Publications

BACKGROUND: A predictive model for early-stage classic Hodgkin's lymphoma (cHL) does not exist. Leveraging patient-level data from large clinical trials and registries, we developed and validated a model that we term the Early-Stage cHL International Prognostication Index (E-HIPI) to predict 2-year progression-free survival (PFS).

METHODS: We developed the model using the Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis (TRIPOD) guidelines in 3000 adults with newly diagnosed early-stage cHL from four international phase III clinical trials conducted from 1994 to 2011. External validation was performed in two cohorts, totaling 2360 treated patients from five international cHL registries (1996 to 2019). Two-year PFS was estimated using a Cox model with pretreatment variables selected using backward elimination. Internal validation corrected for overfitting. External validation assessed discrimination and calibration. The final model was also compared against European Organisation for Research and Treatment of Cancer (EORTC) favorable or unfavorable status.

RESULTS: The median age in the development cohort was 31.2 years; 77.4% had stage II disease. The estimated 2-year PFS was 93.7%. Final variables retained in the model were sex and continuous values of maximum tumor diameter (MTD), and levels of hemoglobin and albumin. The optimism-corrected C statistic in the development cohort was 0.63 (95% confidence interval, 0.60 to 0.69). Two-year PFS was lower in the validation cohorts 1 (90.3%) and 2 (91.6%). In validation cohort 1, the C statistic was 0.63 and the calibration slope was near 1, but overall calibration indicated underprediction, which improved on updating the intercept. The performance was similar in validation cohort 2. In addition, higher-risk E-HIPI scores were associated with worse outcomes in both the EORTC unfavorable and favorable subgroups. When included altogether in one Cox model, the E-HIPI was associated with PFS, whereas EORTC favorable or unfavorable status was not. Online risk calculators were developed (https://rtools.mayo.edu/holistic_ehipi/).

CONCLUSIONS: Utilizing objective, continuous, and readily available variables, we developed and validated a new prediction model for early-stage cHL. Male sex, lower hemoglobin or albumin levels, and higher MTDs were associated with worse PFS. (Funded by the National Cancer Institute; grant number, NCI R01 CA 262265-04.).

The optimal treatment of patients with diffuse large B-cell lymphoma (DLBCL) or Hodgkin lymphoma (HL) with preexisting cardiomyopathy is uncertain. An anonymous, electronic survey was distributed by e-mail to three US lymphoma cooperative groups, two community hospitals, and twelve academic medical systems, and distributed at one international lymphoma meeting. Fifty hematology-oncology providers caring for patients with lymphoma were included. In response to a vignette of a 67-yo with Stage III DLBCL with LVEF of 40-45%, 15 (30%) would use non-anthracycline regimens, 13 (26%) R-CHOP with liposomal doxorubicin instead of doxorubicin, 11 (22%) R-CHOP without modification and 6 (12%) R-CHOP with a continuous doxorubicin infusion. In a second vignette of a patient with HL in remission after frontline treatment with doxorubicin cumulative dose 300 mg/m2, 16 (32%) would order an echocardiogram after treatment. There was substantial variability in preferred treatment regimens with preexisting cardiomyopathy and in cardiac monitoring after anthracycline.

BACKGROUND: Fluoropyrimidines, such as 5-fluorouracil (5-FU) and capecitabine, are vital in gastrointestinal cancer treatment but can cause coronary vasospasm (CV). Although calcium channel blockers and nitrates enable rechallenge, the optimal management of patients who cannot tolerate oral medications remains uncertain.

CASE PRESENTATION: A 38-year-old man with metastatic gastric adenocarcinoma developed 5-FU-induced CV during 5-FU, leucovorin, oxaliplatin, and docetaxel chemotherapy. Rechallenge with extended-release nifedipine and isosorbide mononitrate was initially successful, but worsening dysphagia precluded oral prophylaxis. Transdermal nitroglycerin was attempted but failed, necessitating 5-FU interruption and sublingual nitroglycerin. Because of inadequate oncologic response and human epidermal growth factor receptor 2 positivity, treatment transitioned to trastuzumab.

CONCLUSIONS: This case highlights the challenge of 5-FU rechallenge in patients unable to take oral prophylaxis. Transdermal nitroglycerin monotherapy proved insufficient, suggesting that intravenous prophylaxis may be required. Future studies should determine optimal strategies for preventing CV in patients with a similar presentation.

Anthracyclines are an effective treatment for hematologic malignancies but have significant risk of cardiotoxicity that increases with lifetime dose, best characterized for doxorubicin. However, patients may receive different anthracycline formulations, and cardiotoxic dose equivalency for nondoxorubicin anthracyclines is uncertain, making it challenging to calculate a patient's lifetime dose to make decisions about safety of additional anthracycline treatment and risk stratification for monitoring and cardioprotective strategies. In addition, dexrazoxane reduces the risk of cardiovascular toxicity with anthracyclines but how to incorporate previous dexrazoxane treatment into risk stratification is unclear. Here, a young woman previously treated with anthracyclines as induction therapy for acute myeloid leukemia and concern for previous anthracycline cardiotoxicity presented with disease relapse. Because optimal therapy included retreatment with anthracyclines, this case demonstrates the multidisciplinary discussion for her case, reviewing the risks and benefits of repeat anthracycline exposure and detailing the evidence for strategies to monitor and prevent worsening cardiotoxicity.

