The Role of Glucocorticoids in the Treatment of Non- Hodgkin Lymphoma

Review Article

Ann Hematol Oncol. 2016; 3(7): 1103.

The Role of Glucocorticoids in the Treatment of Non- Hodgkin Lymphoma

Lamar ZS1,2*

1Department of Internal Medicine, Section on Hematology and Oncology, Wake Forest School of Medicine, USA

2Comprehensive Cancer Center, Wake Forest Baptist Medical Center, Winston Salem, USA

*Corresponding author: Zanetta S. Lamar, Department of Internal Medicine, Section on Hematology and Oncology, Wake Forest School of Medicine, Medical Center Blvd, Winston Salem, NC 27157, USA

Received: June 18, 2016; Accepted: August 22, 2016; Published: August 24, 2016


First line chemotherapy for aggressive non-Hodgkin lymphoma (NHL) typically involves high doses of glucocorticoids (GCs) over several days. The most commonly used combination chemotherapy regimen for NHL includes cyclophosphamide, adriamycin, vincristine, and prednisone (CHOP) or given with rituximab (R-CHOP). The dose of prednisone used in the R-CHOP regimen varies in historical studies and in current clinical trials. There is a paucity of prospective data outlining the management of hyperglycemia during chemotherapy in diabetics or the risk of hyperglycemia or steroid-induced hyperglycemia during or following chemotherapy. Often, the adverse short and long-term effects of high doses of GCs are not reported in clinical trials. We will discuss the history of GC incorporation into combination chemotherapy for lymphoma, the potential implications of liberal GC use in this population, and the opportunities for further research.

Keywords: Glucocorticoid; Steroid; Non-Hodgkin lymphoma; Diabetes; Cancer; Hyperglycemia


Glucocorticoids (GCs) are a class of steroid hormones produced in the adrenal cortex and are responsible for regulation of physiologic functions and stress related homeostasis in humans [1]. The most common endogenous GC is cortisol. Exogenously administered systemic GCs include dexamethasone, prednisolone, triamcinolone and prednisone. Synthetic steroids are made from cholic acid obtained from cattle or plants and further modified into oral, injectable or topical agents [2]. Clinicians use synthetic GCs for a variety of benign and malignant diseases [3-5]. GCs have been known to affect the volume, structure, and function of lymphoid tissue since 1944, when cortisone was found to cause tumor regression in a murine model [6]. Further studies confirmed this finding and now GCs are widely used in the treatment of hematologic malignancies [7]. GCs are effective when combined with chemotherapy, but are also effective for treatment of cancer-related nausea, pain, anorexia, and other chemotherapy-related side effects. In lymphomas, the use of GCs in combination with cytotoxic chemotherapy is particularly attractive because of non-overlapping toxicity. Although used in many therapeutic settings, GCs are associated with many adverse effects such as weight gain, immunosuppression, and osteoporosis. Moreover, at high doses GCs may result in insulin resistance causing overt diabetes in pre-diabetics or worsening underlying diabetes in those with mild disease.

What is the mechanism of action as a cancer therapeutic?

The ability of GCs to affect proliferation and apoptosis in malignant cells is predominantly initiated by mechanisms mediated by the binding of GCs to the GC receptor (GCR), an intracellular ligand-dependent transcription factor [8]. Once activated by their ligand, the GCR can act through transactivation or transrepression to mediate pro-apoptotic signaling pathways [9]. While GC-induced apoptosis is dependent on adequate levels of the GCR, the mechanism of GC-induced apoptosis is complex and involves multiple signaling pathways [10,11]. In hematologic malignancies, pathways involved in GC induced apoptosis include transactivation of Bim, a BH-3 only protein and apoptosis inducing member of the Bcl-2 family, and inhibition of the pro-survival transcription factors, AP-1 and NF-kB [12]. The transcriptional upregulation of Bim results in initiation of the intrinsic apoptotic pathway, via activation of Bax/Bak complexes, mitochondrial destabilization through mitochondrial outer membrane permiablization (MOMP), formation of the apoptosome and ultimately activation of Caspase 9 and the executioner caspase, Caspase 3 [13]. In solid tumors, such as breast and prostate cancer, the molecular mechanisms of GC induced apoptosis are less welldefined and the benefits of GCs as a cancer therapeutic are less clear [14].

