Professor G.A. Panshin, PhD T.B. Izmailov, MD P.V. Datsenko

FGBU "Russian Scientific Center of Radiology" of the Ministry of Health of Russia, Moscow, Russia

The influence of prognostic factors on the effectiveness of radiation therapy of primary malignant brain gliomas (Grade III)

Introduction

Brain tumors are a heterogeneous group of various intracranial tumors, benign or malignant, arising from starting the abnormal uncontrolled cell division, which in the past is a normal part of the fabric of the brain (neurons, glial cells, astrocytes, oligodendrocytes, ependymal cells), lymphatic tissue, blood vessels of the brain, cranial nerves, meninges, skull, iron formations of the brain (pituitary and pineal gland), or arising from the metastasis of the primary tumor localized in any other organ of the patient (3,6). Malignant brain tumors occur in almost any age, but, basically, they are observed in the elderly, but also registered a significant morbidity among children and adolescents, who account for a high percentage of all cancers in children. There are several types of primary brain tumors. Among adults, the most common (about 60%) are astrocytomas, also known as gliomas, and malignant gliomas - glioblastoma multiforme and anaplastic gliomas (anaplastic astrocytoma, anaplastic oligodendrogliomas and anaplastic oligoastrocytoma) are the most common infiltrative primary brain tumors. Histologically, they are divided into four grade, different versions of which occur with varying frequency and differ in their forecast. In particular, glioblastoma multiforme is the most common and is known for its aggressive growth and, ultimately, is characterized by an extremely poor prognosis (6). Many patients after primary treatment is almost always very quickly relapse or progression of the disease and improve quality of life of patients in this clinical situation is one of the main goals of treatment (2, 7). The average life expectancy of patients after the establishment of the diagnosis is, on average, 9 - 12 months. As the results of epidemiological studies conducted in developed countries, is now widely observed increase in the incidence of brain tumors. For example, in the U.S. in 1990, the incidence of primary brain tumors by 100 thousand people was 8,2 (20 500 new cases of primary brain tumors), in 1995 – 10,9 (28 500), in 2000 - 12,8 (35 000), in 2003 – 14,0 (40 600) (7). Currently, each year in Europe there are nearly 13 000 new cases of glioblastoma (2, 11). To date, the current stage of development is characterized by high neurooncology introduction of advanced technologies, improving diagnosis and treatment of tumors of the central nervous system, providing a focus of biomedical research. Undoubtedly, the key to effective treatment of brain tumors is their early detection and obtain the most complete diagnostic information about the location and size of the tumor, the sources of its blood supply, the relationship with the surrounding brain structures and anatomical structures, the establishment of its real histological structure. The treatment of malignant gliomas of the brain is one of the most difficult tasks in neurooncology. At the present stage, the most effective is a comprehensive approach to the treatment of malignant gliomas, as no separate treatment method used did not significantly increase the lifetime of the patient. Undoubtedly, significant nibolee is surgical intervention to the most complete removal of tumors.
However, due to the lack of clear boundaries between the tumor and medulla macroscopically complete removal of malignant gliomas, with high probability, can be accomplished only with the refined preoperative diagnosis of their distribution and location. For a relatively small amount of gliomas is the best way to remove the tumor resection of the lobe along with most of neoplasm or its removal by the perifocal area. When the rest of the tumor in order to achieve the possible results of the most important non-radical surgery to adjuvant chemotherapy, immune therapy, and, of course, during the testimony, first radiation treatment. At the same time, regardless of the surgical intervention, malignant, aggressive-occurring brain gliomas (Grade III-IΥ) radiation therapy is mandatory adjuvant procedure in the treatment of these patients. At the same time, the value of adjuvant radiation therapy for malignant tumors of the central nervous system to date is under discussion. However, meta-analysis of 12 randomized trials in which the total number of patients was 3004 patients with verified malignant brain tumors showed that the use of chemotherapy in conjunction with radiation therapy contributes, in general, increase the life expectancy of patients by 6% and reduces the risk of death by 15 % (10). In addition, recent randomized study by the European Organization for Research and Treatment of Cancer (EORTC) and the National Cancer Institute of Canada (NCIC) demonstrated a statistically significant increase in survival in patients with glioblastoma multiforme, while postoperative use Temodal and radiation therapy followed by adjuvant therapy Temodal at Compared with patients who received only adyuvantnaya radiation therapy (9). It is known that, to obtain a greater effect on the conductivity of the combined and complex treatment of cancer using radiation therapy should be used conformal radiation techniques combined with modern radiomodifying agents and chemotherapy, allowing, in particular, in malignant glioblastomas seek to reduce the volume of irradiated normal brain more than 20% (5, 12). At present, applying radiation therapy in the independent or advantnom types of malignant gliomas using a traditional classic mode fractionation radiation dose at which to develop focal dose of 2Gy and total - brought to 60 Gy. However, it is well known that the degree of damage to increase tumor neobhodmo increase disposable focal dose, which will, in the end, when summing a dose similar to the use of classical technique of irradiation, very significantly reduce the overall length of the course of radiation therapy, which is essential also from an economic point of view. Thus, the application of a single focal dose of 3 Gy total dose of 51-54 Gy focal fed for 17-18 fractions (3,5 weeks). At the same time, the same dose, according to the linear quadratic model, is a dose of 62-64 Gy, sold for 6,5 weeks of radiation therapy with a single focal dose of 2 Gy. According to the multivariate analysis, patients with tumors of the central nervous system of local tumor control probability determined by the level just a total focal dose. However, even the cure of the primary tumor did not significantly affect overall survival when only radiotherapy, and for combined treatment increases only their median overall survival (4, 8). The purpose of this study was to attempt to identify the most important prognostic factors affecting, in the end, the results of the treatment of primary malignant brain gliomas third grade.