Classic Hodgkin lymphoma is a highly curable lymphoma that affects primarily younger patients. The therapeutic landscape has evolved and generally consists of varying combinations of chemotherapy and immunotherapy as well as radiation in selected cases. Although most patients are cured of their lymphoma, there is a risk for late treatment-related cardiotoxicity that affects long-term survival and quality of life in this population. Careful consideration of baseline cardiac function and risk factors should be undertaken prior to proceeding with anthracycline-based therapies or thoracic radiation, as adjuvant cardiac-focused efforts may serve to mitigate the risk for cardiovascular dysfunction in this population. This review outlines the evidence supporting current recommendations for assessing baseline cardiotoxicity risk, implementing risk reduction strategies and treatment modifications, the role of multidisciplinary evaluation in high-risk patients, and strategies for long-term cardiac monitoring to minimize treatment-related cardiac morbidity and mortality.

BACKGROUND: The appropriate duration of anticoagulation for venous thromboembolism (VTE) in patients who have a transient provoking factor (e.g., surgery, trauma, or immobility) and concomitant enduring risk factors is uncertain.

METHODS: In this single-center, double-blind, randomized trial, adults with VTE after the occurrence of a transient provoking factor who had at least one enduring risk factor and had completed at least 3 months of anticoagulation were assigned to receive oral apixaban (at a dose of 2.5 mg twice daily) or placebo for 12 months. The primary efficacy outcome was the first symptomatic recurrent VTE. The primary safety outcome was the first episode of major bleeding according to the criteria of the International Society on Thrombosis and Hemostasis.

RESULTS: A total of 600 patients underwent randomization (mean age, 59.5 years; female sex, 57.0%; non-White race, 19.2%). The trial population had a broad range of provoking factors and enduring risk factors. Symptomatic recurrent VTE occurred in 4 of the 300 patients (1.3%) in the apixaban group and in 30 of the 300 patients (10.0%) in the placebo group (hazard ratio, 0.13; 95% confidence interval [CI], 0.04 to 0.36; P<0.001). Major bleeding occurred in 1 patient in the apixaban group and none in the placebo group. Clinically relevant nonmajor bleeding was observed in 14 of 294 patients (4.8%) in the apixaban group and in 5 of 294 patients (1.7%) in the placebo group (hazard ratio, 2.68; 95% CI, 0.96 to 7.43; P = 0.06). One patient in the apixaban group and 3 patients in the placebo group died, with no deaths attributed to cardiovascular or hemorrhagic causes. Nonhemorrhagic, nonfatal adverse events occurred in 6 patients (2.0%) in each group.

CONCLUSIONS: Among patients with provoked VTE and enduring risk factors, low-intensity therapy with apixaban for 12 months resulted in a lower risk of symptomatic recurrent VTE than placebo, with a low risk of major bleeding. (Funded by Bristol-Myers Squibb-Pfizer Alliance; HI-PRO ClinicalTrials.gov number, NCT04168203.).

Analyses of multi-source data, such as data from multi-center randomized trials, individual participant data meta-analyses, or pooled analyses of observational studies, combine information to estimate an overall average treatment effect. However, if average treatment effects vary across data sources, commonly used approaches for multi-source analyses may not have a clear causal interpretation with respect to a target population of interest. In this paper, we provide identification and estimation of average treatment effects in a target population underlying one of the data sources in a point treatment setting for failure time outcomes potentially subject to right-censoring. We do not assume the absence of effect heterogeneity and hence our results are valid, under certain assumptions, when average treatment effects vary across data sources. We derive the efficient influence functions for source-specific average treatment effects using multi-source data under two different sets of assumptions, and propose a novel doubly robust estimator for our estimand. We evaluate the finite-sample performance of our estimator in simulation studies, and apply our methods to data from the HALT-C multi-center trials.

BACKGROUND: In randomized trials, the intention-to-treat effect is the effect of assignment to treatment strategies. The concept of assignment may not be clearly defined when using observational data to emulate a target trial.

AIMS: We aimed to assess the practical implications of using data on prescription versus dispensation as analogues of treatment assignment in observational analyses.

METHODS: We used the primary care-derived Swedish Primary Care Cardiovascular Database of individuals with newly diagnosed hypertension between 2006 and 2014 and linked registers. We compared the effect of two antihypertensive drug classes on the five-year risk of cancer and ischemic heart disease. Treatment assignment was first mapped using prescription data, and then dispensation data. With unique confounding structures, we sequentially adjusted for different classes of risk factor due to uncertainty over the choice of relevant confounders for prescription vs. dispensation.

RESULTS: 7770 individuals were eligible when assignment was defined using prescription compared with 5964 when defined using dispensation. For both cancer and ischemic heart disease outcomes, both higher and lower relative risks of the outcome were consistent with our data. Effect estimates did not vary with the choice of prescription or dispensation data as analogues of assignment, nor with sequential adjustment for class of risk factor.

CONCLUSION: The mapping of prescription or dispensation data to treatment assignment influences the size and characteristics of the study population and the structure of confounding. However, we found no clear numerical differences in effect estimates in this study. Further investigation is required in other settings.