RU2681299C2 - Method of diagnostics of relapses states of pilocytic astrocytoma of the brain after the radiotherapy and treatment at detection of relapses or other conditions - Google Patents

Abstract

FIELD: medicine.SUBSTANCE: group of inventions refers to medicine, radiology, radiosurgery in oncology, diagnostics using magnetic resonance imaging with relapsed states of pilocytic astrocytomas of the brain after radiation therapy and treatment for the detection of relapses or other conditions. With the revealed pilocytic astrocytomas of intracranial localization after the course of treatment in the form of radiation therapy and/or radiosurgery during the first 12 months after the course of radiotherapy and/or radiosurgery according to the MRI data of the head with contrast enhancement (c/e) in the case of an increase in the tumor volume by more than 20–25 %, in the absence of clinical deterioration, the tumor pseudo-progressive condition is diagnosed. During the first 12 months after the course of radiotherapy and/or radiosurgery according to the MRI of the head with c/e in the case of an increase in tumor volume by more than 20–25 %, taking into account both cystic and a solid component of the tumor, and reveal the expansion of the zone of accumulation of contrast on T1-weighted images (WI), and also with the expansion of the zone of the altered signal on T2-WI, the state between tumor progression and pseudo-progression is diagnosed. Further, if a clinical deterioration is recorded in the dynamics with a further increase in tumor volume, a recurrence of the pilocytic astrocytoma of the brain is diagnosed. If a further increase in tumor volume is recorded in the absence of clinical deterioration, a pseudo-progression is diagnosed. For the treatment of patients diagnosed by this method, the following is used. In the state of pseudo-progression, specific antitumor treatment is not prescribed and further dynamic monitoring examination of the MRI of the head with c/e is carried out. With an increase in tumor volume on MRI with deterioration of the condition in the form of focal and/or cerebral neurological symptoms – a state on the Karnofsky score of 80 points and above, perform anti-edematous therapy using dexamethasone 0.15 mg/kg of body weight per day, dividing into 2–3 doses for 10–15 days, stabilizing the patient's condition, conduct further dynamic monitoring. In the absence of the effect of anti-edematous therapy and further deterioration of the state – according to the Karnofsky score, less than 80 points, and also in the presence of signs of increased intracranial pressure and/or occlusive hydrocephalus, the mass effect is surgically eliminated.EFFECT: inventions provide detection of pseudo-progression in patients with pilocytic astrocytomas, who have undergone radiotherapy, which allows the transfer of more than 90 % of patients with signs of an increase in the tumor volume in the early periods after irradiation from the category of patients with tumor recurrence to the category of patients with pseudo-progression, and exclude them from further antitumor treatment that they do not need (repeat operations, chemotherapy, repeated radiation therapy), exclude patients from the category of relapses after radiation treatment, increasing the effectiveness of stereotaxic radiation in the treatment of such patients with this pathology; in patients with clinical impairment against the background of pseudo-progression, to maintain the sufficiency of minimally invasive surgery for the removal of symptoms of mass effect.4 cl, 2 dwg, 2 ex

Description

The invention relates to medicine, namely to radiosurgery in oncology. It may find application in the diagnosis of relapsed conditions of cerebral piloid astrocytes after radiation therapy and for treatment in the detection of relapses or other conditions.

Piloid astrocytoma (PA), a low-grade glial tumor (WHO grade I), is the most common benign brain tumor in children (Louis et al. 2016). It is much less common in adult patients (Walker 2004). The primary treatment for patients with PA is surgical removal of the tumor (Burkhard et al. 2003).