Materials and methods

In a computer database of the Centre in December 2010 is 537 patients diagnosed with primary brain tumors of various origins. In this case, the degree of malignancy grade I-II was verified in 108 (20,1%) patients, grade III - in 98 (18,2%) and grade ІҮ in 286 (53,2%) patients. The age of patients with malignant brain tumors grade III ranged from 16 to 72 years, with a mean age of 41,2 years, and median – 39,6 years.

In our study, malignant brain tumor grade III more often diagnosed in females (51,5%).

Of the 98 patients 76 (77,5%) patients was conducted subtotal resection, of whom subsequently died of 8 (8,2%, median follow-up – 8,8 months). Total removal of the tumor was performed in 23 (23,5%) patients, of whom one died (4,3%, with a median follow – 4,5 months).

All patients after surgical stage, the adjuvant radiation or chemoradiation therapy. In this case, a single focal dose equal to 2 Gy. was used in 41 patients and was adjusted for daily rhythm of exposure to 60 Gy and 3 Gy - 57 patients and total focal dose corresponded to efficiency 60-62 Gy. As a chemotherapeutic agent used in all cases Temodal.

According to an international study (EORTC trial 22844 22 845) in 2002, proposed the basic EORTC prognostic factors (12) for overall survival in adult patients with brain tumors, low-grade (grade I-II), including:

1) Age 40 years.

2) The largest tumor size> 6 cm.

3) Tumor goes past the halfway line.

4) Net astrocytoma.

5) The presence of neurological symptoms prior to surgery.

Based on the extracted factors were identified EORTC groups with low (a combination of "0-2"), and high (3-5) levels of risk for overall survival. In our study, we tried to study their role in primary malignant brain tumors grade III. Furthermore, in addition we have also addressed issues related to the influence of the level of KPS and the methodology radiotherapy and its combination with chemotherapy on overall survival as the possible use of them as informative factors.

