HL

Vitamin D deficiency linked to poor outcome in patients with Hodgkin lymphoma

Vitamin D, a precursor of the corticosteroid hormone calcitriol, is not only important for appropriate calcium homeostasis and bone heath, but some studies suggest that its higher levels are associated with lower risk of developing certain types of cancer.1,2 Recently, the incidence of Hodgkin lymphoma (HL) has been demonstrated to peak during early spring, which coincides with lower levels of vitamin D after winter months due to insufficient exposure to the UVB irradiation required for vitamin D synthesis.3–5 Sven Borchmann and colleagues carried out a randomized, case-controlled study to further evaluate the association between vitamin D deficiency and the incidence of HL, as well as its impact on patients’ mortality.6

Study design and patient characteristics
  • Patients enrolled on trials with the German Hodgkin Study Group were randomised to risk-adapted first-line treatment with chemotherapy with or without radiotherapy
    • patients with early-stage favourable HL (HD7)7
    • patients with early-stage favourable unfavourable HL (HL8)8
    • patients with advanced-stage HL (HD9)9
  • Two matched non-relapsed case control patients were used for each patient with relapsed or progressive disease
Main results
  • In total, 351 patients were analyzed with a median follow-up of 13 years
  • Patient characteristics were similar, with the exception of seasonal diagnosis effect (Table 1)
  • Median pre-treatment vitamin D level was 30nm/L and was similar between treatment arms and stages
  • At baseline, 50% of patients were categorized as vitamin D deficient
  • As expected, patients diagnosed during winter were most likely to have insufficient/deficient levels of vitamin D, while those diagnosed during the summer were most likely to have sufficient levels
Table 1. Selected patient characteristics by vitamin D status

 

Deficient
(<30nmol/L; %)
n= 175

Insufficient
(between ≥30nmol/L and <50nmol/L; %)
n= 83

Sufficient
(≥50nmol/L; %)
n= 93

P

Median age

32 (16–75)

33 (17–71)

31 (16–66)

0.73

Sex

Female

Male

 

73 (42)

102 (58)

 

27 (33)

56 (67)

 

41 (44)

52 (56)

 

0.21

Diagnosis season

Summer

Autumn

Winter

Spring

 

33 (19)

36 (21)

52 (30)

54 (31)

 

21 (25)

17 (20)

16 (19)

29 (35)

 

43 (46)

22 (24)

13 (14)

15 (16)

 

<0.0001*

IPS

<2

≥2

 

88/129 (68)

41/129 (32)

 

53/71 (75)

18/71 (25)

 

64/84 (76)

20/84 (24)

 

0.52

* summer versus other seasons; IPS, International Scoring System

  • There was no correlation between the performance status or hematological toxicity and the level of vitamin D at diagnosis
  • Across all studies and treatment arms pre-treatment vitamin D deficiency was associated with relapsed/refractory (R/R) disease
    • 63% of R/R cases versus 41% of relapse-free cases were recorded as vitamin D deficient (p< 0.001)
  • No adverse effect on clinical outcomes was observed in patients with insufficient levels of vitamin D when compared to those with sufficient levels
  • Patients with baseline vitamin D deficiency had significantly lower progression-free survival (PFS) (HR= 2.13; 95% CI, 1.84–2.48; p< 0.001) and overall survival (OS) (HR= 1.82; 95% CI, 1.53–2.15; p< 0.001) compared to patients with higher vitamin D levels
    • 5-year PFS difference 10.2% (95% CI, 0.8–19.6)
    • 10-year PFS difference 17.6% (95% CI, 6.9–28.4)
    • 5-year OS difference 2% (95% CI, -5.3–9.3)
    • 10-year OS difference 11.1% (95% CI, 2.1–20.2)
  • In vitro studies revealed increased cytotoxic effect of doxorubicin and etoposide on HL cells pre-treated with physiological doses of calcitriol. Moreover, supplementation with vitamin D in combination with chemotherapy in animal models resulted in significantly reduced tumour growth (p=0.008), compared to placebo or monotherapies
Conclusion

Based on preclinical and clinical data, the authors advocate for further clinical trials in patients with HL to include monitoring of vitamin D levels and supplementation to further elucidate its role in control of HL.

References
  1. Budhathoki S. et al. Plasma 25-hydroxyvitamin D concentration and subsequent risk of total and site specific cancers in Japanese population: large case-cohort study within Japan Public Health Center-based Prospective Study cohort. BMJ. 2018 Mar 7;360:k671. DOI: 10.1136/bmj.k671
  2. Heath AK. et al. Vitamin D status and mortality: A systematic review of observational studies. Int J Environ Res Public Health. 2019 Jan 29;16(3). DOI: 10.3390/ijerph16030383
  3. Yu HJ. et al. Analysis of 25-Hydroxyvitamin D Status According to Age, Gender, and Seasonal Variation. J Clin Lab Anal. 2016 Nov;30(6):905-911. DOI: 10.1002/jcla.21955
  4. Borchmann S. et al. Hodgkin Lymphoma has a seasonal pattern of incidence and mortality that depends on latitude. Sci Rep. 2017 Nov 2;7(1):14903. DOI: 10.1038/s41598-017-14805-y
  5. Porojnicu AC. et al. Season of diagnosis is a prognostic factor in Hodgkin's lymphoma: a possible role of sun-induced vitamin D. Br J Cancer. 2005 Sep 5;93(5):571-4. DOI: 10.1038/sj.bjc.6602722
  6. Borchmann S. et al. Pretreatment vitamin D deficiency is associated with impaired progression-free and overall survival in Hodgkin lymphoma. J Clin Oncol. 2019 Oct 17:JCO1900985. DOI: 10.1200/JCO.19.00985
  7. Engert A. et al. Two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine plus extended-field radiotherapy is superior to radiotherapy alone in early favorable Hodgkin’s lymphoma: Final results of the GHSG HD7 trial. J Clin Oncol. 2007;25:395-3502. DOI: 10.1200/JCO.2006.07.0482
  8. Engert A. et al. Involved-field radiotherapy is equally effective and less toxic compared with extended-field radiotherapy after four cycles of chemotherapy in patients with early-stage unfavorable Hodgkin’s lymphoma: Results of the HD8 trial of the German Hodgkin’s Lymphoma Study Group. J Clin Oncol.2003; 21:3601-3608. DOI: 10.1200/JCO.2003.03.023
  9. Diehl V. et al. BEACOPP, a new dose-escalated and accelerated regimen, is at least as effective as COPP/ABVD in patients with advanced-stage Hodgkin’s lymphoma: Interim report from a trial of the German Hodgkin’s Lymphoma Study Group.J Clin Oncol. 1998; 16:3810-3821. DOI: 10.1200/JCO.1998.16.12.3810
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