However, in patients with the so-called. deep-seated tumors (optic pathways, subcortical nodes, brain stem) radical surgery is rarely feasible. After incomplete removal of the tumor, as well as in the event of relapse / continued tumor growth, in patients older than 5 years, the standard treatment is the use of modern methods of radiation treatment - steretactic radiation - stereotactic radiosurgery (CPX) and stereotactic radiotherapy (CPT) (Simonova et al. 2005 ; Terashima et al. 2013; Trunin et al. 2012).

et al. 2013).According to many authors, stereotactic radiosurgery (CPX) and stereotactic radiotherapy (CPT) contribute to prolonged remission or slow tumor progression in patients with inoperable tumors after incomplete removal and in case of tumor recurrence. Therefore, it seems relevant to determine the place and role of CPX and CPT in the complex treatment of patients with deep-seated PA. The use of modern methods of radiation treatment contributes to long-term remission of the disease in most patients: according to many foreign authors, the 5-year relapse-free survival rate (5 DBS) in irradiated patients is 60-90% versus 20-40% in unirradiated patients with residual tumors (Hadjipanayis et al. 2002; Simonova et al. 2005;

et al. 2013).

At the same time, the use of stereotactic technology can significantly reduce the radiation load on the surrounding healthy tissue, which reduces the risk of radiation reactions and radiation complications. This is especially important in pediatric patients.

Known is the work described in “Tumors of the HEAD and NECK”, a peer-reviewed scientific and practical journal, 3/2012, “Stereotactic radiotherapy and radiosurgery in the treatment of patients with deep-localized piloid astrocytomas of the brain,” Yu. Yu. Trunin, A.V. Golanov, A.N. Konovalov, L.V. Shishkina, G.E. Gorlachev, S.K. Gorelyshev, I.N. Pronin, E.A. Khukhlaeva N.K. Serova, A.G. Korshunov, A.Kh. Bekyashev, M.V. Ryzhova, M.V. Galkin, Sh. U. Kadyrov, B.C. Sorokin, N.A. Mazerkina, S.A. Maryashev, E.R. Vetlova, N.A. Antipina, V.V. Kostyuchenko, A.S. Pankova [https://cyberleninka.ru/article/n/stereotaksicheskaya-radioterapiya-i-radiohirurgiya-v-lechenii-patsientov-s-piloidnymi-astrotsitomami-golovnogo-mozga-glubinnoy].

It was noted in the work that CPT and CPX are effective methods in the treatment of primary patients with PA and patients with relapses of PA, regardless of the location of the tumor, and should be performed early after non-radical removal of the tumor. Control of tumor growth at the present time (median follow-up 22.7 months) is 98%.

An increase in tumor volume due to the cystic component in the early stages after CPT and CPX is not a “true” tumor recurrence and, in the absence of an increase in neurological symptoms, does not require special treatment.

Risk factors for the appearance of cystic changes in the tumor are localization of PA in the cerebellum and subcortical structures, high doses of CPT and CPX, and the presence of cysts in the tumor at the time of stereotactic irradiation.

It is recommended that patients with cystic tumors and tumors located in the area of the cerebrospinal fluid tract at the stage of the first operation prior to the radiotherapy perform the installation of the Ommaya system in the cyst cavity and (or) bypass surgery. In this work, it is noted that this will allow many patients to exclude repeated surgery after RT with an increase in tumor volume due to the cystic component.

The technical problem of the known methods is that approximately 23% of patients available for follow-up observation after irradiation showed an increase in the volume of the tumor due to the cystic component and an increase in the degree of accumulation of I / O within 3-12 months after radiation treatment. These changes on MRI (increase in tumor volume by more than 20-25%) in the neurosurgical and neuroradiological community are today regarded as the progression (relapse, continued growth) of the tumor and as a result: recommendation for reoperation.

A study of the authors of the present invention from 2005-2016 showed that in some cases we should not talk about relapse, but about a temporary increase in the tumor after radiation treatment - pseudoprogression.

The closest analogue is the work described in “Tumors of the HEAD and NECK”, a scientific and practical peer-reviewed journal, 1/2016, “INCREASING THE VOLUME OF PILOID ASTROCYTOM OF THE MIDDLE BRAIN: RECURRENCE OR PSEUDOPROgression? CLINICAL OBSERVATION ”, Trunin Yu.Yu., Golanov AV, Kostyuchenko VV, Galkin MV, Khukhlaeva EA, Konovalov AN [https://cyberleninka.ru/article/n/uvelichenie-obema-piloidnoy-astrotsitomy-srednego-mozga-retsidiv-ili-psevdoprogressiya-klinicheskoe-nablyudenie].

