[Extent of resection in patients with glioblastoma]. / Stepen' khirurgicheskoi rezektsii pri glioblastome.

OBJECTIVE: To investigate the impact of resection quality on subsequent survival of patients with glioblastoma. MATERIAL AND METHODS: There were 141 patients with morphologically confirmed glioblastoma (grade 4). Fractionation with the prescribed dose of 2 and 3 Gy was alternately used (pairwise modeling strategy). Total resection was performed in 29.8% of patients (EOR: 100%; n=42), subtotal - 56.7% (EOR: 70-99%; n=80). Extent of resection 1-69% was registered in 19 patients (13.5%). RESULTS: As of December 2022, 124 out of 141 patients (87.9%) were diagnosed with primary progression, 101 (71.6%) ones died. We analyzed the threshold role of EOR. The most informative level was 70% (p=0.002). EOR 100% was followed by median overall survival about 32.2 months (95% Cl: 15.3-49.1), EOR 70-99% - 21.3 months (95% Cl: 15.1-27.5), EOR 1-69% - 10.3 months (95% Cl: 3.8-16.9; p=0.003). Fractionation mode with the prescribed dose of 3 Gy partially eliminated significance of EOR (p=0.148) in contrast to standard fractionation (p=0.015). Tumor growth in the interval between surgery and radiotherapy (REP) reduces significance of EOR (p=0.042). Inclusion of second-line therapy with bevacizumab in multivariate analysis model (OR=0.488; p=0.002) makes EOR less significant (OR=0.749; p=0.085) in contrast to REP (OR=2.482; p<0.0001). CONCLUSION: To date, the principle of maximum safe resection remains fundamental in neurosurgery. EOR about 70% is sufficient regarding overall survival, but total resection should be sought if possible.

[Early progression of glioblastoma before radiotherapy]. / Rannee progressirovanie do luchevoi terapii pri glioblastome.

OBJECTIVE: To analyze the influence of continued growth of glioblastoma between surgery and radiotherapy on subsequent survival. MATERIAL AND METHODS: Fractionation with a prescribed dose of 2 and 3 Gy was alternately applied using a pairwise modeling strategy in 140 patients with morphologically confirmed glioblastoma (grade 4). Early progression of disease between microsurgery and radiotherapy was diagnosed in 60 patients, and no tumor growth was noted in 80 patients. RESULTS: The minimum period of early progression was 0.33 months, maximum - 4.27 months (median 1.1 (95.0% CI: 0.9-1.3)). The most significant predictors of early progression were resection quality (p<0.0001), large residual tumor (p=0.003) and no MGMT promoter methylation (p=0.001). IDH1 status did not affect early progression. In residual tumor ≥1.2 cm3, the median period of early progression was 1.9 months (n=70; 95% Cl: 1.3-2.5), <1.2 cm3 - 3.5 months (n=70; p=0.019). After resection of less than 76% of tumor, this value was 1.1 months (n=28), ≥76% - 3.1 months (n=112; p=0.006). Without tumor growth, the median overall survival was 33.41 months (n=80; 95% Cl: 27.1-39.7), with early progression - 16.03 months (n=60; 95% Cl: 13.5-18.6; p<0.0001). This predictor was significant for fractionation with a prescribed dose of 3 Gy (p<0.0001) and standard radiotherapy (2 Gy; p=0.028). By December 2022, 26 out of 40 patients without early progression survived two years after treatment (3 Gy) (65%, median not reached). In case of fractionation with a prescribed dose of 2 Gy, 20 patients survived this period (50%, median reached). CONCLUSION: Almost half of patients with newly diagnosed glioblastoma develop early progression between microsurgery and radiotherapy. Therefore, patients with and without early progression should be probably assigned to different prognostic groups regarding overall survival.

[Superselective intra-arterial administration of bevacizumab with blood-brain barrier disruption in patients with recurrent malignant gliomas: case report and literature review]. / Superselektivnoe vnutriarterial'noe vvedenie bevatsizumaba s otkrytiem gematoentsefalicheskogo bar'era u patsientov s retsidivnymi zlokachestvennymi gliomami: obzor literatury i klinicheskii sluchai.

Glioblastoma multiforme is characterized by persistent recurrent course despite surgical, radio- and chemotherapeutic treatment. The outcomes of superselective intra-arterial administration of bevacizumab with blood-brain barrier disruption in patients with recurrent glioblastoma have been published. The authors reported significant increase in overall survival (up to 2.5 years). We report treatment of recurrent glioblastoma in a young patient with progressive course of disease despite 4 previous neurosurgical interventions, radiotherapy and first-line chemotherapy. Superselective intra-arterial administration of bevacizumab with blood-brain barrier disruption made it possible to achieve clinical response and improve neurological status.

[Short-term survival prediction scale in patients with metastatic brain disease caused by lung and breast cancer]. / Shkala prognoza kratkosrochnoi vyzhivaemosti pri metastaticheskom porazhenii golovnogo mozga u bol'nykh rakom legkogo i molochnoi zhelezy.

