Maximum tumor diameter is associated with event-free survival in PET-negative patients with stage I/IIA Hodgkin lymphoma.

Introduction: the high cure rates achieved in early-stage (ES) Hodgkin lymphoma (HL) are one of the great successes of hemato-oncology, but late treatment-related toxicity undermines long-term survival. Improving overall survival and quality of life further will require maintaining disease control while potentially de-escalating chemotherapy and/or omitting radiotherapy to reduce late toxicity. Accurate stratification of patients is required to facilitate individualized treatment approaches. Response assessment using 18F-fluorodeoxyglucose positron emission tomography (PET) is a powerful predictor of outcome in HL,1,2 and has been used in multiple studies, including the United Kingdom National Cancer Research Institute Randomised Phase III Trial to Determine the Role of FDG–PET Imaging in Clinical Stages IA/IIA Hodgkin’s Disease (UK NCRI RAPID) trial, to investigate whether patients achieving complete metabolic remission (CMR) can be treated with chemotherapy alone.3-5 These PET-adapted trials have demonstrated that omitting radiotherapy results in higher relapse rates, but without compromising overall survival.3-5 For the 75% of patients who achieved CMR in RAPID, neither baseline clinical risk stratification (favorable/unfavorable) nor PET (Deauville score 1/2) predicted disease relapse; additional biomarkers are needed.1 Tumor bulk has long been recognized as prognostic in HL,1,6 but there remains uncertainty about the significance and definition of bulk in the era of PET-adapted treatment.7 We performed a subsidiary analysis of RAPID to assess the prognostic value of baseline maximum tumor dimension (MTD) in patients achieving CMR. Methods: ee have previously reported the RAPID trial design, primary results, and outcomes according to pretreatment risk stratification and PET score.1,3 Patients were aged 16 to 75 years with untreated ES-HL and without B-symptoms or mediastinal bulk (mass > 1/3 internal mediastinal diameter at T5/6).6 Metabolic response after 3 cycles of ABVD chemotherapy (doxorubicin, bleomycin, vinblastine, and dacarbazine) was centrally assessed using PET (N = 562). Patients with CMR (ie, Deauville score 1-2) were randomly assigned to receive involved field radiotherapy (IFRT; n = 208) or no further therapy (NFT; n = 211). PET-positive patients (score, 3-5; n = 143) received a fourth cycle of ABVD and IFRT. Baseline disease assessment was performed by computed tomography, and bidimensional target lesion measurements were reported by local radiologists in millimeters. The association of baseline MTD with HL-related event-free survival (EFS: progression or HL-related death) and progression-free survival (PFS) (progression or any-cause death) was assessed using Kaplan-Meier and Cox regression analyses. Non-HL deaths were either related to primary treatment toxicity or occurred in HL remission.1 United Kingdom ethical approval for the RAPID trial was via the UK Multicentre Research ethics committee. Results and discussion: baseline patient characteristics have been previously described.1 Median age was 34 years (range, 16-75 years); 184 (37.4%) of 492 patients had unfavorable risk by European Organisation for Research and Treatment of Cancer criteria, and 155 (32.3%) of 480 by German Hodgkin Study Groupcriteria. Median MTD for patients achieving CMR was 3.0 cm (interquartile range, 2.0-4.0 cm) and 3.0 cm (interquartile range, 1.8-4.5 cm) in the NFT and IFRT groups, respectively, whereas PET-positive patients had a median MTD of 3.9 cm (interquartile range, 2.8-5.1 cm). After a median follow-up of 61.6 m, 44 HL progression events occurred: 21 NFT, 9 IFRT and 14 PET-positive. No patient received salvage treatment without documented progression. Only 5 HL-related deaths occurred (1 IFRT, 4 PET-positive), and 12 non-HL deaths (4 NFT, 6 IFRT, 2 PET-positive).1 For patients with CMR (N = 419), there was a strong association between MTD and EFS (hazard ratio [HR], 1.19; 95% confidence interval [CI], 1.02-1.39; P = .02), adjusting for treatment group, with an approximate 19% increase in HL risk per centimeter increase in MTD. The association was similar in both treatment groups (NFT HR, 1.20 [95% CI, 0.99-1.44; P = .06]; IFRT HR, 1.19 [95% CI, 0.92-1.55; P = .19]). The observed effect sizes did not markedly change after adjusting for baseline clinical risk factors, and similar results were observed for PFS (supplemental Table 1). In contrast, for PET-positive patients, there was no association between MTD and EFS (HR, 0.88; 95% CI, 0.70-1.11; P = .29) or PFS (HR, 0.87; 95% CI, 0.70-1.08; P = .21). In an exploratory analysis within the NFT group, MTD was dichotomized using increasing 1-cm intervals to investigate the relationship between MTD thresholds and EFS. The largest effect size was observed with an MTD threshold of ≥5 cm (Table 1). Similar results were observed for PFS; this threshold also performed best in time-dependent receiver operating characteristic curve analyses. It was not possible to assess MTD thresholds in the IFRT group with only 9 events. Among all randomized patients, 79 (18.9%) had MTD of ≥5 cm, the majority with mediastinal (n = 43), supraclavicular (n = 17), or cervical (n = 16) locations. Five-year EFS for patients with MTD of ≥5 cm randomly assigned to NFT and IFRT was 79.3% (n = 39; 95% CI, 66.6%-92.0%) and 94.9% (n = 40; 95% CI, 88.0%-100%), respectively (P = .03; Figure 1)