It is described in the work that patients with identified piloid astrocytomas of intracranial localization, after a course of radiation therapy, patients are observed in a specialized institution with a control MRI of the head from / every 3-6 months during the first year after irradiation, and then every 6- 12 months or if the patient worsens - an increase in neurological symptoms, with the possible detection of pseudoprogression of the tumor with a pronounced increase in tumor volume.

In this work, the authors presented a clinical observation of a patient with PA of the midbrain, who in the first 7 months after irradiation showed a marked increase in tumor volume according to magnetic resonance imaging (MRI), followed by its complete regression without any antitumor treatment. Observation of the patient, regular assessment of the clinical condition and changes in MRI in comparison with similar clinical observations and literature data suggest that an increase in PA volume in the early stages after radiation treatment, as a rule, is pseudoprogression, and not a true tumor progression. It was indicated that understanding this phenomenon would improve the assessment of the results of radiation treatment of patients with PA and exclude unnecessary antitumor treatment in this category of patients.

The technical problem of the prototype is that there were no clear recommendations for the diagnosis of pseudoprogression and the methodology for further treatment of patients, depending on the expressed condition of the patient.

Thus, the objective of the present invention is the diagnosis of these cases and the treatment after radiation treatment.

The technical result of the invention is:

- identification of the phenomenon of "pseudo-progression" in patients with piloid astrocytomas who underwent radiation therapy, which will allow transferring the majority of patients (more than 90%) with signs of an increase in tumor volume in the early stages after irradiation from the category of patients with tumor recurrence to the category of patients with “Pseudo-progression” and exclude them from further antitumor treatment that they do not need (repeated operations, chemotherapy, repeated radiation therapy);

- the exclusion of a larger number of patients from the category of "relapses" after radiation treatment can increase the effectiveness of modern methods of stereotactic radiation in the treatment of patients with this pathology;

- in patients with clinical impairment, against the background of pseudo-progression, a minimal measure of invasive surgery (i.e., radical surgery is not required) is sufficient measure to relieve symptoms of mass effect (compression of brain structures).

The specified technical result is achieved due to the fact that the claimed method for the diagnosis of recurrent conditions in patients with identified piloid astrocytomas of intracranial localization, after a course of radiation therapy, in which patients are observed in a specialized institution with a control MRI of the head from / to every 3-6 months during the first year after irradiation, and then every 6-12 months or when the patient worsens - an increase in neurological symptoms, with the possible detection of pseudoprogress and tumors with a marked increase in tumor volume, characterized in that

- during the first 12 months after the course of radiation therapy / radiosurgery, according to the MRI of the head with to / in the case of an observed increase in tumor volume, but in the absence of clinical deterioration, the state of pseudoprogression is diagnosed;

- during the first 12 months after the course of radiation therapy / radiosurgery, according to the MRI of the head from the c / a in the case of an observed increase in the volume of the tumor, both the cystic and solid component, and detecting the expansion of the accumulation zone of the c / in on T1-weighted images , as well as expanding the zone of the altered signal on T2 weighted images, diagnose the condition as between tumor progression and pseudoprogression, after which additional diagnostic research methods and observation are carried out in order to identify an accurate diagnosis over time according to the above procedure, and if, over time, a clinical deterioration and increase in tumor volume are recorded, then relapse of the piloid astrocytoma of the brain is diagnosed, and in the case of an observed increase in tumor volume, but in the absence of clinical deterioration, the state of pseudoprogression is diagnosed;

- during the first 12 months after a course of radiation therapy / radiosurgery, according to an MRI of the head with a c / a in the case of an observed increase in tumor volume when signs of tumor recurrence are detected according to the results of a study of histological material or signs of a further tumor increase according to the results of dynamic observation on MRI, tumor recurrence.

