SUPPORTIVE AND PALLATIVE CARE IN CANCER

Corticoterapia – o metodă terapeutică importantă în terapia oncologică

 Corticotherapy – an important therapeutic method in cancer treatment

First published: 14 decembrie 2019

Editorial Group: MEDICHUB MEDIA

DOI: 10.26416/OnHe.49.4.2019.2736

Abstract

Improving the quality of life for the oncology patients, both in the early and in terminal stages of the disease, is one of the main goals of the therapy. Glucocorticoids are indispensable nowadays in the oncological treatment, yet more than 50 years have passed since the introduction of corticotherapy into medical practice, being used either as a single treatment, or as adjuvant therapy. The indications of corticotherapy in oncological diseases are various, the treatment being used both in oncological emergencies and in controlling the side effects of specific therapies. Cortisol (hydrocortisone) is the main corticosteroid hormone of human adrenocortex. Synthetic glucocorticoids are molecules (21 Carbon atoms) derived from the hydrocortisone formula, being used in oncological clinical practice due to their different roles and effects:  cytolytic, antiemetic, analgesic, decompressive, antihypercalcemic agent, as palliative treatment in the advanced stages of the disease. Therefore, multiple indications of corticotherapy in this pathology call for the frequent use of this treatment in various stages of the oncological disease. However, the side effects of glucocorticosteroids should not be ignored, but by short-term administration, the side effects are relatively low and controllable.

Keywords
corticotherapy, cancer, adjuvant treatment, palliative care

Rezumat

Îmbunătăţirea calităţii vieţii pacienţilor oncologici, atât la cei diagnosticaţi în stadiile incipiente ale bolii, cât şi la cei aflaţi în stadiul terminal, este unul dintre scopurile ac­ti­vi­tă­­ţii medicale în acest domeniu. La peste 50 de ani după in­­tro­­du­ce­rea în prac­ti­ca medicală a corticoterapiei, glu­co­cor­ti­coi­zii sunt astăzi in­dis­pen­sa­bili în tratamentul on­co­lo­gic. În bolile neoplazice, cor­tico­terapia are un rol extrem de im­por­tant, fiind utilizată fie ca tratament unic, fie ca te­ra­pie adjuvantă. Indicaţiile cor­ti­co­terapiei în afecţiunile on­co­lo­gi­ce sunt mul­ti­ple, acest tratament fiind utilizat atât în ur­gen­ţe­le on­co­lo­gi­ce, cât şi în controlul efectelor secundare ale terapiilor on­co­lo­gi­ce. Cortizolul (hi­dro­cor­tizonul) este prin­ci­pa­lul hor­mon cor­ti­co­ste­roid al adre­no­cor­texului uman. Glu­co­cor­ti­coi­zii sin­te­tici sunt molecule (21 de atomi de Carbon) derivate din for­mu­la hi­dro­cor­ti­zo­nului, fiind utilizaţi în practica clinică on­co­lo­gi­că datorită ac­ţiu­nii lor: acţiune citolitică, acţiune an­ti­eme­ti­că, acţiune anal­ge­zi­că, acţiune decompresivă, ac­ţiu­ne anti­hi­per­cal­ce­mian­tă, ca tratament paliativ în fa­ze­le avansate ale bolii. Prin ur­ma­re, indicaţiile multiple ale cor­ti­co­te­ra­piei în această pa­to­lo­­gie impun utilizarea frecventă a acestui tratament în di­fe­ri­te eta­pe ale evoluţiei afecţiunilor on­co­lo­gice. Nu trebuie ig­no­ra­te însă efectele secundare ale glu­co­cor­ti­co­ste­roi­zi­lor, dar, prin ad­mi­nis­tra­rea pe perioade scurte, efec­tele se­cun­dare sunt re­lativ reduse şi controlabile.

Improving the quality of life for cancer patients, both in the early and terminal stages of the disease, is one of the main goals of this therapy.

Nowadays, glucocorticoids are indispensable in the oncological treatment, although more than 50 years have passed since the introduction of corticotherapy into medical practice, being used either as a single treatment, or as adjuvant therapy.