The most commonly used initial steroid for NHL is prednisone, although dexamethasone is often used in other hematologic malignancies. While the superiority of prednisone versus dexamethasone has not been extensively studied in NHL, in pediatric acute lymphoblastic leukemia (ALL), dexamethasone results in lower incidences of relapse, particularly in the central nervous system, as compared to prednisone or prednisolone, but is associated with increased toxicity [15-17]. In adult ALL, dexamethasone is not superior to prednisolone and is associated with comparable toxicity [18].

How does glucose metabolism occur in cancer cells?

In 1926, Otto Warburg postulated that in the presence of oxygen, malignant cells have increased glucose consumption as compared to non-malignant cells leading to increased lactic acid levels [19]. This observation helped to coin the term aerobic glycolysis. Indeed, for reasons that are still being elucidated, cancer cells show increased utilization of the glycolytic pathway [20]. Understanding this increased glucose metabolism provides a means for clinicians to utilize a technology developed to detect glucose utilization in cells, the positron emission tomography (PET) scan [21]. A PET scan is a nuclear medicine imaging procedure that uses a radiotracer, and in combination with a computed tomography (CT) scans produces images of targeted anatomical regions (CT), highlighting areas of increased glucose metabolism (PET). The most commonly used glucose analog radiotracer is 18-fluorodeoxyglucose (FDG), which was developed out of the need for a radiotracer with a longer halflife [22]. FDG, and other radiolabeled glucose derivatives, compete with glucose for energy utilization. However, when these radiolabeled analogs are processed, they become phosphorylated, like glucose, but cannot be further processed. This intermediate moiety is trapped in cells, providing a means for the potential detection of certain cancers like lymphomas [23]. The National Comprehensive Cancer Network (NCCN) recommends a PET-CT scan for initial staging of FDGavid lymphomas. The scans can be more useful for identifying bone marrow infiltration than bone marrow biopsies in certain situations [24]. In 2014, the Lugano criteria were published and PET-CT scans were recommended for response assessment in FDG-avid lymphomas [25]. The results of interim PET scans are prognostic of survival in Hodgkin lymphoma [26].

How are glucocorticoids used in the treatment of lymphoma?

Cortisone acetate and adrenocorticotropic hormone were first clinically available in 1948, with the initial published studies on its use in patients with lymphomas in 1949 [27]. Figure 1 describes the significant events that led to the combination chemotherapy regimen used in NHL. In the early 1950’s, Rosenthal published the results of ten patients with lymphosarcoma and Hodgkin lymphoma treated with ACTH. The use of ACTH resulted in decreased organomegaly, adenopathy, hemolytic anemia, and improved appetite in some patients. The benefit, however, was only temporary [28]. Another study was then undertaken to evaluate the impact of “massive doses” of steroids defined as up to 500 milligrams of prednisone or prednisolone daily in patients with refractory lymphomas. Objective though transient remissions were obtained, but the complications of diabetes, infection, psychosis, and gastric ulceration or perforations were “forbidding” in their opinion. The authors concluded that “it is clear that massive steroid therapy can be justified only as a heroic measure to meet a desperate situation and then administration must be limited to a relatively brief period of time” [29]. In the early 1960’s, Kofman, et al. sought to determine the most effective prednisolone dose and evaluated response to therapy based on Karnofsky performance status. Although, Kofman noted “when the impressive array of side effects due to corticosteroids is reviewed, it is surprising that corticosteroids have any role in clinical medicine”. He documented tumor regressions in 28 patients out of the 53 treated. Further, this study found that patients that did not respond to 30 mg of prednisolone/day did respond to daily doses of 100 to 200 mg, but that none of patient’s refractory to 100 to 200 mg responded to larger doses [30]. Currently, prednisone remains the most commonly used steroid in first-line combination regimens. Dexamethasone has been incorporated in salvage regimens such as combined with cytarabine and cisplatin (DHAP) or gemcitabine and cisplatin (GDP). Using rituximab as a backbone, the dose of dexamethasone in R-DHAP and R-GDP is 40 mg daily on days 1 through 4 [31,32]. Methylprednisolone is combined with etoposide, cisplatin, and cytarabine in (ESHAP). The dose of methylprednisolone used is 500 mg daily for 5 days [33]. Prednisone is considered an intermediate acting synthetic steroid while dexamethasone is considered long acting.

Citation: Lamar ZS. The Role of Glucocorticoids in the Treatment of Non-Hodgkin Lymphoma. Ann Hematol Oncol. 2016; 3(7): 1103. ISSN : 2375-7965