Are Higher Doses of Consolidation Radiation Therapy Necessary in Diffuse Large B-cell Lymphoma Involving Osseous Sites?

PURPOSE: This study aimed to evaluate whether higher doses of consolidation radiation therapy (RT), which have been traditionally recommended for osseous sites in diffuse large B-cell lymphoma (DLBCL), are still necessary. METHODS AND MATERIALS: Patients with DLBCL with osseous involvement treated with first-line chemotherapy followed by consolidation RT between 1995 and 2016 were reviewed. The primary endpoint was 5-year freedom from local recurrence, estimated using the Kaplan-Meier method. Outcomes based on the RT dose received were also assessed. RESULTS: A total of 51 patients were identified. The most common chemotherapy regimens were rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (80%) and cyclophosphamide, doxorubicin, vincristine, and prednisone (12%) with a median of 6 cycles (range, 3-8 cycles). After chemotherapy, 82% of patients achieved a complete response (CR), and 18% achieved a partial response (PR). All patients in PR were deemed appropriate for consolidation RT. The median dose was 29 Gy (24 Gy for CR; 36 Gy for PR). After a median follow-up of 86 months, 8 patients relapsed, with 2 relapses in the RT field after consolidation RT of 30 and 39.6 Gy, respectively. Overall, the 5-year freedom from local recurrence was 96% (95% confidence interval [CI], 91%-100%), disease-free survival was 76% (95% CI, 65%-89%), and overall survival was 86% (95% CI, 76%-96%). No dose-response relationship was observed. CONCLUSIONS: In patients with DLBCL with osseous involvement who achieved a CR after first-line chemotherapy, 20 to 30 Gy of consolidation RT led to high rates of local control. Higher doses should be reserved for patients in PR.

Phase 2 Study of Dose-Reduced Consolidation Radiation Therapy in Diffuse Large B-Cell Lymphoma.

PURPOSE: To evaluate the feasibility of reducing the dose of consolidation radiation therapy (RT) in diffuse large B-cell lymphoma. METHODS AND MATERIALS: This phase 2 study enrolled patients with diffuse large B-cell lymphoma, not otherwise specified and primary mediastinal (thymic) large B-cell lymphoma in complete response on positron emission tomography-computed tomography imaging after ≥4 cycles of a rituximab/anthracycline-containing combination chemotherapy regimen. Consolidation RT used a dose of 19.5 to 20 Gy. The primary endpoint was 5-year freedom from local recurrence. RESULTS: Sixty-two patients were enrolled between 2010 and 2016. Stage distribution was as follows: I to II (n = 49, 79%) and III to IV (n = 13, 21%). Bulky disease (defined as ≥7.5 cm or ≥10 cm) was present in 23 (40%) and 16 (28%) patients, respectively. Chemotherapy was R-CHOP (then list the drugs) in 58 (94%) and R-EPOCH (then list the drugs) in 4 (6%) with a median of 6 cycles. With a median follow-up of 51 months, 7 patients developed disease progression (6 outside the RT field, 1 within the RT field). Freedom from local recurrence at 5 years was 98% (90% lower confidence bound, 88%). Progression-free and overall survival at 5 years were 83% and 90%, respectively. CONCLUSIONS: With more effective systemic therapy (e.g., addition of rituximab) and more refined chemotherapy response assessment (e.g., positron emission tomography-computed tomography), the dose of RT in combined modality treatment programs may potentially be reduced to 20 Gy. This achieves excellent local control with the potential to decrease acute and long-term side effects.

Chemotherapy or Combined Modality Therapy for Early-stage Hodgkin Lymphoma.

BACKGROUND/AIM: Optimizing treatment of early-stage Hodgkin lymphoma (HL) requires balancing cure with potential acute and late toxicities from treatment. We reviewed our institutional experience with chemotherapy alone (ChT) versus combined modality therapy (CMT). MATERIALS AND METHODS: Patients with stage I-II classical HL in a complete response (CR) by functional imaging after chemotherapy were included. Progression-free survival (PFS) and overall survival (OS) were calculated and a multivariate analysis (MVA) was performed. RESULTS: A total of 136 patients with a CR to chemotherapy were identified. Consolidation radiation therapy (RT) was administered to 117 while 19 received no further therapy. PFS (5 years) was 97% with CMT and 84% with chemotherapy alone (p=0.02). Long-term (10 year) survival was no different (96 vs. 94%, p=0.8). On MVA, CMT improved PFS. Secondary malignancies were rare and no cardiac events were observed. CONCLUSION: Consolidation RT results in superior PFS in early-stage Hodgkin lymphoma with minimal added toxicity.