Positron Emission Tomography Score Has Greater Prognostic Significance Than Pretreatment Risk Stratification in Early-Stage Hodgkin Lymphoma in the UK RAPID Study.

PURPOSE: Accurate stratification of patients is an important goal in Hodgkin lymphoma (HL), but the role of pretreatment clinical risk stratification in the context of positron emission tomography (PET) -adapted treatment is unclear. We performed a subsidiary analysis of the RAPID trial to assess the prognostic value of pretreatment risk factors and PET score in determining outcomes. PATIENTS AND METHODS: Patients with stage IA to IIA HL and no mediastinal bulk underwent PET assessment after three cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine; 143 PET-positive patients (PET score, 3 to 5) received a fourth doxorubicin, bleomycin, vinblastine, and dacarbazine cycle and involved-field radiotherapy, and 419 patients in complete metabolic remission were randomly assigned to receive involved-field radiotherapy (n = 208) or no additional treatment (n = 211). Cox regression was used to investigate the association between PET score and pretreatment risk factors with HL-specific event-free survival (EFS). RESULTS: High PET score was associated with inferior EFS, before (P .4). CONCLUSION: In RAPID, a positive PET scan did not carry uniform prognostic weight; only a PET score of 5 was associated with inferior outcomes. This suggests that in future trials involving patients without B symptoms or mediastinal bulk, a score of 5 rather than a positive PET result should be used to guide treatment escalation in early-stage HL

Favourable outcomes for high-risk diffuse large B-cell lymphoma (IPI 3-5) treated with front-line R-CODOX-M/R-IVAC chemotherapy: results of a phase 2 UK NCRI trial.

BACKGROUND: Outcomes for patients with high-risk diffuse large B-cell lymphoma (DLBCL) treated with R-CHOP chemotherapy are suboptimal but, to date, no alternative regimen has been shown to improve survival rates. This phase 2 trial aimed to assess the efficacy of a Burkitt-like approach for high-risk DLBCL using the dose-intense R-CODOX-M/R-IVAC regimen. PATIENTS AND METHODS: Eligible patients were aged 18-65 years with stage II-IV untreated DLBCL and an International Prognostic Index (IPI) score of 3-5. Patients received alternating cycles of CODOX-M (cyclophosphamide, vincristine, doxorubicin and high-dose methotrexate) alternating with IVAC chemotherapy (ifosfamide, etoposide and high-dose cytarabine) plus eight doses of rituximab. Response was assessed by computed tomography after completing all four cycles of chemotherapy. The primary end point was 2-year progression-free survival (PFS). RESULTS: A total of 111 eligible patients were registered; median age was 50 years, IPI score was 3 (60.4%) or 4/5 (39.6%), 54% had a performance status ≥2 and 9% had central nervous system involvement. A total of 85 patients (76.6%) completed all four cycles of chemotherapy. There were five treatment-related deaths (4.3%), all in patients with performance status of 3 and aged >50 years. Two-year PFS for the whole cohort was 67.9% [90% confidence interval (CI) 59.9-74.6] and 2-year overall survival was 76.0% (90% CI 68.5-82.0). The ability to tolerate and complete treatment was lower in patients with performance status ≥2 who were aged >50 years, where 2-year PFS was 43.5% (90% CI 27.9-58.0). CONCLUSIONS: This trial demonstrates that R-CODOX-M/R-IVAC is a feasible and effective regimen for the treatment of younger and/or fit patients with high-risk DLBCL. These encouraging survival rates demonstrate that this regimen warrants further investigation against standard of care. TRIAL REGISTRATION: ClinicalTrials.gov (NCT00974792) and EudraCT (2005-003479-19)

