Эндокринные последствия химиотерапии у детей: интервью с профессором Нанду Таланджи
Это интервью мы подготовили специально для родителей и специалистов, которые сталкиваются с вопросами роста, гормонального развития и эндокринных последствий после лечения онкологических заболеваний у детей. Многие семьи проходят сложный путь: от длительной химиотерапии и таргетной терапии до пересадки костного мозга и применения ингибиторов тирозинкиназы. При этом влияние лечения на гормональную систему, рост, пубертат и функцию щитовидной железы часто остаётся недооценённым.
Профессор Нанду Таланджи — один из ведущих детских эндокринологов с международным опытом работы в Великобритании и ОАЭ. Он является экспертом мирового уровня по вопросам роста, пубертата, щитовидной железы, последствий тяжёлой терапии, а также исследователем, благодаря которому были одобрены ключевые препараты инсулина для детей.
Мы обратились к нему с наиболее частыми и важными вопросами, которые волнуют семьи после онкологического лечения. Его ответы — это сочетание науки, клинического опыта и глубокого понимания того, через что проходят дети и их родители.
Надеемся, что это интервью поможет лучше разобраться в тонкостях обследования, своевременного выявления нарушений и правильного сопровождения детей на пути восстановления.
Growth and Growth Delay in Children After Oncology Treatment
Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of Ph+ leukemia, but they can have an impact on a child’s growth. Here’s what current research tells us:
Impact on Growth: Studies have shown that TKIs, particularly imatinib and dasatinib, can lead to a decrease in growth velocity (the speed at which a child grows) in some children. This effect seems to be more pronounced in children who start TKI therapy before puberty.
Mechanisms: TKIs work by blocking specific enzymes called tyrosine kinases. While this is very effective at stopping the growth of cancer cells, these enzymes are also involved in many normal bodily processes, including the development and growth of bones. By interfering with these pathways, TKIs can slow down the normal process of bone formation and elongation.
Reversibility: The good news is that the effects of TKIs on growth may not be permanent. Research suggests that when TKI therapy is stopped, many children experience a period of "catch-up" growth. The extent of this catch-up growth can vary from child to child and may depend on factors like the child’s age, the duration of TKI therapy, and their pubertal status.
It is crucial to have regular growth monitoring while your child is on TKI therapy. If there are concerns about your child’s growth, their oncologist and an endocrinologist (a doctor specializing in hormones) can work together to determine the best course of action.
Determining when to intervene for growth delay is a decision that your child’s healthcare team will make in close consultation with you. Here are some of the key indicators they will look at:
Growth Charts: The most important tool for monitoring a child’s growth is the growth chart. Your child’s height and weight will be plotted on a standardized growth chart at each visit. A significant deviation from their previous growth curve, or a drop in their growth percentile, is a red flag.
Growth Velocity: Growth velocity is the rate of growth over a specific period, usually measured in centimeters or inches per year. A growth velocity that is consistently below the normal range for a child’s age is a cause for concern. While there isn’t a single number that applies to all children, a growth velocity of less than 4−5 cm per year in a pre-pubertal child would typically need further investigation.
Bone Age: A bone age X-ray (usually of the Left hand and wrist) can help determine if a child’s skeletal maturation is delayed compared to their chronological age. A significant difference between bone age and chronological age can be a sign of a growth problem.
Pubertal Status: The timing of puberty is also an important factor. Delayed puberty can contribute to a slower growth rate.
If you are concerned about your child’s growth, it’s important to bring it up with your doctor. They can perform a thorough evaluation to determine if the growth delay is within the expected range for a child who has undergone cancer treatment, or if it requires further investigation and potential intervention.
Growth hormone (GH) therapy can be a very effective treatment for children with growth hormone deficiency, but its use in childhood cancer survivors, requires careful consideration.
Key Criteria for GH Therapy: The primary indication for GH therapy is a confirmed diagnosis of growth hormone deficiency. This is usually diagnosed through a combination of blood tests and stimulation tests that measure the body’s ability to produce growth hormone. In addition to confirmed GH deficiency, other factors that are considered include the child’s growth rate, bone age, and overall health.
Safety Considerations in Post-Oncology Patients: GH does not cause cancer, but it may stimulate the growth of cancer cells if they are still present (or another cancer develops). Consequently, the main safety concern with GH therapy in cancer survivors is the theoretical risk that it could stimulate growth of any remaining cancer cells. However, numerous studies have been conducted on this topic, and the current consensus is that for most childhood cancer survivors, GH therapy does not increase the risk of cancer recurrence. The decision to start GH therapy is always made on a case-by-case basis, after a thorough discussion of the potential risks and benefits.