Consolidation Radiation Therapy for Patients With Advanced Hodgkin Lymphoma in Complete Metabolic Response According to PET-CT or Gallium Imaging.

INTRODUCTION: The purpose of this study was to evaluate the role of consolidation radiation therapy (RT) in advanced Hodgkin lymphoma (HL) in the setting of a complete metabolic response (CR) to chemotherapy (ChT). PATIENTS AND METHODS: Patients with stage III/IV HL treated with ChT alone or combined modality therapy (CMT) between 1992 and 2012 were reviewed. Only patients in a CR according to positron emission tomography-computed tomography (PET-CT) or gallium imaging were included. Clinical end points were estimated using the Kaplan-Meier method and a multivariate analysis using the Cox proportional hazards model was performed. RESULTS: Ninety patients were identified (46 CMT; 44 ChT alone). Median follow-up was 50 months. ChT (median 6 cycles) consisted primarily of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine; 74%) or an ABVD hybrid (10%). Post-ChT imaging consisted of PET-CT (71%) or gallium (29%). RT plans primarily included all initially involved sites of disease with a median dose of 21 Gy (range, 13-31 Gy). CMT was associated with improved 5-year progression-free survival (PFS; 88% vs. 65%, respectively; P < .001) and overall survival (97% vs. 78%, respectively; P = .002) compared with ChT alone. In multivariate analysis, age younger than 45 years (hazard ratio [HR], 0.23; 95% confidence interval [CI], 0.07-0.74; P = .013) and CMT (HR, 0.32; 95% CI, 0.11-0.96; P = .04) were independently associated with improved PFS. Secondary malignancies were comparable in both cohorts (5 with CMT, 4 with ChT), whereas cardiac events were slightly more frequent with CMT (5 vs. 2). CONCLUSION: Low-dose RT, administered to all sites of original involvement, was associated with improved PFS, even in the setting of a metabolic CR after ABVD.

Low-dose consolidation radiation therapy for early stage unfavorable Hodgkin lymphoma.

PURPOSE: The German Hodgkin Study Group (GHSG) trial HD11 established 4 cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) and 30 Gy of radiation therapy (RT) as a standard for early stage (I, II), unfavorable Hodgkin lymphoma (HL). Additional cycles of ABVD may allow for a reduction in RT dose and improved toxicity profile. METHODS AND MATERIALS: Patients treated with combined modality therapy at the Duke Cancer Institute for early stage, unfavorable HL by GHSG criteria from 1994 to 2012 were included. Patients who did not undergo post-chemotherapy functional imaging (positron emission tomography or gallium imaging) or who failed to achieve a complete response were excluded. Clinical outcomes were estimated using the Kaplan-Meier method. Late effects were also evaluated. RESULTS: A total of 90 patients met inclusion criteria for analysis. Median follow-up was 5 years. Chemotherapy consisted primarily of ABVD (88%) with a median number of 6 cycles. The median dose of consolidation RT was 23.4 Gy. Four patients had relapses, 2 of which were in-field. Ten-year progression-free survival (PFS) and overall survival (OS) were 93% (95% confidence interval [CI]: 0.82-0.97) and 98% (95% CI: 0.92-0.99), respectively. For the subset of patients (n=46) who received 5 to 6 cycles of chemotherapy and ≤ 24 Gy, the 10-year PFS and OS values were 88% (95% CI: 70%-96%) and 98% (95% CI: 85% - 99%), respectively. The most common late effect was hypothyroidism (20%) with no cardiac complications. Seven secondary malignancies were diagnosed, with only 1 arising within the RT field. CONCLUSIONS: Lower doses of RT may be sufficient when combined with more than 4 cycles of ABVD for early stage, unfavorable HL and may result in a more favorable toxicity profile than 4 cycles of ABVD and 30 Gy of RT.

Improving outcomes in advanced DLBCL: systemic approaches and radiotherapy.