Favourable outcomes for high-risk diffuse large B-cell lymphoma (IPI 3–5) treated with front-line R-CODOX-M/R-IVAC chemotherapy: results of a phase 2 UK NCRI trial

Background: Outcomes for patients with high-risk diffuse large B-cell lymphoma (DLBCL) treated with R-CHOP chemotherapy are suboptimal but, to date, no alternative regimen has been shown to improve survival rates. This phase 2 trial aimed to assess the efficacy of a Burkitt-like approach for high-risk DLBCL using the dose-intense R-CODOX-M/R-IVAC regimen. / Patients and methods: Eligible patients were aged 18–65 years with stage II–IV untreated DLBCL and an International Prognostic Index (IPI) score of 3–5. Patients received alternating cycles of CODOX-M (cyclophosphamide, vincristine, doxorubicin and high-dose methotrexate) alternating with IVAC chemotherapy (ifosfamide, etoposide and high-dose cytarabine) plus eight doses of rituximab. Response was assessed by computed tomography after completing all four cycles of chemotherapy. The primary end point was 2-year progression-free survival (PFS). / Results: A total of 111 eligible patients were registered; median age was 50 years, IPI score was 3 (60.4%) or 4/5 (39.6%), 54% had a performance status ≥2 and 9% had central nervous system involvement. A total of 85 patients (76.6%) completed all four cycles of chemotherapy. There were five treatment-related deaths (4.3%), all in patients with performance status of 3 and aged >50 years. Two-year PFS for the whole cohort was 67.9% [90% confidence interval (CI) 59.9–74.6] and 2-year overall survival was 76.0% (90% CI 68.5–82.0). The ability to tolerate and complete treatment was lower in patients with performance status ≥2 who were aged >50 years, where 2-year PFS was 43.5% (90% CI 27.9–58.0). / Conclusions: This trial demonstrates that R-CODOX-M/R-IVAC is a feasible and effective regimen for the treatment of younger and/or fit patients with high-risk DLBCL. These encouraging survival rates demonstrate that this regimen warrants further investigation against standard of care. / Trial Registration: ClinicalTrials.gov (NCT00974792) and EudraCT (2005-003479-19)

The Effect of Badger Culling on Breakdown Prolongation and Recurrence of Bovine Tuberculosis in Cattle Herds in Great Britain

Abstract Bovine tuberculosis is endemic in cattle herds in Great Britain, with a substantial economic impact. A reservoir of Mycobacterium bovis within the Eurasian badger (Meles meles) population is thought to have hindered disease control. Cattle herd incidents, termed breakdowns, that are either 'prolonged' (lasting $240 days) or 'recurrent' (with another breakdown within a specified time period) may be important foci for onward spread of infection. They drain veterinary resources and can be demoralising for farmers. Randomised Badger Culling Trial (RBCT) data were re-analysed to examine the effects of two culling strategies on breakdown prolongation and recurrence, during and after culling, using a Bayesian hierarchical model. Separate effect estimates were obtained for the 'core' trial areas (where culling occurred) and the 'buffer' zones (up to 2 km outside of the core areas). For breakdowns that started during the culling period, 'reactive' (localised) culling was associated with marginally increased odds of prolongation, with an odds ratio (OR) of 1.7 (95% credible interval [CI] 1.1-2.4) within the core areas. This effect was not present after the culling ceased. There was no notable effect of 'proactive' culling on prolongation. In contrast, reactive culling had no effect on breakdown recurrence, though there was evidence of a reduced risk of recurrence in proactive core areas during the culling period (ORs and 95% CIs: 0.82 (0.64-1.0) and 0.69 (0.54-0.86) for 24-and 36-month recurrence respectively). Again these effects were not present after the culling ceased. There seemed to be no effect of culling on breakdown prolongation or recurrence in the buffer zones. These results suggest that the RBCT badger culling strategies are unlikely to reduce either the prolongation or recurrence of breakdowns in the long term, and that reactive strategies (such as employed during the RBCT) are, if anything, likely to impact detrimentally on breakdown persistence

Hydroxychloroquine and short-course radiotherapy in elderly patients with newly diagnosed high-grade glioma: a randomized phase II trial

