RU2620541C1 - Method for growth hormone deficiency prediction for patients after radiotherapy and polychemotherapy of postcranial fossa tumors performed in childhood - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: method for growth hormone (GH) deficiency prediction for patients after postcranial fossa (PCF) tumors radiotherapy and chemotherapy performed in childhood, which consists in IGF-1 level estimation in plasma, calculation of the underlying disease remission period duration, and measurement of the father's height, GH deficiency probability is calculated by the following formula: P=4.323+(0.00203×A)-(0.03055×B)-(0.01806×C), where P is prediction, A is IGF-1 levek (ng/ml), B is remission duration (years), C is father's height (cm).

EFFECT: method makes it possible to predict the development of growth hormone deficiency in patients after postcranial fossa tumors treatment in childhood and is simple and affordable in clinical practice.

2 tbl, 2 ex

Description

The invention relates to medicine, namely to endocrinology and oncology.

In recent years, in the Russian Federation there has been a steady increase in cancer incidence in children. If in 1994 this indicator was 9.8 per 100,000 children aged 0-14, then in 2013 it rose to 12.5 per 100,000. Along with this, a significant decrease in mortality. In 2013, 998 children aged 0-17 years old died of malignant neoplasms in Russia (3.7 per 100,000 children), which is significantly lower than in 1994 when 1,888 children died (5.9 per 100,000) ( Kaprin A.D., Starinsky V.V., Petrova G.V. Malignant neoplasms in Russia in 2013 (morbidity and mortality). 2015.250 p.).

In the structure of malignant neoplasms in children, brain tumors (OGM) occupy second place in prevalence, second only to hemoblastoses. In Russia in 2013, neoplasms of the brain and other parts of the central nervous system (CNS) accounted for 17.2% of all malignant tumors of childhood (0-14 years). Most often, OGM in children has an infratentorial localization, i.e. located in the posterior cranial fossa (RFA) (43-63% of cases) (Aikardi J. Diseases of the nervous system in children: in 2 volumes // 2. M.: Panfilova Publishing House; BINOM. Knowledge Laboratory, 2013. P. 557-585). However, despite the steady increase in cancer incidence in children, complex treatment (surgical treatment, radiation and polychemotherapy) has made significant progress. Over the past decades, there has been an improvement in prognosis for these patients. So, the 5-year survival rate of children after complex treatment of OGM is approximately 60-70% (O. Zheludkova, Treatment of brain tumors in children // Doctor. 2011. No. 12. P. 22-27).

With an increase in survival, doctors of various specialties are increasingly faced with the long-term consequences of antitumor therapy, including violations of the endocrine system.

The most common endocrine consequence of cranial irradiation (KO) used in the treatment of tumors of HF in childhood is growth hormone deficiency (GH). According to various sources, when 30–50 Gy is exposed to the hypothalamic-pituitary region, the incidence of GH deficiency can vary from 50 to 100% (Darzy K.N., Shalet SM Hypopituitarism following radiotherapy. // Pituitary. 2009. Vol. 12. P. 40-50). According to the results of a study on the long-term endocrine effects in patients after treatment of OGM in childhood, which included 1607 patients, the relative risk of developing a GR deficiency was 277.8 times higher than a healthy population (Gurney JG et al. Endocrine and cardiovascular late effects among adult survivors of childhood brain tumors: Childhood Cancer Survivor Study. // Cancer. 2003. Vol. 97. P. 663-673). The results of various prospective studies suggest that when the diencephalic region is irradiated with a dose of 35 Gy or more 5 years after antitumor therapy, GH deficiency is observed in almost 100% of cases. According to Uday S. et al. GR deficiency after treatment of medulloblastoma was detected in 97%, the median time from the end of treatment to the development of this pathology was 1.7 years (0.7-15 years) (Uday S, Murray RD, Picton S, et al. Endocrine sequelae beyond 10 years in survivors of medulloblastoma. // Clin Endocrinol (Oxf). 2015. Vol. 83 (5). P. 663-670). GH deficiency is one of the main factors that slow down growth. According to ChildhoodCancerSurvivorStudy, in 40% of patients after antitumor therapy with OHM, the final growth does not exceed the 10th percentile. Low final growth inevitably leads to a deterioration in the quality of life and complicates social and psychological adaptation. Previously, GH deficiency was considered a childhood pathology. However, to date, it has been proven that GH deficiency in adults leads to various disorders, such as abdominal obesity, a decrease in lean body mass, dyslipidemia (in particular, an increase in total cholesterol, LDL), a decrease in bone mineral density, impaired contractile function of the heart, and a decrease muscle strength and endurance, sleep disturbances, decreased quality of life. In this regard, it is extremely important to identify GH deficiency not only in children, but also in adults in order to select adequate replacement therapy with recombinant GH drugs.