Preferably:

- when diagnosing the state of pseudoprogression, specific antitumor treatment is not prescribed, further dynamic monitoring of the patient is carried out, with a follow-up examination of MRI of the head from / to, examination of a neurosurgeon / radiologist in a specialized institution / department;

- when diagnosing an increase in tumor volume on MRI, accompanied by a slight worsening of the condition - an increase in focal and / or cerebral neurological symptoms, the state according to the Karnowski scale is 80 points or higher, the first stage is anti-edema therapy using dexamethasone 0.15 mg / kg body weight in day, dividing into 2-3 doses for 10-15 days, and after stabilization of the patient, conduct further dynamic observation;

- in the absence of the effect of ongoing anti-edema therapy and further deterioration of the patient’s condition — the Karnowski scale is less than 80 points, and also if there are signs of increased intracranial pressure / occlusal hydrocephalus at any stage of diagnosis, operations are performed: from minimally invasive surgery to repeated removal of the tumor for eliminate the mass effect.

When diagnosing a tumor recurrence, the patient is referred for consultation by a neuro-oncologist, radiologist and neurosurgeon to decide on the further antitumor treatment of the patient.

In order to exclude the recurrence of the tumor, after its repeated removal, the histological material is analyzed and compared with the histological material from the first operation, if it was performed.

Brief Description of the Drawings

In FIG. 1 shows an example of pseudoprogression of piloid astrocytoma of the midbrain after radiation treatment in patient A. 16 years old.

In FIG. Figure 2 shows an example of a histological examination of a tumor in a patient with suspected relapse.

The implementation of the invention

In our prospective study, which lasted from 2005-2016, 303 patients with PA (one of the largest series in the world literature) who underwent stereotactic irradiation in the radiology department of the Scientific Research Center for Neurosurgery named after N.N. Burdenko with a diagnosis of "piloid astrocytoma." Evaluation of patient treatment results was carried out on the basis of a comparison of the clinical picture of the disease with the results of x-ray studies (magnetic resonance imaging (MRI) of the head with contrast enhancement).

In 57 patients (23% of patients available for follow-up observation) after irradiation, an increase in the volume of the tumor due to the cystic component and an increase in the degree of accumulation of I / O were noted within 3-12 months after radiation treatment. These changes in MRI (increase in tumor volume by more than 20-25%) in the neurosurgical and neuroradiological community are regarded as the progression (relapse, continued growth) of the tumor.

Given the absence of clinical deterioration, in most patients (34 patients or 60%) we continued dynamic observation with a control MRI study with contrast enhancement every 2-3 months. Observation of this group of patients confirmed the absence of further tumor progression in most patients (31 patients or 91%) of this group: on the contrary, a gradual independent tumor regression was observed, without any antitumor treatment. Those. it was a question of a temporary increase in the tumor after radiation treatment - pseudoprogression. The phenomenon of pseudoprogression - as a temporary increase in the volume of the tumor and the accumulation zone of the contrast medium - is described in patients with tumors such as neuromas, metastases and malignant gliomas. In patients with piloid astrocytomas, there is no description of such a phenomenon in the literature, except that reflected in the prototype [https://cyberleninka.ru/article/n/uvelichenie-obema-piloidnoy-astrotsitomy-srednego-mozga-retsidiv-ili-psevdoprogressiya -klinicheskoe-nablyudenie]. Only 3 patients (9%) had further tumor growth, requiring repeated surgery, which confirmed (in histology analysis) tumor recurrence.

In 22 patients (40%), against the background of an increase in the volume of the treated tumor, repeated surgical removal of the tumor was performed - puncture or emptying of existing cysts (10 patients) or removal of a cystic tumor (12 patients). Repeated morphological and immunohistochemical analysis of histological material and its comparison with histology from the first operation showed an increase in reactive degenerative changes in the tumor: the appearance of foci of necrosis, a large number of cysts, pronounced hyalinosis of the vessel walls, an increase in nuclear and cellular polymorphism, a decrease in the proliferative index Ki67. In general, it was possible to note the absence of an increase in malignancy and an increase in the regressive degenerative component in all patients. (Fig. 2). According to a histological (including immunohistochemical) study, no signs of tumor recurrence (progression) were detected in any re-operated patient.