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma. Approximately half of patients will present with advanced (stage III/IV) disease. The cornerstone of treatment is a combination of chemotherapy and immunotherapy, most commonly R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone). Efforts to improve upon R-CHOP-including more chemotherapy cycles, dose-dense chemotherapy, alternative drug combinations, high-dose chemotherapy with autologous stem cell transplant, and maintenance rituximab-have generally proved unsuccessful. There is a growing body of retrospective and prospective data, however, suggesting a benefit for consolidation radiation therapy (RT) in select patients with advanced DLBCL. Consolidation RT has been shown to improve outcomes for patients with advanced DLBCL generally, and in specific instances including initially bulky disease, bone involvement, or in the setting of a partial response to systemic therapy. In these settings consolidation RT is highly efficacious at achieving local disease control and improving overall outcomes.

Low-dose whole brain radiotherapy combined with radiosurgery for primary CNS lymphoma achieving partial response to induction methotrexate-based chemotherapy.

PURPOSE: For patients with primary CNS lymphoma who achieve complete response (CR) after induction methotrexate-based chemotherapy with rituximab, low-dose whole brain radiation therapy (LD-WBRT) appears effective and is well tolerated. For patients who respond to induction methotrexate-based chemotherapy with or without rituximab but have unifocal residual disease less than 3 cm in size, we hypothesized that LD-WBRT combined with radiosurgery would be effective at controlling residual disease and well tolerated. METHODS: Four adult patients with primary CNS lymphoma with a favorable response to induction chemotherapy but had residual disease less than 3 cm were identified. Induction chemotherapy consisted of methotrexate with or without additional agents including rituximab. LD-WBRT comprised 2340 cGy in 13 fractions. This was immediately preceded or followed by a single radiosurgery treatment of 12 12.5 Gy to the focus of residual disease defined on contrast enhanced T1 weighted MRI. RESULTS: The median follow-up was 17.1 months (range 10-23 months). All patients had residual disease after induction chemotherapy but achieved complete response (CR) following LD-WBRT and radiosurgery. Three patients remained free of disease. One patient developed distant brain recurrence 12 months after radiation but remained alive at last follow-up (17 months). No treatment-related neurotoxicity was observed. CONCLUSIONS: The combination of induction methotrexate-based chemotherapy with or without rituximab, LD-WBRT and radiosurgery appears effective and well tolerated in patients with primary CNS lymphoma who achieve a partial response (PR) to chemotherapy with minimal residual disease. Longer follow-up and larger patient numbers are clearly needed for confirmation.

Validating a prognostic scoring system for postmastectomy locoregional recurrence in breast cancer.

PURPOSE: This study is designed to validate a previously developed locoregional recurrence risk (LRR) scoring system and further define which groups of patients with breast cancer would benefit from postmastectomy radiation therapy (PMRT). METHODS AND MATERIALS: An LRR risk scoring system was developed previously at our institution using breast cancer patients initially treated with modified radical mastectomy between 1990 and 2001. The LRR score comprised 4 factors: patient age, lymphovascular invasion, estrogen receptor negativity, and number of involved lymph nodes. We sought to validate the original study by examining a new dataset of 1545 patients treated between 2002 and 2007. RESULTS: The 1545 patients were scored according to the previously developed criteria: 920 (59.6%) were low risk (score 0-1), 493 (31.9%) intermediate risk (score 2-3), and 132 (8.5%) were high risk (score ≥4). The 5-year locoregional control rates with and without PMRT in low-risk, intermediate-risk, and high-risk groups were 98% versus 97% (P=.41), 97% versus 91% (P=.0005), and 89% versus 50% (P=.0002) respectively. CONCLUSIONS: This analysis of an additional 1545 patients treated between 2002 and 2007 validates our previously reported LRR scoring system and suggests appropriate patients for whom PMRT will be beneficial. Independent validation of this scoring system by other institutions is recommended.

Long-term survival data of triple modality treatment of stage IIB-III-IVA cervical cancer with the combination of radiotherapy, chemotherapy and hyperthermia - an update.