The "gold standard" for the diagnosis of GH deficiency is a test with insulin hypoglycemia (IHG). In addition to it, other stimulation tests, for example, a test with glucagon, with arginine, L-dopa, are used in clinical practice to diagnose GR deficiency.

Test procedure with IHG:

- blood sampling at - 15 ', 0' (to determine the level of GR);

- intravenous administration of short-acting insulin (0.1-0.2 U / kg) diluted in 5-10 ml of 0.9% p-pa NaCl;

- blood sampling at 15 ', 30', 45 ', 60', 90 ', 120' (to determine the level of GR);

- with the development of symptoms of hypoglycemia (glycemia less than 2.2 mmol / l), intravenous administration of 40-60 ml of a 40% glucose solution.

In the Russian Federation, the criteria for the diagnosis of GH deficiency are developed only for children. Total somatotropic insufficiency is diagnosed with a maximum release of GR on the background of stimulation of less than 7 ng / ml, a partial deficiency is diagnosed with a peak of release of GR from 7 to 10 ng / ml (Dedov II, Melnichenko GA Endocrinology: national leadership. Moscow: GEOTAR-Media, 2009.1072 pp.). For adults, threshold values are not specified, which is probably due to the fact that they almost do not receive HR replacement therapy. Diagnostic criteria for this disease in adults are described in several foreign clinical guidelines. According to the consensus of the GrowthHormoneResearch Society for 2007, in adults with peak release of GH in a sample with IGH or in a sample with glucagon less than 3 ng / ml (3 μg / l), one can speak of GH deficiency (But KKY Consensus guidelines for the diagnosis and treatment of adults with GH deficiency II: A statement of the GH Research Society in association with the European Society for Pediatric Endocrinology, Lawson Wilkins Society, European Society of Endocrinology, J // Eur. J. Endocrinol. 2007. Vol. 157, No. 6 P. 695-700). According to the clinical recommendations of the American Association of Clinical Endocrinologists (AACE) from 2009 (Cook DM et al. Guidelines for Use of Growth Hormone in Clinical Practice // Endocr Pr. 2009. Vol. 15 (Suppl. P. 29.)), and TheEndocrine Community (USA) 2011 (Molitch ME et al. Evaluation and treatment of adult growth hormone deficiency: an Endocrine Society clinical practice guideline. // J. Clin. Endocrinol. Metab. 2011. Vol. 96, No. 6 P. 1587-1609), this disorder in adult patients is diagnosed with a peak in the release of GH in the sample with IHG less than 5 ng / ml (5 μg / l), in the sample with glucagon less than 3 ng / ml (3 μg / l).

Earlier in domestic practice, research was carried out on the endocrine effects in children after treatment for HFN tumors, the results of which revealed that 78% of these patients have GH deficiency (Mazerkina N.A. Endocrine disorders after complex treatment of chiasmal malignant tumors Sellar region and posterior cranial fossa in children. Abstract of dissertation for the degree of Doctor of Medical Sciences. Moscow, 2008). However, never before in the Russian Federation has the issue of GH deficiency been studied in adults who underwent chemoradiotherapy of children with thyroid cancer.

In the foreign literature, a method for predicting the peak of GH emission (based on the GH value is used to diagnose GH deficiency) is presented in the stimulation test in children after conformal exposure to OGM (Merchant T.E. et al. Growth hormone secretion after conformal radiation therapy in pediatric patients with localized brain tumors // J. Clin. Oncol. 2011. Vol. 29, No. 36. P. 4776-4780). This model is quite simple to use, does not require expensive laboratory and instrumental studies. The method allows to predict the peak of the release of GH in the stimulation test, depending on the radiation dose to the hypothalamic region and the time elapsed after RT. GH deficiency after radiation therapy develops due to damage to the hypothalamus. It is believed that insulin hypoglycemia stimulates the release of GR by acting on the hypothalamic receptors, while arginine and L-dopa directly affects the level of the pituitary gland. In this study, the diagnosis of GR deficiency was performed using an arginine and L-dopa test, which could have contributed to the fact that the actual prevalence of GR deficiency could be underestimated. It should be noted that when creating this model, children were examined, which makes it impossible to use it for adults. In addition, the development of this method did not take into account the localization of the tumor. In addition, it should be noted that all patients studied for the development of this method were subjected to conformal irradiation. However, this type of radiation therapy began to be used in Russia only during the last 2-3 years.

Although they are used to evaluate GH secretion in stunted children, their use in individuals after cranial irradiation can underestimate the prevalence of radio-induced GH deficiency.

In another prognostic model of GH deficiency after treatment of OGM, also developed abroad, such signs as the level of insulin-like growth factor-1 (IGF-1) and weight, expressed in Z-scores, and the dose of radiation therapy for the hypothalamus are taken into account. The accuracy of the method is 0.883, which, of course, is a reflection of its good quality, but, nevertheless, the accuracy can be higher. When developing this method of forecasting, as well as in the above work, children were studied, which does not allow its use in adults. And, in addition, patients with OGM of various localization were studied (Nua C. et al. Predicting the probability of abnormal stimulated growth hormone response in children after radiotherapy for brain tumors // Int. J. Radiat. Oncol. Biol. Phys. 2012 Vol. 84, No. 4. P. 990-995).

