Costache Daniel MD
University Emergency Military Central Hospital “Dr. Carol Davila”
Is there a link between biological therapy in psoriasis and organ cancer?
Authors: D. O. Costache, Alexandra I. Lulache, Raluca S. Costache
At the basis of modern therapies there are two fundamental pillars, namely the clinical trials with a significant number of patients on one hand and the clinical experience accumulated on millions of patients on the other hand.
By summing up these two fundamental factors we obtain complex results, not always congruent, but which allow us to analyze in objective terms both the efficacy of the treatment and the safety of the pharmacological products used and, last but not least, the profile of the candidates for treatment.
There is often a bias association or pathological conditions such as vulgar psoriasis or Crohn’s disease. Today no one is surprised to find out to a psoriatic patient the coexistence of metabolic syndrome, inflammatory bowel disease, depression or inflammatory heart disease, their common point being the uncontrolled systemic inflammation triggered by an unknown cause.
Knowing the involvement of the inflammatory system in the control of cellular multiplication in the body, the discussion about the correlations between chronic systemic inflammatory syndrome and hematological or organ tumors is absolutely natural. There is ample evidence on the role of TNF-α in regulating tumor promotion and propagation and at least six characteristic aspects are currently set offering advantages to cells for in vivo survival. These aspects are: promoting autocrine cell growth signals, installing insensitivity to anti-growth signals, favoring angiogenesis, avoiding apoptosis pathways, favoring tissue and metastasis invasiveness mechanisms, unrestricted cellular replication.
Numerous studies prove the involvement of TNF-α in regulating tumor promotion and propagation.
Table 1: TNF-α in the regulation of tumor promotion and propagation
– production of NO (DNA alterations, mediated cGMP tumor promotion)
– autocrine growth and survival factor for malignant cells
– activation of E6 / E7 mRNA in HPV-infected cells
– activation of Src kinase
– tissue remodeling by matrix metalloproteinases
– control of leukocyte infiltration by cytokine modulation
– inhibition of E-cadherin, nucleolar growth of b catenin
– increased tumor motility (invasiveness)
– epithelial-mesenchymal transition
– induction of angiogenic factors
– loss of androgen response
– resistance to cytotoxic medication
Because of these particularly complex and complementary effects at the same time which shows beyond any comments that the body has very well-balanced scales regarding its inflammatory mechanisms of antitumor defense, an immunomodulatory treatment to influence circulating and tissue titres of TNF can rightly raise questions and concerns.
Table 2: TNF-α in counteracting neoplasia
– intratumoral TNF injection – blood flow stop, intratumoral haemorrhage, vascular necrosis
– PMN tumor colonization
– inhibition of tumor growth by macrophages and NK cells (Blankenstein, 1991)
– NK and LAK induced tumor destruction and rejection (Baxevanis, 2000)
– antitumor immunity and elimination of tumor-induced CTL
– favoring induced cytochrome c mitochondrial apoptosis
– c-myc dependent apoptosis
– inhibition of NF-κB activation
Clinical trials, meta-analyzes, data from international registries and last but not least the clinical experience of specialists are the powerful tools we have at hand when we assert that there is no data to date that anti-α-TNF therapies would be incriminated in the induction of neoplasia whether organ or hematologic. The initial concerns that linked biological therapy to the development of lymphomas appear in the light of current information as obsolete.
However, it would be irresponsible not to admit that biological therapy, like all other immunosuppressed therapeutic formulas, could not favor the development of a pre-existing or de novo neoplasm. By analyzing the above-mentioned balance disorder, anti-α-TNF biological therapies may, to an unpredictable extent, help to avoid immune surveillance by existing neoplasms at the time of initiation but insufficiently developed to detect with the currently available methods.
The vigilant post-marketing surveillance of medicinal products is vital, due to the circumstances of clinical trials, which make it possible to find that in current practice medication is also used in categories of patients explicitly excluded in clinical trials and, therefore, data on safety are relatively incomplete, if any at all. Meta-analyzes support a number of these disadvantages of clinical trials, primarily the limited number of patients. However, the duration of individual exposure to active molecules does not change, although data are reported in the patient-years of statistical form type of exposure…
A meta-analysis of 9 clinical trials shows a 3-fold higher risk (OR 3.3 with 95% CI) to develop malignancy in anti-α-TNF-treated patients compared to the control, the risk being proportional to the dose administered. NB, the rate of cancer in the study mentioned in the control arm was abnormally low…
To illustrate this reality we present a clinical case illustrative for the risks to both patients and physicians, despite the good faith of both.