BACKGROUND: Advanced cervical cancer is routinely treated with radiotherapy and cisplatin-containing chemotherapy. Hyperthermia has been shown to improve the results of both radiotherapy and cisplatin. The feasibility of the combination of all three modalities was demonstrated and reported in a study of 68 previously untreated cervical cancer patients in 2005. Long-term follow-up is presented here. METHODS: Sixty-eight patients with advanced cervical cancer were prospectively registered in the USA, Norway and the Netherlands, and treated with a combination of radiotherapy (external beam radiotherapy and brachytherapy for a biologically effective dose of at least 86.7 Gy), chemotherapy (at least four courses of weekly cisplatin (40 mg/m(2))) and locoregional hyperthermia (four weekly sessions). Long-term follow-up was gathered and recurrence-free survival (RFS) and overall survival (OS) curves and survival estimates were obtained. RESULTS: Median follow-up was 81 months. Tumours in 28 patients have recurred, 21 of whom have died. Five-year RFS from the day of registration in the study is 57.5% (95%CI: 46.6-71.0) and five-year OS is 66.1% (95%CI: 55.1-79.3). Differences between countries can be explained by patient characteristics. CONCLUSION: The long-term survival results of the combination of full-dose radiotherapy, chemotherapy and hyperthermia fall well within previous reports for this patient group in randomised trials. The small trial size and lack of randomisation do not permit further interpretation.

Radiotherapy dose-response analysis for diffuse large B-cell lymphoma with a complete response to chemotherapy.

OBJECTIVE: To examine the efficacy of different radiation doses after achievement of a complete response to chemotherapy in diffuse large B-cell lymphoma (DLBCL). METHODS: Patients with stage I-IV DLBCL treated from 1995-2009 at Duke Cancer Institute who achieved a complete response to chemotherapy were reviewed. In-field control, event-free survival, and overall survival were calculated using the Kaplan-Meier method. Dose response was evaluated by grouping treated sites by delivered radiation dose. RESULTS: 105 patients were treated with RT to 214 disease sites. Chemotherapy (median 6 cycles) was R-CHOP (65%), CHOP (26%), R-CNOP (2%), or other (7%). Post-chemotherapy imaging was PET/CT (88%), gallium with CT (1%), or CT only (11%). The median RT dose was 30 Gy (range, 12-40 Gy). The median radiation dose was higher for patients with stage I-II disease compared with patients with stage III-IV disease (30 versus 24.5 Gy, p < 0.001). Five-year in-field control, event-free survival, and overall survival for all patients was 94% (95% CI: 89-99%), 84% (95% CI: 77-92%), and 91% (95% CI: 85-97%), respectively. Six patients developed an in-field recurrence at 10 sites, without a clear dose response. In-field failure was higher at sites ≥ 10 cm (14% versus 4%, p = 0.06). CONCLUSION: In-field control was excellent with a combined modality approach when a complete response was achieved after chemotherapy without a clear radiation dose response.

Impact of consolidation radiation therapy in stage III-IV diffuse large B-cell lymphoma with negative post-chemotherapy radiologic imaging.

PURPOSE: While consolidation radiation therapy (i.e., RT administered after chemotherapy) is routine treatment for patients with early-stage diffuse large B-cell lymphoma (DLBCL), the role of consolidation RT in stage III-IV DLBCL is controversial. METHODS AND MATERIALS: Cases of patients with stage III-IV DLBCL treated from 1991 to 2009 at Duke University, who achieved a complete response to chemotherapy were reviewed. Clinical outcomes were calculated using the Kaplan-Meier method and were compared between patients who did and did not receive RT, using the log-rank test. A multivariate analysis was performed using Cox proportional hazards model. RESULTS: Seventy-nine patients were identified. Chemotherapy (median, 6 cycles) consisted of anti-CD20 antibody rituximab combined with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP; 65%); cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP; 22%); or other (13%). Post-chemotherapy imaging consisted of positron emission tomography (PET)/computed tomography (CT) (73%); gallium with CT (14%); or CT only (13%). Consolidation RT (median, 25 Gy) was given to involved sites of disease in 38 (48%) patients. Receipt of consolidation RT was associated with improved in-field control (92% vs. 69%, respectively, p = 0.028) and event-free survival (85% vs. 65%, respectively, p = 0.014) but no difference in overall survival (85% vs. 78%, respectively, p = 0.15) when compared to patients who did not receive consolidation RT. On multivariate analysis, no RT was predictive of increased risk of in-field failure (hazard ratio [HR], 8.01, p = 0.014) and worse event-free survival (HR, 4.3, p = 0.014). CONCLUSIONS: Patients with stage III-IV DLBCL who achieve negative post-chemotherapy imaging have improved in-field control and event-free survival with low-dose consolidation RT.

Breast conservation therapy: the influence of molecular subtype and margins.