The indications of corticotherapy in oncological diseases are various, the treatment being used both in oncological emergencies and for controlling the side effects of specific therapies.

Cortisol (hydrocortisone) is the main corticosteroid hormone of human adrenocortex. Synthetic glucocorticoids are molecules (21 C atoms) derived from the hydrocortisone formula, being used in oncological clinical practice due to their different roles and effects: cytolytic, antiemetic, analgesic, decompressive, antihypercalcemic agent, and as palliative treatment in the advanced stages of the disease.

Cytolytic action

By attaching to the cytoplasmic receptor, a steroid-receptor complex is formed, through which it gets into the nucleus, and stimulates the transmutation of mRNA, thereby modifying the protein synthesis of specific enzymes. The cytolytic action of glucocorticoids might be a consequence of inducing apoptosis and inhibiting cellular proliferation(1).

Immunosuppression is another action caused by the antiproliferative effect on lymphocytes. On the other hand, it plays an important role in accelerating the release of neutrophils from the bone marrow, which is why they are used in the treatment of chemotherapy-induced neutropenia(1).

Antiemetic effect

Nausea and vomiting can produce nutritional depletion, through the associated anorexia, resulting in the unveiling of different metabolic disorders. The physiological and psychological impact on the patient can be so strong, that it can lead to quiting treatments with curable intent(1).

The association between corticotherapy and the main antiemetic treatment of that time – metoclopramide – occurred in the early 1980s, followed at the end of the same decade by the development of 5-HT3 receptor antagonists, the combination of corticosteroid therapy with these antagonists being currently the treatment of chemotherapy-induced emesis(1,14).

Corticotherapy, whose mechanism is still insufficiently known, has an important role in controlling chemotherapy-induced emesis by diverse effects(15):

  • influencing prostaglandin activity in the brain;

  • reduction of moderate brain edema caused by changes in the blood-brain barrier by some chemotherapy regimes;

  • prevents the release of serotonin in the gastrointestinal tract.

Glucocorticosteroids are effective as single agents in controlling acute emesis (in the first 24 hours after chemotherapy), but are also active in delayed emesis. Dexamethasone (p.o. or i.v.) and methylprednisolone (single dose or multiple administrations) have equal benefits. Currently, corticosteroids are used to control acute emesis, delayed emesis and radiation-induced emesis.

The combination of dexamethasone with 5-HT3 antagonists (ondansetron, granisetron, palonosetron) provides greater protection (92%) than dexamethasone alone (81%).

The recommended doses of dexamethasone are 8 mg/day i.v./days 1-3 of chemotherapy administration, with prolonged administration in case of delayed emesis(1).

Analgesic role

Pain is a complex syndrome that has a great impact both on the quality of life and the psychology of the patient. Pain in cancer may be a consequence of the disease itself, or may result from treatments, including surgery, radiotherapy and chemotherapy.

Although it appears late in the natural evolution of the disease, pain is the most common symptom in cancer.

Corticosteroids are used in patients with bone pain, medullary compression, increased intracranial pressure, visceral pain and advanced neoplasia by reducing edema and relieving pressure on compressed structures(2).

Analgesic action is related to their anti-inflammatory effect, reducing edema, and to their role in stabilizing the injured or inflamed nerve.

Corticosteroids inhibit phospholipase A that transforms phospholipids from the cell membrane into arachidonic acid which transforms into prostaglandins, powerful pain receptors stimulants, having the role of transmitting the nervous influx from peripheral to central nervous structures.

Corticotherapy reduces edema and lowers pressure on compressed structures and has a beneficial effect on the patient general condition.

It is recommended in painful syndromes generated by medullary or nerve compression, intracranial hypertension, neuropathic pain, bone metastases, and lymphedema(2).

Decompressive effect

Superior vena cava compression syndrome (SVCS)

Causes: compression, direct invasion, thrombosis.