It must be emphasized that, to date, on the whole, more than 70 different factors for each treated patient, reflecting the initial extent of disease, methods of treatment, the effectiveness and failure in integrated computer-based Center.

In this study, for the analysis of treatment failure used correlation analysis and the calculation of cumulative survival by Kaplan-Meier method. Moreover, when the numerical value of the correlation coefficient less than 0,19 was regarded as communication is very weak, from 0,20 to 0,29 - as weak, from 0,30 to 0,49 - as a moderate, 0,50 to 0,69 - and the average of 0,70 or higher - a strong (1).

Findings

In our study the most significant for overall survival were the following prognostic factors (Table 1).

Table 1. The correlation between overall survival and prognostic factors in brain tumors grade III.

PROGNOSTICHEKY FACTOR	tumors grade ІІІ (n=98)
Age ≥ 40 years	r=0,16 (<0,05)
Tumor size > 6 cm	r=0,28 (<0,01)
Displacement of midline structures	r = 0,21 (<0,05)
Net astrocytoma	r = 0,11
neurological deficit	r = 0,05
Index Karnofsky < 70	r=0,25 (<0,05)
prognostic factors: «0–3» and «4–6»	r=0,45 (<0,01)

Note: r – correlation coefficient

As follows from Table 1, the most informative factor for overall survival in brain tumors were grade III patient age (r = 0,16; p <0,05), tumor size more than 6 cm in greatest dimension (r = 0,28 , p <0,01), the transition of tumor center line offset midline structures of the brain (r = 0,21; p <0,05) and Index Karnofsky (KPS) (r = 0,25 (<0,05), in while the presence of neurological deficits, such dependencies have been received.

The analysis also found that the total distribution of prognostic factors in groups of low-and high-risk ("0 - 3" and "4 - 6") had the highest correlation dependence for malignant brain tumors grade III (r = 0,45; p <0,01).

According to our data the total number of patients in the low-risk (made up of 79 persons (median follow-up – 8,2 months), three of whom died (3,7%), and in high-risk - of 19 patients (median follow-up – 10,2 months) died seven (52,6%, p <0,05).

In this case, the presence of "0 - 3" predictors 5,3 year overall survival was 92% (median follow-up – 8,2 months), and the "4 - 6" of prognostic factors - 46% (median follow-up – 10,2 months; p <0,05). It must be emphasized that, in general, nine patients (9,2%) with the number of risk factors for 0 - 3 experienced a 10-year period after the start of a special treat.

Referring to the data on overall survival in malignant brain tumors grade III according to the age, it was found that in patients younger than 40 years 3-5 year survival rate was 93,1% (1 of 47 patients died), as you get older ( over 40 years) – 70,2% (of the 52 patients died 7) (p = 0,067).

At the same time, as the results of the study, the most informative factor for overall survival in malignant brain tumors was grade III tumor size, and with a very high degree of reliability (r = 0,28; p <0,01).

Thus, during the initial transverse size of tumors more than 6 cm significantly reduced overall survival, particularly 3-5 year survival rate, respectively, 69,6% and 93,1% (p = 0,043).

Total 3-5 year survival in both groups with / without dislocation midline of the brain was, respectively, 64,5% and 97,4% (median follow-up 6,8 and 9 months, p = 0,27).

In the group of patients with primary brain tumors were more common grade III patients with KPS equal to 70-80%, ie capable of normal daily activity or active work. The average value of the index in this group was 75,7%, with a median - 80% (most common value). The total number of patients with a Karnofsky index of less than 60% (the ability to self-lost) was 13 (13,2%).

It must be emphasized that the level of the Karnofsky index in patients with primary malignant brain tumors grade III had a significant correlation with subsequent mortality and corresponded to the value 0,28 (p <0,01).

When grade III in patients without mortality 95% confidence interval, Karnofsky index corresponded 76,5%, at the time, as well from deceased patients – 63,7%.