Thus, as a result of a prospective study of a large group of patients with piloid astrocytomas, on the basis of long-term dynamic observation in non-operated patients and on the basis of histological / immunohistochemical studies of biopsy in operated patients, a phenomenon of a temporary increase in the volume of piloid astrocytes after irradiation (pseudoprogression phenomenon) was revealed, which is not a relapse (as previously thought) and does not require special antitumor treatment, in the absence of a clinic worsening of the patient's condition.

Studies have shown that patients with intracranial localization piloid astrocytomas, after a course of radiation therapy, need dynamic monitoring in a specialized institution with a control MRI of a head from / to every 3-6 months during the first year after irradiation, then every 6-12 months or with a worsening of the patient's condition (an increase in neurological symptoms).

During the first 12 months after a course of radiation therapy / radiosurgery, according to an MRI scan of a head with c / a, it is possible to increase the volume of the tumor (both the cystic and solid components) and expand the area of accumulation of c / in on T1-weighted images, as well as the expansion zones of the altered signal on T2 weighted images, which must be differentiated between tumor progression and pseudoprogression. Additional diagnostic research methods, such as PET heads with methionine, CT perfusion studies, etc., are usually not used for differential diagnosis, because often give false positives.

With an increase in tumor volume on MRI in the first 12 months after a course of radiation therapy / radiosurgery and in the absence of clinical deterioration, a specific antitumor treatment is not required. Further dynamic monitoring of the patient may be recommended, with a follow-up examination (MRI of the head from / to, examination by a neurosurgeon / radiologist in a specialized institution / department), every 2-3 months or if the patient worsens. With an increase in tumor volume on MRI, accompanied by a slight worsening of the condition (an increase in focal and / or cerebral neurological symptoms, the state according to the Karnowski scale is 80 points or higher), the first step is the possibility of anti-edema therapy (dexamethasone 0.15 mg / kg body weight per day , divided into 2-3 doses) within 10-15 days. When stabilizing the patient's condition, further dynamic observation is carried out.

In the absence of the effect of ongoing anti-edema therapy and further deterioration of the patient's condition (the Karnowski scale is less than 80 points), as well as if there are signs of increased intracranial pressure / occlusal hydrocephalus (at any stage of diagnosis), it is recommended to consider the possibility of surgery: from minimally invasive surgery (shunting / puncture of the cyst, etc.) until the tumor is removed again to eliminate the mass effect. To exclude a tumor recurrence, after its repeated removal, it is necessary to analyze the histological material and compare it with the histological material from the first operation (if performed).

If signs of tumor recurrence are detected (according to the results of a study of histological material) or signs of further tumor growth according to dynamic observation on MRI, consultation of a neuro-oncologist, radiologist and neurosurgeon is necessary to resolve the issue of further anti-tumor treatment of the patient.

The detection of this phenomenon in patients with piloid astrocytomas who underwent radiation therapy will allow transferring the majority of patients (more than 90%) with signs of an increase in tumor volume in the early stages after irradiation from the category of patients with “tumor recurrence” to the category of patients with “pseudoprogression” and exclude them from further, not necessary for them, antitumor treatment (repeated operations, chemotherapy, repeated radiation therapy).

The exclusion of a large number of patients from the category of "relapses" after radiation treatment indicates the high efficiency of modern methods of stereotactic radiation in the treatment of patients with this pathology.

In patients with clinical impairment, against the background of pseudo-progression, minimally invasive surgery is sufficient (radical surgery is not required) to relieve symptoms of the mass effect (compression of brain structures), because subsequently, in most patients (more than 90%), there is an independent regression of the existing residual tumor.