These can be generated by primary malignant tumors (bronchopulmonary cancers, lymphomas, mediastinal tumors) or metastatic malignant tumors (breast, testicle etc.). In SVCS there are administered dexamethasone 16 mg/day or high doses of hydrocortisone hemisuccinate: 100-500 mg/day i.v., followed by reduced doses every 6-8 hours. The mechanism of action is unclear: reducing local swelling associated with inflammation results in reduced obstruction(12).

The treatment of this serious syndrome is an oncological emergency and requires besides corticotherapy the following treatment(13):

  • oxigen terapy, for dyspnea, hypoxia;

  • furosemide 20-40 mg i.v., to reduce edema;

  • emergency radiotherapy (3x4 Gy);

  • chemotherapy;

  • the placement of a stent, with rapid relief in 90% of cases, being the elective treatment; surgical decompression, in acute obstruction(2).

Spinal cord compression

This is also an oncological emergency, and the delayed diagnosis and treatment can lead to irreversible paralysis.

It develops in 1-5% of systemic cancers when primary tumor or metastases cause spinal compression with neurological deficit(10,11).

It is due in particular to extradural metastases (95%) invading the spine: 70% located in the thoracic region, 20% in the lumbosacral region, 10% cervical, 10-40% multifocal(2).

Common causes: breast cancer, prostate cancer, lung cancer, multiple myeloma, lymphoma.

Treatment: corticotherapy – dexamethasone i.v. 16-20 mg can reduce edema associated with 20-30 Gy decompressive radiotherapy – in 1-2 weeks in radiosensitive tumors, especially in those with multiple compression areas; high doses of dexamethasone (loading dose 100 mg, then 16 mg x 4/day) may be given with advantage over reduced doses in pain control, increased bladder control, but with higher risk of side effects common to corticosteroids(2).

Antihypercalcemic agent

Hypercalcemia, defined as an increased serum calcium concentration over the normal range, is the most common metabolic disorder in neoplastic patients, and may be associated with bone metastases. It is commonly associated with breast cancer (50%), lung cancer, renal and malignant hematopoietic neoplasia (15%)(2).

The mechanisms involved in decreasing serum calcium levels by the corticosteroids are multiple, the main being the inhibition of bone resorption in bone metastasis. Other mechanisms implied: glucocorticoids increase urinary calcium excretion and diminish intestinal absorption, corticotherapy has anti-vitamin D action, reduces tubular phosphorus resorption, inhibits prostaglandins and osteoclast activation factor and has antitumor activity(9).

High doses of hydrocortisone, 250-500 mg i.v. at 8 hours or dexamethasone 16-24 mg/day, may be effective in the treatment of hypercalcemia associated with malignant lymphoproliferation (non-Hodgkin’s lymphoma and multiple myeloma). The decrease in serum calcium is, however, slow. Maintenance therapy should be performed with prednisone 10-30 mg/day p.o.(2).

Besides the aforementioned situations, cortico­steroids are used as an adjunct treatment of osteoclast inhibitors(2).

Corticotherapy as a palliative treatment
in the advanced stages of the disease

Cerebral edema

It occurs due to cerebral metastases or primary cerebral tumors. Frequently primary cancer: lung cancer, breast cancer, malignant melanoma(8).

The invasion of malignant cells causes the release of leukotrienes and other soluble mediators responsible for vasodilatation, increased capillary permeability and edema(1).

Treatment of intracranial hypertension

Corticotherapy reduces edema by inhibiting arachidonic acid conversion to leukotrienes and thus decreasing vascular permeability. It has also anti-inflammatory and anti-emetic effect, cytostatic effect in lymphomas, and antitumor effect in glioblastomas(7).

The emergency treatment requires dexametaxone 16-24 mg/day, metilprednisolone 250-1000 mg/day plus, when it is possible, an associated treatment with radiotherapy +/- chemotherapy(2).

Other indications of corticotherapy

Treatment of immunotherapy-related side-effects

Both cytotoxic T lymphocyte antigen-4 (CTLA-4) and programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) inhibitors have a vast immune-related side-effects primarily related to T-cell activation and can have an effect on any organ or tissue.

Skin toxicity: grade 1-2 side effects are generally managed with topical glucocorticosteroids, emollients, and antihistamines. Grade 3 requires treatment interruption and oral prednisone, 0.5 to 1 mg/kg/day, until the improvement to grade 1(3).