PURPOSE: To evaluate treatment results and prognostic factors, especially margin status and molecular subtype, in early-stage breast cancer patients treated with breast conservation therapy (BCT). METHODS AND MATERIALS: The records of 1,058 Stage I or II breast cancer patients treated with BCT (surgical excision plus radiotherapy) at Duke University Medical Center, Durham, North Carolina, from 1985-2005 were retrospectively reviewed. Conventional receptor analyses were used as surrogate markers for molecular subtype classification (luminal A, luminal B, Her2 positive, and basal like). Actuarial estimates of overall survival (OS), cause-specific survival (CSS), failure-free survival, and locoregional control (LRC) were computed by use of Kaplan-Meier plots. We analyzed prognostic variables for significance using Cox proportional hazards univariate and multivariate analysis. The study was approved by the Duke University Medical Center Institutional Review Board. RESULTS: The median age of the patients was 56 years (range, 18-89 years). Of the patients, 80% had T1 disease and 66% N0 disease pathologically. With a median follow-up of 9.8 years, an in-breast recurrence developed in 53 patients and 10 patients had nodal failure. For all patients, the 10-year CSS rate was 94%; LRC rate, 94%; and failure-free survival rate, 88%. Luminal A patients had a CSS rate of 95% and LRC rate of 99%. Basal-type patients appeared to do worse, with regard to both CSS rate (74%) and LRC rate (76%), but the numbers were small and the difference was not statistically significant. LRC rates of patients with negative margins (widely negative, close, and extent of margin not known) were virtually identical (93%, 96%, and 94%, respectively). Those with positive margins appeared to fare slightly worse based on LRC rate (88%), but again, the numbers were small and the difference was not statistically significant. CONCLUSIONS: BCT remains the treatment of choice for early-stage breast cancer patients irrespective of molecular subtype. Negative margins of excision are desirable, but the width of the negative margin does not influence outcome.

Preoperative single fraction partial breast radiotherapy for early-stage breast cancer.

PURPOSE: Several recent series evaluating external beam accelerated partial breast irradiation (PBI) have reported adverse cosmetic outcomes, possibly related to large volumes of normal tissue receiving near-prescription doses. We hypothesized that delivery of external beam PBI in a single fraction to the preoperative tumor volume would be feasible and result in a decreased dose to the uninvolved breast compared with institutional postoperative PBI historical controls. METHODS AND MATERIALS: A total of 17 patients with unifocal Stage T1 breast cancer were identified. Contrast-enhanced subtraction magnetic resonance images were loaded into an Eclipse treatment planning system and used to define the target volumes. A "virtual plan" was created using four photon beams in a noncoplanar beam arrangement and optimized to deliver 15 Gy to the planning target volume. RESULTS: The median breast volume was 1,713 cm(3) (range: 1,014-2,140), and the median clinical target volume was 44 cm(3) (range: 26-73). In all cases, 100% of the prescription dose covered 95% of the clinical target volume. The median conformity index was 0.86 (range: 0.70-1.12). The median percentage of the ipsilateral breast volume receiving 100% and 50% of the prescribed dose was 3.8% (range: 2.2-6.9) and 13.3% (range: 7.5-20.8) compared with 18% (range: 3-42) and 53% (range: 24-65) in the institutional historical controls treated with postoperative external beam PBI (p = .002). The median maximum skin dose was 9 Gy. The median dose to 1 and 10 cm(3) of skin was 6.7 and 4.9 Gy. The doses to the heart and ipsilateral lung were negligible. CONCLUSION: Preoperative PBI resulted in a substantial reduction in ipsilateral breast tissue dose compared with postoperative PBI. The skin dose appeared reasonable, given the small volumes. A prospective Phase I trial evaluating this technique is ongoing.

Combined-modality therapy for early-stage Hodgkin lymphoma: maintaining high cure rates while minimizing risks.