Background: Effective treatment for patients at least 70 years with newly diagnosed glioblastoma remains challenging and alternatives to conventional cytotoxics are appealing. Autophagy inhibition has shown promising efficacy and safety in small studies of glioblastoma and other cancers. Methods: We conducted a randomized phase II trial to compare radiotherapy with or without hydroxychloroquine (2:1 allocation). Patients aged at least 70 years with newly diagnosed high-grade glioma deemed suitable for short-course radiotherapy with an ECOG performance status of 0–1 were included. Radiotherapy treatment consisted of 30 Gy, delivered as 6 fractions given over 2 weeks (5 Gy per fraction). Hydroxychloroquine was given as 200 mg orally b.d. from 7 days prior to radiotherapy until disease progression. The primary endpoint was 1-year overall survival (OS). Secondary endpoints included progression-free survival (PFS), quality of life, and toxicity. Results: Fifty-four patients with a median age of 75 were randomized between May 2013 and October 2016. The trial was stopped early in 2016. One-year OS was 20.3% (95% confidence interval [CI] 8.2–36.0) hydroxychloroquine group, and 41.2% (95% CI 18.6–62.6) radiotherapy alone, with a median survival of 7.9 and 11.5 months, respectively. The corresponding 6-month PFS was 35.3% (95% CI 19.3–51.7) and 29.4% (95% CI 10.7–51.1). The outcome in the control arm was better than expected and the excess of deaths in the hydroxychloroquine group appeared unrelated to cancer. There were more grade 3–5 events in the hydroxychloroquine group (60.0%) versus radiotherapy alone (38.9%) without any clear common causation. Conclusions: Hydroxychloroquine with short-course radiotherapy did not improve survival compared to radiotherapy alone in elderly patients with glioblastoma

Herd-level risk factors of bovine tuberculosis in England and Wales after the 2001 foot-and-mouth disease epidemic

We present the results of a 2005 case–control study of bovine tuberculosis (bTB) breakdowns in English and Welsh herds. The herd management, farming practices, and environmental factors of 401matched pairs of case and control herds were investigated to provide a picture of herd-level risk factors in areas of varying bTB incidence. A global conditional logistic regression model, with region-specific variants, was used to compare case herds that had experienced a confirmed bTB breakdown to contemporaneous control herds matched on region, herd type, herd size, and parish testing interval. Contacts with cattle from contiguous herds and sourcing cattle from herds with a recent history of bTB were associated with an increased risk in both the global and regional analyses. Operating a farm over several premises, providing cattle feed inside the housing, and the presence of badgers were also identified as significantly associated with an increased bTB risk. Steps taken to minimize cattle contacts with neighboring herds and altering trading practices could have the potential to reduce the size of the bTB epidemic. In principle, limiting the interactions between cattle and wildlife may also be useful; however this study did not highlight any specific measures to implement

Thrombotic microangiopathy in untreated myeloma patients receiving carfilzomib, cyclophosphamide and dexamethasone on the CARDAMON study

Proteasome inhibitors have been associated with thrombotic microangiopathy (TMA) — a group of disorders characterised by occlusive microvascular thrombosis causing microangiopathic haemolytic anaemia, thrombocytopenia and end‐organ damage. To date, carfilzomib‐associated TMA has predominantly been described in relapsed/refractory myeloma patients. We report eight patients with newly diagnosed myeloma who experienced TMA events while receiving carfilzomib on the phase II CARDAMON trial. The first three occurred during maintenance single‐agent carfilzomib, two occurred at induction with carfilzomib given with cyclophosphamide and dexamethasone (KCd) and three occurred during KCd consolidation. At TMA presentation 6/8 were hypertensive; 7/8 had acute kidney injury and in three, renal impairment persisted after resolution of TMA in other respects. The mechanism of carfilzomib‐associated TMA remains unclear, though patients with known hypertension seem particularly susceptible. Given the first three cases occurred during maintenance after a longer than five‐week treatment break, a protocol amendment was instituted with: aggressive hypertension management, carfilzomib step‐up dosing (20 mg/m2 on day 1) at start of maintenance before dose escalation to 56 mg/m2 maximum, and adding 10 mg dexamethasone as premedication to maintenance carfilzomib infusions. No further TMA events occurred during maintenance following this amendment and the TMA incidence reduced from 4·2 to 1·6 per 1 000 patient cycles