An object of the present invention is to provide a method for predicting the development of growth hormone deficiency in adult patients who have received chemoradiotherapy for children with CFH in children.

The problem is solved by a method for predicting growth hormone deficiency in patients after radiation and polychemotherapy of tumors of the posterior cranial fossa performed in childhood, consisting in determining the level of IGF-1 in plasma, calculating the length of the period of remission of the underlying disease and measuring the growth of the father, and calculating the likelihood of developing failure GR by the formula:

P = 4.323 + (0.00203xA) - (0.03055xV) - (0.01806xC).

Where:

P - forecast,

And the level of IGF-1 (ng / ml),

In - the duration of remission (years),

C - father's height (cm),

and with a value of P <1.2, the prognosis of the development of GH deficiency is 100%, with P> 1.2 - a forecast of 54.55%.

When developing a method for predicting at the first stage, a diagnosis of GH deficiency was performed using the "gold standard" of diagnosis — a test with IHG — in 28 adult patients after treatment of tumors of the gastrointestinal tract in childhood, then the prevalence of this pathology was estimated. At the second stage, during the correlation analysis, the most significant factors that are highly reliably associated with the development of GH deficiency were identified. The most significant of them were included in the prognostic model. When analyzing the growth of parents, it was found that only the growth of the father has a reliable relationship with the development of GR deficiency, the growth of the mother with the manifestation of this pathology is not reliably associated, therefore, was not included in the prognostic model. At the last stage of work, a multivariate analysis using the linear regression method was used to construct a mathematical model for predicting GH deficiency in patients after treatment of tumors of the gastrointestinal tract in childhood (Table 1).

Based on the developed model, a formula was obtained for calculating the forecast:

P = 4.323 + (0.00203 × A) - (0.03055 × B) - (0.01806 × C).

Where:

P - forecast,

And the level of IGF-1 (ng / ml),

In - the duration of remission (years),

C - father's height (cm).

The obtained forecast value can be converted into the probability of the development of growth hormone deficiency in accordance with the following table (Table 2).

curve, this method has a high discriminating ability - the area under the curve is 0.905, which suggests that the technique is very high quality: increasing the sensitivity correlates with maintaining a very high specificity.

The practical application of the presented method consists in the fact that in patients after treatment of a tumor of the gastrointestinal tract in childhood, the necessary indicators are examined, namely, the level of IGF-1 is determined in the blood, the duration of remission is calculated, and the father’s growth is measured. These data are substituted into the formula developed on the basis of the mathematical model, based on the results of which the forecast value is calculated.

For the convenience of daily use, the formula for calculating the forecast value is once entered into Microsoft Office Excel. Next, data is entered into the cells. As a result, the value of the forecast for the development of GH deficiency is calculated.

Clinical example No. 1

A 20-year-old patient M. was treated for medulloblastoma (a tumor of HF) at the age of 13 years. He entered the clinic with complaints of weakness, fatigue, excess weight. Blood was taken from a patient on an empty stomach in the morning to determine various parameters, including IGF-1. So, according to a laboratory examination of IGF-1 - 345 ng / dl. The duration of remission was 7 years. Father's height - 183 cm.

The prognosis for this patient will be:

4.323 + 0.00203 × 345-0.03055 × 7-0.01806 × 183 = 1.505.

The probability of developing GH deficiency for this patient is 54.55%.

Clinical example No. 2

A 17-year-old patient R. was treated for anaplastic ependymoma (HF tumor) at the age of 15 years. Upon receipt complained of drowsiness, weakness, overweight. Blood was taken from a patient in the morning on an empty stomach: IGF-1 - 40 ng / dl. The duration of remission is 2 years. Father's height - 180 cm.

The prognosis for this patient will be:

4.323 + 40 × 0.00203-2 × 0.03055-180 × 0.01806 = 1.092.

The probability of developing GH deficiency for this patient is 100%.

Claims (8)

A method for predicting growth hormone deficiency in patients after radiation and polychemotherapy of tumors of the posterior cranial fossa in childhood, which consists in determining the level of insulin-like growth factor-1 (IGF-1) in plasma, calculating the length of the period of remission of the underlying disease and measuring the height of the father, calculate the likelihood of developing GH deficiency by the formula: P = 4.323 + (0.00203 × A) - (0.03055 × B) - (0.01806 × C). Where: P - forecast And the level of IGF-1 (ng / ml), In - the duration of remission (years), C - father's height (cm), and with a value of P <1.2, the prognosis of the development of GH deficiency is 100%, with P> 1.2 - a forecast of 54.55%.