Multiple randomized studies have demonstrated that chemotherapy, most commonly ABVD (doxorubicin [Adriamycin], bleomycin, vinblastine, dacarbazine), followed by consolidation radiation therapy is the most effective treatment program for early-stage Hodgkin lymphoma. With a combined-modality approach, the great majority of patients are cured of their disease. It is also apparent that both chemotherapy and radiation therapy can increase the risk of complications in the decades following treatment, with second cancers and cardiac disease being the most common. Most studies,evaluating such risks primarily include patients treated in decades past with what are now considered outdated approaches, including high-dose, wide-field radiation therapy. The treatment of Hodgkin lymphoma has evolved significantly, particularly in regard to radiation therapy. In combination with chemotherapy, much lower doses and smaller fields are employed, with success equivalent to that achieved using older methods. Many studies have shown a significant decline in both the rates of second cancers and the risk of cardiac disease with low-dose radiation confined to the original extent of disease. In favorable patients, as few as 2 cycles of ABVD have been shown to be effective. The current combined-modality approach seeks to maintain high cure rates but minimize risks by optimizing both chemotherapy and radiation therapy

Durable palliation of breast cancer chest wall recurrence with radiation therapy, hyperthermia, and chemotherapy.

BACKGROUND AND PURPOSE: Chest wall recurrences of breast cancer are a therapeutic challenge and durable local control is difficult to achieve. Our objective was to determine the local progression free survival (LPFS) and toxicity of thermochemoradiotherapy (ThChRT) for chest wall recurrence. METHODS: Twenty-seven patients received ThChRT for chest wall failure from 2/1995 to 6/2007 and make up this retrospective series. All received concurrent superficial hyperthermia twice weekly (median 8 sessions), chemotherapy (capecitabine in 21, vinorelbine in 2, and paclitaxel in 4), and radiation (median 45 Gy). Patients were followed up every 1.5-3 months and responses were graded with RECIST criteria and toxicities with the NCI CTC v4.0. RESULTS: Twenty-three (85%) patients were previously irradiated (median 60.4 Gy) and 22 (81%) patients received prior chemotherapy. Median follow-up was 11 months. Complete response (CR) was achieved in 16/20 (80%) of patients with follow-up data, and 1 year LPFS was 76%. Overall survival was 23 months for patients with CR, and 5.4 months in patients achieving a partial response (PR) (p=0.01). Twenty-two patients experienced acute grade 1/2 treatment related toxicities, primarily moist desquamation. Two patients experienced 3rd degree burns; all resolved with conservative measures. CONCLUSIONS: ThChRT offers durable palliation and prolonged LPFS with tolerable acute toxicity, especially if CR is achieved.

Hyperthermia combined with radiation therapy for superficial breast cancer and chest wall recurrence: a review of the randomised data.

Hyperthermia has long been used in combination with radiation for the treatment of superficial malignancies, in part due to its radiosensitising capabilities. Patients who suffer superficial recurrences of breast cancer, be it in their chest wall following mastectomy, or in their breast after breast conservation, typically have poor clinical outcomes. They often develop distant metastatic disease, but one must not overlook the problems associated with an uncontrolled local failure. Morbidity is enormous, and can significantly impair quality of life. There is no accepted standard of care in treating superficial recurrences of breast cancer, particularly in patients that have previously been irradiated. There is a substantial literature regarding the combined use of hyperthermia and radiotherapy for these superficial recurrences. Most of it is retrospective in nature, but there are several larger phase III randomised trials that show an improved rate of clinical complete response in patients treated with both modalities. In this review article, we will highlight the important prospective data that has been published regarding the combined use of hyperthermia and radiation.

Hyperthermia for locally advanced breast cancer.

Hyperthermia (HT) has a proven benefit for treating superficial malignancies, particularly chest wall recurrences of breast cancer. There has been less research utilising HT in patients with locally advanced breast cancer (LABC), but available data are promising. HT has been combined with chemotherapy and/or radiotherapy in the neoadjuvant, definitive and adjuvant setting, albeit in series with small numbers of patients. There is only one phase III trial that examines hyperthermia in LABC, also with relatively small numbers of patients. The goal of this review is to highlight important research utilising HT in patients with LABC as well as to suggest future directions for its use.

Overcoming drug resistance in mantle cell lymphoma using a combination of dose-dense and intense therapy.

We present a study of the prevalence of genetic polymorphisms and expression of genes encoding the drug-resistance proteins glutathione S-transferases (GSTs) in order to gain insights into the pattern of failure evident in mantle cell lymphoma. We note a high preponderance of genetic alterations conferring resistance to standard chemotherapy in this illness. Concurrent with this investigation, we present a series of patients who were provided dose-dense and intense chemotherapy to circumvent these drug-resistance mechanisms. High responses were noted, though durable remissions were few, indicating non-traditional chemotherapy options are important to investigate in this illness.