consolidation involved‐field radiotherapy (IFRT). Involved‐node radiotherapy (INRT) is a new concept to DLBCL, aimed to reduce radiotherapy‐induced toxicities. We retrospectively review the long‐term outcomes of limited‐stage DLBCL treated with abbreviated systemic therapy and radiotherapy focusing on field size: IFRT versus INRT.

Synergism of Heat Shock Protein 90 and Histone Deacetylase Inhibitors in Synovial Sarcoma

Current systemic therapies have little curative benefit for synovial sarcoma. Histone deacetylase (HDAC) inhibitors and the heat shock protein 90 (Hsp90) inhibitor 17-AAG have recently been shown to inhibit synovial sarcoma in preclinical models. We tested combinations of 17-AAG with the HDAC inhibitor MS-275 for synergism by proliferation and apoptosis assays. The combination was found to be synergistic at multiple time points in two synovial sarcoma cell lines. Previous studies have shown that HDAC inhibitors not only induce cell death but also activate the survival pathway NF-κB, potentially limiting therapeutic benefit. As 17-AAG inhibits activators of NF-κB, we tested if 17-AAG synergizes with MS-275 through abrogating NF-κB activation. In our assays, adding 17-AAG blocks NF-κB activation by MS-275 and siRNA directed against histone deacetylase 3 (HDAC3) recapitulates the effects of MS-275. Additionally, we find that the NF-κB inhibitor BAY 11-7085 synergizes with MS-275. We conclude that agents inhibiting NF-κB synergize with HDAC inhibitors against synovial sarcoma.

Chromosomal alterations in oligodendroglial tumours over multiple surgeries: is tumour progression associated with change in 1p/19q status?

Background Oligodendroglial neoplasms have morphologic and genotypic heterogeneity. Loss of heterozygosity (LOH) of 1p and/or 19q is associated with increased treatment responsiveness and overall survival. However, the pathogenesis of treatment-resistance is unknown. We sought to determine if tumour progression is due to a proliferating sub-population of tumour cells with intact 1p, or if recurrent tumours retain 1p/19q LOH. Methods 24 patients with oligodendroglial neoplasms, possessing biopsy samples taken at diagnosis and at progression, were identified. 53 tumour specimens were available for LOH analysis of 1p and 19q, using PCR amplification of multiple microsatellite markers. 40 were also tested for 9p and 10q. Results At diagnosis, the median age was 34 (24–66) years, 14 were male. 19 tumours were WHO Grade II, and 5 were high grade. The most common genomic status was 19q LOH (70%). 13 (54%) tumours were 1p LOH at diagnosis: of these, 12 were 19q LOH, and 1 was 19q uninformative. All 12 patients with 1p/19q LOH primary tumours had persistent co-deletion at progression. 9 (38%) tumours were 1p intact at diagnosis, and 8 remained 1p intact in the progressed tumours. There was little heterogeneity of 9p and 10q between tumours at diagnosis and progression. Conclusion 100% of oligodendroglial tumours with 1p/19q LOH, demonstrated persistent 1p/19q LOH in the progressed tumour. Therefore, progression of these tumours is not due to a proliferating sub-population of treatment-resistant, 1p intact tumour cells. We propose that additional mutations contribute to this aggressive phenotype, however, 9p LOH or 10q LOH are unlikely to be involved.