For patients with Hodgkin lymphoma (HL), having vitamin D deficiency prior to starting treatment appears to be associated with worse progression-free survival (PFS) and overall survival (OS), according to results published in the Journal of Clinical Oncology. The findings suggest that future clinical trials should incorporate vitamin D screening, as well as replacement, to determine whether vitamin D replacement improves outcomes.
“Vitamin D deficiency is described as a modifiable risk factor for the incidence of and mortality in many common cancers,” explained Sven Borchmann, MD, from the University of Cologne in Germany, and co-authors. “Despite a recognized seasonal pattern of incidence and mortality in HL, vitamin D deficiency has not been thoroughly evaluated in this disease.”
In this study, researchers determined the prognostic relevance of pretreatment vitamin D deficiency in 351 patients prospectively enrolled in three German Hodgkin Study Group trials, which included those with early-stage favorable, early-stage unfavorable, and advanced-stage HL. These trials randomized participants to receive risk-adapted firstline treatment – ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine), COPP (cyclophosphamide, vincristine, procarbazine, and prednisone), or BEACOPP (bleomycin, etoposide, and doxorubicin plus COPP), with or without radiation therapy.
Patient characteristics were well balanced across the included trials: Median age was 32 years (range = 16-75) and most participants (58%) had an International Prognostic Score <2.
Baseline vitamin D deficiency was associated with significantly inferior survival outcomes.
The median pretreatment serum 25-hydroxy vitamin D level at baseline was 30 nmol/L, and half of patients were categorized as vitamin D deficient:
- deficient (<30 nmol/L): 175 patients (50%)
- insufficient (30 to <50 nmol/L): 83 patients (23.6%)
- sufficient (≥50 nmol/L): 93 patients (26.4%)
“Sufficient vitamin D levels were observed most frequently in patients diagnosed during summer months (June to August), whereas deficient or insufficient levels were most often diagnosed in winter,” the authors reported. Despite this seasonality effect, there were no differences in patients’ clinical characteristics based on their baseline vitamin D status.
Over a median follow-up of 13 years (range not reported), the researchers observed that pretreatment vitamin D deficiency was significantly more common in patients who later developed relapsed/refractory disease, compared with matched relapse-free patients (68% vs. 41%; p<0.001), regardless of disease stage at diagnosis.
Participants who had insufficient or sufficient vitamin D levels at baseline had similar five-year and 10-year PFS and OS rates; however, vitamin D deficiency was associated with significantly inferior survival outcomes (TABLE). This translated to approximately twofold higher risks for poor survival outcomes for vitamin D–deficient patients:
- hazard ratio (HR) for PFS: 2.13 (95% CI 1.84-2.48; p<0.001)
- HR for OS: 1.82 (95% CI 1.53-2.15; p<0.001)
“The difference in OS primarily resulted from a higher proportion of HL–related deaths in patients with baseline deficiency of vitamin D,” they wrote.
To corroborate the results from this initial analysis, the authors then performed a series of cytotoxic assays on HL cell lines cultured with and without calcitriol, a synthetic version of vitamin D3. Pretreatment with vitamin D appeared to enhance the antiproliferative effects of both doxorubicin and etoposide, compared with the activity in untreated cell lines (p value not reported).
“Both agents are key components of the two most commonly used firstline regimens in HL: ABVD and BEACOPP,” the authors noted. However, calcitriol pretreatment appeared to have no effect on the cytotoxicity of bleomycin and cisplatin.
In vivo mouse models showed that the combination of chemotherapy and vitamin D supplementation was “markedly more effective” in controlling tumor growth, compared with placebo-treated controls or with either vitamin D supplementation or doxorubicin alone (p=0.008).
Although the study results suggest that adequate levels of vitamin D may improve the efficacy of cytotoxic agents, these were based on in vitro and in vivo models, limiting their generalizability to patients with HL. They also were not able to determine the best schedule for vitamin D replacement in patients with deficiency.
To clarify the role of vitamin D replacement in HL, and its effect on treatment efficacy, Dr. Borchmann and co-authors encourage vitamin D screening be included in clinical trials of patients with HL. Given the low harm associated with vitamin D replacement, however, the authors concluded, “In the absence of such high-level, prospective evidence, treating institutions may wish to consider an individual approach to [screening and replacement].”
Borchmann S, Cirillo M, Goergen H, et al. Pretreatment vitamin D deficiency is associated with impaired progression-free and overall survival in Hodgkin lymphoma. J Clin Oncol. 2019 October 17. [Epub ahead of print]