GH Therapy During TKI Therapy: The use of GH therapy while a child is still taking TKIs is a more complex issue. There is less research on the safety and effectiveness of this combination. It likely would be less effective due the mode of action of the TKIs. The decision to use GH therapy in this situation would be made by a team of specialists, including your child’s oncologist and endocrinologist, and would involve very close monitoring. In general, we recommend treatment with GH only after all oncology therapy is complete (typically for at least a year).
Is it possible and safe to stimulate growth while a child continues taking TKIs?
This is an area of active research and discussion among specialists. While there are concerns about the potential interactions between growth-stimulating therapies and TKIs, it is not an absolute contraindication. The decision would be highly individualized and would depend on a number of factors, including:
The specific TKI being used.
The child’s underlying diagnosis and risk of relapse.
The severity of the growth delay.
The results of a thorough endocrine evaluation.
If growth stimulation is being considered while your child is on TKIs, it would be managed by a multidisciplinary team of experts and would involve very close monitoring of both your child’s growth and their cancer status.
Delayed puberty is another potential long-term effect of cancer treatment. Here’s what we know:
Causes of Delayed Puberty: Cancer treatments, including certain types of chemotherapy and radiation, can affect the parts of the brain that control puberty (the hypothalamus and pituitary gland) or the reproductive organs themselves (the ovaries in girls and the testes in boys). TKIs may also play a role, but more research is needed to fully understand their impact on puberty.
Signs of Delayed Puberty: In girls, delayed puberty is generally defined as no breast development by age 13 or no menstrual periods by age 15. In boys, it’s defined as no testicular enlargement by age 14.
When is Hormonal Intervention Indicated? If a child has a confirmed diagnosis of delayed puberty, hormonal therapy may be recommended. This usually involves giving low doses of estrogen (for girls) or testosterone (for boys) to help kick-start the pubertal process. The goal of hormonal therapy is to help the child go through puberty in a way that is as close to normal as possible, which includes promoting the pubertal growth spurt and the development of secondary sexual characteristics.
The decision to start hormonal therapy is made by an endocrinologist after a thorough evaluation. They will consider the child’s age, bone age, and overall health, as well as the potential psychological and social benefits of initiating puberty.
Block 2: Endocrine Evaluation During TKI Therapy
Блок 2: Эндокринная оценка во время терапии TKI
Which endocrine evaluations are essential for children treated with TKIs? Does this approach align with international standards?
Children on TKI therapy require regular monitoring of their endocrine system, as these medications can affect several different hormonal pathways. The following evaluations are generally considered essential and are in line with international recommendations:
Growth Monitoring: Regular measurement of height and weight, plotted on a growth chart, is the cornerstone of endocrine monitoring.
Thyroid Function: Blood tests to measure thyroid-stimulating hormone (TSH) and free thyroxine (free T4) are important to screen for hypothyroidism.
Bone and Mineral Metabolism: Blood tests for vitamin D, calcium, and phosphorus are recommended, as TKIs can sometimes affect bone health.
Growth Factors: Measuring insulin-like growth factor 1 (IGF-1) and IGF-binding protein 3 (IGFBP-3) can provide information about the growth hormone axis.
Pubertal Assessment: A clinical assessment of pubertal stage is important to monitor for any delays.
Glucose Metabolism: Depending on the specific TKI and the child’s risk factors, monitoring for insulin resistance and diabetes may be recommended.
This comprehensive approach to endocrine monitoring is consistent with the guidelines and recommendations from major pediatric oncology and endocrinology societies around the world.
The optimal monitoring interval can vary depending on the child’s age, the specific TKI they are taking, and their individual clinical situation. However, a general guideline is as follows:
Block 3: Endocrine Follow-Up After Completion of Oncology Treatment
Блок 3: Эндокринное наблюдение после завершения лечения онкологии
Which laboratory and imaging evaluations are recommended for children who have completed prolonged cancer therapy (especially leukemia), not currently on TKIs, at 3−6−12 months?
For children who have completed cancer therapy, a structured follow-up plan is essential to monitor for any late effects, including endocrine problems. The following evaluations are often recommended in the first year after treatment:
Growth and Puberty: Regular monitoring of height, weight, and pubertal development.
Thyroid Function: Blood tests for TSH and free T4.
Growth Hormone Axis: Measurement of IGF-1 and, if there are concerns about growth, a growth hormone stimulation test may be considered.
Bone Health: A bone density scan (DEXA scan) may be recommended, especially for children who received steroids or have other risk factors for bone problems.
Adrenal Function: In some cases, testing of adrenal function may be necessary, particularly for children who received high-dose steroids.
Vitamins and Micronutrients: Blood tests to check levels of important vitamins and minerals, such as vitamin D and iron.
Imaging studies, such as a thyroid ultrasound or a pituitary MRI, are generally only recommended if there are specific clinical concerns.