In our study, the statistical analysis of the most informative for malignant brain tumors grade III was the Karnofsky index level less than 60%, which recorded significant correlation between it and mortality (r = 0,25; p <0,05).

After special treatment of 53 patients with an initial level of KPS 80-100% with a median follow up 6 months died two (3,7%), with 60-70% of the initial level of 40 patients - 5 (12,5% with a median of 13 months ) and 30-50% of the initial level of the 5 patients - 2 (40%, median 17,8 months).

Thus at the level of initial Karnofsky index of less than 60%, 3-5 year overall survival rate of 51,8%, with 60-70% of the initial level - 75% of the initial level and 80-100% - 94,2% (p = 0,057 ), and in the latter group of patients-nine patients (9,2%) experienced a 10-year period after the start of a special treat.

The study also analyzed the results of treatment with the two modes with single focal irradiation doses to be, respectively, 2 and 3 Gy. At the same time, I would like to emphasize that, after a special treat 41 patients with a single focal dose of 2 Gy (median follow-up – 17,1 months) died 3 (8,1%), and the application of 3 Gy of 57 patients (median follow-up – 4,8 months) - 5 (9,43%, p = 0,66).

In analyzing the data, it follows that as the single focal dose up to 3 Gy, a slight decrease in overall survival. Thus, the total 3-5 year survival rate was 83,1% and 72%, respectively (p = 0,62). However, it must be emphasized that the application of an average dose fractionation mode significantly reduces the length of stay of patients in hospital, which eventually leads to a significant reduction in the cost of treatment.

It is also necessary to emphasize that all 98 patients examined postoperative adjuvant radiotherapy. In this case, only external beam radiation therapy performed 78 patients (median follow-up – 7,8 months), died - 6 (7,7%). Chemoradiotherapy was performed in 20 patients (median follow-up – 14,4 months), died - 2 (10%). Total 3-5 year survival rate in these groups of patients was 75% and 83%, respectively (p=0,96).

However, no significant differences in overall survival in malignant brain tumors grade 3 in patients with conduct independent radiotherapy and chemoradiotherapy were found (p = 0,96). It is likely that to obtain statistically significant differences between groups with different treatment options and low survival rates requires a larger statistical sample.

The modest benefit of chemotherapy in patients with GBM has been widely documented and likely reflects the relative insensitivity of GBM to cytotoxic agents. Conclusion

Currently, neurosurgical and radiological clinics in Russia clear common guidelines for the special treatment of tumors of the central nervous system is not, which is probably due to the heavy contingent of these patients. patients. In this case, the approach to treatment is decided in each case individually or according to protocols approved in the health care setting. While the number of scientific publications on the results and methods of treatment, remains very limited, despite the continued increase in the incidence rates of tumors of the central nervous system. As demonstrated by this study, for grade 3 tumors is a high value and classification of EORTC, designed for low-grade tumors. In this case, the combination of more than three factors identified in it reliably leads to a dramatic reduction in life expectancy.

The obtained results of the treatment of gliomas grade III strongly suggest the importance of the functional state of the patient before the start of the radial phase of special treatment. At the same time, initial Karnofsky index level was a significant predictor for subsequent measurement parameter for overall survival.

From our point of view, external beam radiation therapy high-grade gliomas grade III should be a mandatory component of the special treatment. The analysis of treatment results showed that the increase in single focal dose does not, in general, to a decrease in survival. With this mode, the average radiation dose fractionation can be used in patients who are able to care for themselves independently (KPS more than 70%).

In addition, we believe that today in the treatment of brain tumors are high grade must also apply consistently Temodal chemotherapy in combination with radiotherapy.

In what might be the groups of patients in which surgery, radiotherapy and drug components will be assigned according to certain criteria.

These results indicate the need for "radical" in the treatment of brain tumors are high grade. Even in patients with severe neurological deficit and the inability to remove most of the tumor is possible adjuvant treatment can prolong the lives of a large number of cancer patients who have their satisfactory quality of life.

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