Enterocolitis: grade 3-4 toxicity requires oral or intravenous corticosteroids, 1-2 mg/kg/day, associated with oral or i.v. hydration and simptomatic treatment – antidiarrhoeal agents. Patients who do not respond to this therapy should receive other immunosupresive treatments.

Hypophysitis: hormone replacement treatment should be initiated; high-dose corticosteroids are not necessary, only when neurological problems or headaches are present(3).

Thyroiditis: hormone replacement therapy when necessary or for acute thyroiditis, a short period of high-dose steroids, 1 mg/kg of prednisone, or equivalent(5).

Pneumonitis: it is one of the most frequent side effects. For grade 2 penumonitis, it is administered oral prednisolone 1-2 mg/kg/day until symptoms improve. In grade 3-4 pneumonitis, prednisolone (2-4 mg/kg/day) should be initiated; if the symptoms do not improve in 48-72 hours, other immunosupresive treatments will be administered.

Nutrition of oncological patients

Due to the disease itself or to the specific therapy, cancer patients often have nutritional disorders (manifested by anorexia, weight loss, fatigue and fatigability) and an increased risk of malnutrition. Corticosteroids act for short periods of time by increasing appetite, thus improving body weight and the general state, but at the same time they are catabolic agents that induce muscle loss(1).

Dexamethasone can be given at a dose of 4 mg after a meal for a limited period of time.

Stimulant of the hematopoietic marrow

Another indication of corticotherapy is the post-chemotherapy and post-radiotherapy hematological toxicities, one of the most important side effects in oncological treatments. Indications: secondary anemia, secondary leukopenia, secondary thrombocitopenia, pancytopenia.

Dexamethasone 8-16 mg/day, for 5-7 days. In reduced degrees of toxicity, corticotherapy can be administered alone. In more serious forms, it should be associated with blood transfusions or derivatives(2).

Side effects of corticotherapy

Immunological – immunosuppression; endocrine – hyperglycemia, diabetes, adrenal suppression, hypocortisolism; digestive – ulcers, gastritis; myasthenia of proximal muscles, weight gain, cataract; psychogenic – anxiety, psychic agitation, insomnia, psychic lability(4).

The side effects of corticotherapy require constant monitoring and eventual prophylaxis, two of the most commonly encountered in practice being gastric erosions or the reactivation of pre-existing gastric hypersecretory conditions and hypokalaemia. Both corticosteroid and oncological treatments favor gastric acid secretion, therefore prophylactic measures are taken with anti-H2 inhibitors such as ranitidine or omeprazole. The modification of acid-base and hydro-electrolyte balance can be corrected by dietary regimen rich in potassium(1,2).

The administration of corticosteroid over short periods of time causes relatively reduced side effects, generally psychogenic (psychic agitation, insomnia), reducible by their morning administration (diurnal cycle).

Conclusions

Corticotherapy is a therapeutic method with multiple indications, being used for the management of side effects of oncological therapies, as well as in emergency situations, such as palliative treatment in patients with advanced disease, ensuring the control of symptoms in numerous complications of neoplastic disease.

The use of such corticosteroid therapy is due to its cytolytic, anti-inflammatory, antialgic effects (by inhibiting the synthesis of prostaglandins), antiemetic, hypocalcemiant agent, anti-edema effect, as well as for improving the general state and for its appetite stimulating effect.

Therefore, multiple indications of corticotherapy in this pathology call for the frequent use of this treatment in various stages of oncological disease.

However, the side effects of glucocorticosteroids should not be ignored, but with short-term administration the side effects are relatively low and controllable. 

Conflict of interests: The authors declare no conflict of interests.