Example 1

Patient A. 16 years.

In FIG. 1 shows a gradual increase in piloid astrocytoma of the midbrain within 2-4-7 months after a course of radiation therapy.

It can be noted an increase in tumor volume, an expansion of the accumulation zone of the contrast medium and an increase in the size of the cyst.

This situation is regarded by neurosurgeons and neuroradiologists as a progression of the disease, but given the stable condition of the patient, further antitumor treatment was not carried out. Moreover, in the pictures 24-30-54 months after treatment, a gradual regression of the tumor until its complete disappearance.

Thus, the progression of the tumor is not confirmed and the state of pseudoprogression of the tumor of the midbrain after radiation treatment was diagnosed.

Example 2

In FIG. Figure 2 shows an example of a histological examination of a tumor in a patient with a suspicion of relapse (a - before radiation therapy, b - after radiation therapy). Hematoxylin and eosin staining (H & E), magnification X 100 - bottom photo and X 200 - top photo.

After radiation therapy, the appearance of foci of necrosis is shown (arrow in the upper image) and cysts with hyalinized walls (arrow in the lower image). After radiation therapy, an increase in reactive degenerative changes in the tumor was noted in the form of foci of necrosis, a large number of cysts, hyalinosis of the vessel walls, an increase in nuclear and cellular polymorphism, and a decrease in the proliferative activity index Ki 67. Obviously, there is no increase in malignancy and an increase in the degenerative component. There are no histological signs of tumor recurrence.

Claims (10)

1. A method for the diagnosis of relapse in patients with identified piloid astrocytomas of intracranial localization after a course of treatment in the form of radiation therapy and / or radiosurgery, - in which the patient is observed with the control of MRI of the head with contrast enhancement (f / y), characterized in that: - during the first 12 months after a course of radiation therapy and / or radiosurgery according to an MRI of the head with to / in the case of an increase in tumor volume by more than 20-25% in the absence of clinical deterioration, the state of pseudoprogression of the tumor is diagnosed; during the first 12 months after a course of radiation therapy and / or radiosurgery according to an MRI of the head with c / a in the case of an increase in tumor volume by more than 20-25%, taking into account both the cystic and solid components of the tumor and revealing the expansion of the accumulation zone of the contrast medium on T1-weighted images, as well as with the expansion of the zone of the changed signal on T2-weighted images, the condition between the tumor progression and pseudoprogression is diagnosed and further, if the dynamics record a clinical deterioration with a further increase in volume tumors, relapse of piloid astrocytoma of the brain is diagnosed, and if a further increase in tumor volume is detected in the absence of clinical deterioration, the state of pseudoprogression is diagnosed. 2. A method for the treatment of patients with identified piloid astrocytomas of intracranial localization after a course of radiation therapy and / or radiosurgery, where patients are diagnosed by the method of claim 1, characterized in that: - when diagnosing the state of pseudoprogression, specific antitumor treatment is not prescribed and a further dynamic control examination of the MRI of the head with a / c is performed; - when diagnosing an increase in tumor volume on MRI, accompanied by a worsening condition in the form of an increase in focal and / or cerebral neurological symptoms - a state according to the Karnowski scale of 80 points or higher, anti-edema therapy is performed using dexamethasone 0.15 mg / kg body weight per day, sharing for 2-3 doses for 10-15 days, stabilizing the patient's condition, and conduct further dynamic observation; - in the absence of the effect of ongoing anti-edema therapy and further deterioration of the condition - on the Karnowski scale less than 80 points, as well as in the presence of signs of increased intracranial pressure and / or occlusal hydrocephalus, the mass effect is removed surgically. 3. The method according to p. 2, characterized in that when diagnosing a tumor recurrence, the patient is referred for consultation by a neurooncologist, radiologist and neurosurgeon to resolve the issue of further antitumor treatment of the patient. 4. The method according to p. 2, characterized in that in the case of repeated removal of the tumor, histological material is analyzed and compared with the histological material from the first operation, if it was performed.

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