Какие лабораторные и инструментальные обследования рекомендуются детям, завершившим длительную терапию онкологии (особенно лейкемии), но в настоящее время не получающим TKI, через 3−6−12 месяцев?
Which symptoms should alert parents after treatment completion?
As a parent, you play a vital role in monitoring your child’s health after cancer treatment. Here are some of the symptoms that should prompt you to contact your child’s healthcare team:
Slow Growth: If you notice that your child is not growing as quickly as their peers or that their clothes sizes are not changing.
Lack of Pubertal Development: If your child is not showing any signs of puberty by the expected age.
Sudden Weight Changes: Unexplained weight loss or gain.
Chronic Fatigue: Persistent tiredness that is not relieved by rest.
Cognitive Difficulties: Problems with memory, attention, or school performance.
Bone Pain: Any persistent or unexplained bone pain.
It’s important to remember that these symptoms can have many different causes, but they should always be evaluated by a healthcare professional
Какие симптомы должны насторожить родителей после завершения лечения?
How long does the risk of endocrine complications persist after therapy? Is long-term (multi-year) follow-up necessary?
The risk of endocrine complications can persist for many years after cancer treatment has been completed. Some late effects may not become apparent until several years after treatment. For this reason, long-term, multi-year follow-up is absolutely essential for all childhood cancer survivors.
These follow-up visits are an opportunity to monitor for any late effects, provide early intervention if needed, and support your child’s long-term health and well-being. The frequency of these visits may decrease over time, but they should continue into adulthood.
Block 4: General Questions
Блок 4: Общие вопросы
How does oncological treatment affect the endocrine system as a whole? Which disorders are most common?
Response:
Cancer treatment can have a wide range of effects on the endocrine system, which is the network of glands that produce hormones. The most common endocrine disorders seen in childhood cancer survivors include:
Growth Hormone Deficiency: Leading to slow growth and short stature.
Hypothyroidism: An underactive thyroid gland, which can cause fatigue, weight gain, and slow growth.
Delayed or Precocious (Early) Puberty: Affecting the timing of sexual development.
Fertility Problems: Damage to the ovaries or testes can affect future fertility.
Adrenal Insufficiency: A rare but serious condition where the adrenal glands do not produce enough essential hormones.
Metabolic Syndrome: A cluster of conditions that includes obesity, high blood pressure, and insulin resistance, which can increase the risk of heart disease and diabetes later in life.
What international recommendations exist for endocrine follow-up of children who have undergone blood cancer treatment?
Response:
There are several internationally recognized guidelines for the long-term follow-up of childhood cancer survivors. These guidelines, which are published by organizations like the Children’s Oncology Group (COG) and the International Late Effects of Childhood Cancer Guideline Harmonization Group (IGHG), provide detailed recommendations for endocrine monitoring.
These guidelines emphasize the importance of lifelong, risk-based follow-up care. They provide specific recommendations for the screening and management of the endocrine late effects that we have discussed, including growth problems, thyroid dysfunction, and pubertal abnormalities
What should parents be aware of to avoid missing early signs of endocrine complications?
Response:
Here are some key things to be aware of:
Keep a record of your child’s growth. You can even plot their height and weight on a growth chart at home.
Pay attention to the timing of puberty.
Be aware of the symptoms of hypothyroidism, such as fatigue, weight gain, and feeling cold.
Encourage a healthy lifestyle, including a balanced diet and regular physical activity.
Make sure your child attends all of their scheduled follow-up appointments.
Don’t hesitate to ask questions. If you have any concerns about your child’s health, no matter how small they may seem, bring them up with their healthcare team.
How does the management of Ph+ children on TKI therapy differ from children treated for ALL without TKIs?
Response:
The main difference in the management of Ph+ children on TKI therapy is the need for specific monitoring related to the potential side effects of TKIs. This includes the close monitoring of growth, bone and mineral metabolism, and thyroid function, as we have discussed.
Children with ALL who are not on TKIs still require long-term follow-up for the late effects of chemotherapy and/or radiation, but the specific focus of the endocrine monitoring may be slightly different.
Which corrective measures are most effective — nutrition, vitamin supplementation, physical activity, or hormonal therapy?
Response:
The most effective corrective measures will depend on the specific underlying cause of the problem. It’s often a combination of approaches that works best:
Nutrition: A healthy, balanced diet is the foundation for good growth and development. A registered dietitian can provide guidance on how to optimize your child’s nutrition.
Vitamin Supplementation: If blood tests reveal any vitamin or mineral deficiencies, supplementation will be recommended.
Physical Activity: Regular physical activity is important for bone health and overall well-being.
Hormonal Therapy: If a specific hormone deficiency is diagnosed, such as growth hormone deficiency or hypothyroidism, then hormonal therapy is the most effective treatment.
It's important to work with your child’s healthcare team to develop a comprehensive plan that addresses all of their individual needs.