Bibliografie

 
  1. Nanu A. Corticoterapia în practica medicală. Editura Amaltea. 2003; Bucureşti.
  2. Curs de Oncologie Clinică şi Nursing în Oncologie. Editura Medicală Universitară Craiova, 2015.
  3. Haneen JBAG (ed.). ESMO Handbook of Immuno-oncology. 2018.
  4. Buchman AL. Side effects of corticosteroid therapy. J Clin Gastroenterol. 2001 Oct; 33(4):289-94.
  5. Barroso-Sousa R, Barry WT, Garrido-Castro AC, Hodi FS, Min L, Krop IE, Tolaney SM. Incidence of Endocrine Dysfunction Following the Use of Different Immune Checkpoint Inhibitor Regimens: A Systematic Review and Meta-analysis. JAMA Oncol. 2018; 4(2):173.
  6. King DJ, Brunton J, Barr RD. The influence of corticosteroids on human erythropoiesis. An in vivo study. Am J Pediatr Hematol Oncol. 1988 Winter; 10(4):313-5.
  7. Dietrich J, Rao K, Pastorino S, Kesari S. Corticosteroids in brain cancer patients: benefits and pitfalls, Expert Rev Clin Pharmacol. 2011 Mar; 4(2): 233–242. doi: 10.1586/ecp.11.1
  8. French LA. The Use of Steroids in the Treatment of Cerebral Edema. Bull N Y Acad Med. 1966 Apr; 42(4): 301–311.
  9. Sternlicht H, Glezerman IG. Hypercalcemia of malignancy and new treatment options. Ther Clin Risk Manag. 2015; 11: 1779–1788. 
  10. Skeoch GD, et al. Corticosteroid Treatment for Metastatic Spinal Cord Compression: A Review. Global Spine J. 2017 May; 7(3): 272–279. 
  11. L’Espérance S, et al. Treatment of metastatic spinal cord compression: CEPO review and clinical recommendations. Curr Oncol. 2012 Dec; 19(6): e478–e490. 
  12. Rowell NP, Gleeson FV. Steroids, radiotherapy, chemotherapy and stents for superior vena caval obstruction in carcinoma of the bronchus. Cochrane Database Syst Rev. 2001; (4):CD001316.
  13. Straka C, Ying J, Kong FM, Willey CD, Kaminski J, Nathan Kim DW. Review of evolving etiologies, implications and treatment strategies for the superior vena cava syndrome. Springerplus. 2016; 5: 229. Published online 2016 Feb 29. 
  14. Chu CC, et al. The cellular mechanisms of the antiemetic action of dexamethasone and related glucocorticoids against vomiting. Eur J Pharmacol. 2014 Jan 5; 722:48-54. 
  15. Grunberg SM. Antiemetic activity of corticosteroids in patients receiving cancer chemotherapy: dosing, efficacy, and tolerability analysis. Ann Oncol. 2007 Feb; 18(2):233-40. 

Articole din ediţiile anterioare

REVIEW | Ediţia 4 45 / 2018

Imagistica multiparametrică de rezonanţă magnetică în diagnosticul cancerului de prostată: o necesitate

Ioana G. Lupescu

Cancerul de prostată reprezintă o importantă problemă de sănătate publică. Imagistica prin rezonanţă magnetică (IRM) este cea mai bună modalitate d...

29 decembrie 2018
ONCOLOGY TODAY | Ediţia 3 44 / 2018

Romania in Global Cancer Statistics 2018

30 octombrie 2018
REVIEW | Ediţia 1 46 / 2019

Deficitul de fier şi cancerul – implicaţii clinice

Andreea- Daniela Gheorghe, Andra-Iulia Suceveanu, Adrian-Paul Suceveanu, Doina Tofolean, Laura Mazilu

Anemia este o complicaţie frecventă la pacienţii oncologici, fiind întâlnită atât la momentul diagnosticului, cât şi în cursul terapiilor oncologic...

27 martie 2019
REVIEW | Ediţia 2 51 / 2020

Neutropenia indusă de imunoterapie la pacienţii oncologici – review

Andreea- Daniela Gheorghe, Andra-Iulia Suceveanu, Adrian-Paul Suceveanu, Laura Mazilu

Imunoterapia a schimbat complet abordarea tratamentului şi prognosticul pacienţilor în mai multe tipuri de cancer. Imu­no­te­rapia a demonstrat un ...

19 mai 2020