OBJECTIVE: To develop a prognostic scale suitable for distinguishing a group of poor prognosis with low survival prior to deciding on the appropriateness of radiotherapy. MATERIAL AND METHODS: We analyzed only those patients with reliably known date of death after previous WBRT to determine objective criteria allowing WBRT abandonment. WBRT was carried out in 100 patients with non-small cell lung cancer (n=49) and breast cancer (n=51) and confirmed metastatic brain disease. All procedures have been conducted at the radiotherapy department of the Herzen Moscow Oncology Research Institute since January 2014. The prescribed dose of 3 Gy was ensured in all patients. Total focal dose of 30 Gy delivered in 10 fractions was achieved in 77 cases, 36 Gy delivered in 12 fractions - in 23 cases. RESULTS: Death date was recorded in all patients (n=100) by January 2020. In the electronic SPSS database, death information was digitized for each patient up to 2-24 months, respectively. We identified eight the most significant factors by using of correlation analysis: primary tumor (controlled (0), uncontrolled (1)), number of brain metastases (<17 (0), ≥17 (1)), volume of brain metastases (<48 cm3 (0) ≥48 cm3 (1)), extracranial control (no metastases (0), metastases with positive dynamics after chemotherapy (1), continued growth after chemotherapy (2)), metastatic lesion of liver and lungs, respectively (no (0), yes (1)), functional status (≥ 70% (0), ≤ 60% (1)), carcinomatosis of the meninges (no (0), yes (1)). A simple summation of digital variables for factors 1-8 in each patient resulted a prognostic scale. Low risk of early mortality after WBRT was determined by 0-3 scores, intermediate risk - 4-5 scores, high risk - 6-9 scores. According to univariate analysis (log-rank 0.000), median survival rate varied in these groups: low risk - 15.5 months (11.4-19.7), intermediate risk - 5.26 months (4.6-6.0), high risk - only 1.35 months (0.9-1.8). Only 1 out of 15 high-risk patients (6-9 scores) survived 3 months (3.25 months). Inclusion of all eight factors into multivariate analysis revealed significant impact of only risk group on short-term survival. A 3-month survival in the high-risk group was 20.6 times lower (p=0.002) compared to the low and intermediate risk groups. CONCLUSION: High significance of prognostic model and low informative value of each of the included factors emphasize the advisability of determining risk groups for short-term survival according to the suggested scale for each patient scheduled for WBRT. A simple assessment of separate predictors is pointless to decide whether WBRT is necessary.

[Hypofractionated radiotherapy for glioblastoma: changing the radiation treatment paradigm]. / Gipofraktsionirovanie pri glioblastomakh: izmenenie paradigmy luchevogo lecheniia.

Hypofractionation has the dual advantage of increased cell death with a higher dose per fraction and a reduced effect of accelerated tumor cell repopulation due to a shorter overall treatment time. However, the potential advantage may be offset by increased toxicity in the late-responding neural tissues. Recently, investigators have attempted delivering radical doses of HFRT by escalating the dose in the immediate vicinity of the enhancing tumor and postoperative surgical cavity and reported reasonable outcomes with acceptable toxicity levels. Three different studies of high-dose HFRT have reported on the paradoxical phenomenon of improved survival in patients developing radiation necrosis at the primary tumor site. The toxicity criteria of RTOG and EORTC have defined clinically or radiographically suspected radionecrosis as Grade 4 toxicity. However, most patients diagnosed with radiation necrosis in the above studies remained asymptomatic. Furthermore, the probable association with improved survival would strongly argue against adopting a blind approach for classifying radiation necrosis as Grade 4 toxicity. The data emerging from the above studies is encouraging and strongly argues for further research. However, the majority of these studies are predominantly retrospective or relatively small single-arm prospective series that add little to the overall quality of evidence. Notwithstanding the above limitations, HFRT appears to be a safe and feasible strategy for glioblastoma patients.

[Hodgkin's lymphoma and radiotherapy].

After a median observation time of 4,5 years, 440 patients with Hodgkin's lymphoma stage I-IV to the Ann Arbor classification were treated with radiotherapy (2200 lymph areas) and ABVD (n=204) or BEACOPP (n=117) or CEA/ABVD (lomustine, etoposide, adriamycine, bleomycine, vinblastine and dacarbacine; n=119) regimens in 1995-2012. Correct allocation of groups with "CR or PR ≥80%" and "PR: 0-79%", after first-line chemotherapy, is extremely important for following RT planning. Adaptation of patients with Hodgkin's lymphoma can take place only after successful treatment, the probability of relapse and fear of repeated courses strongly interfere with this process, especially in the first years after its closure. Duration of remission period, especially in young people, is no less important than the criteria for overall survival. It is impossible to build recommendations for treatment for Hodgkin's lymphoma, based only on long-term survival rates. Importance of radiotherapy in reducing the number of relapses is undeniable, so the idea that the development of the role of chemotherapy in the treatment of the ray method Hodgkin's lymphoma gradually becomes secondary is in serious doubt. Our findings suggest the importance of both maintaining a high disease-free survival and reducing long-term complications in designing treatments of Hodgkin's lymphoma.

[Evaluation the effectiveness of radiation therapy high-grade gliomas based on the model of TDF (time-dose fractionation)].

There were showed the possibility of using the model of TDF, through which it was possible to take into account the selection of fractionation of radiation for high-grade gliomas and to judge the effectiveness of treatment. Currently, the basis of adjuvant radiation therapy in patients with primary high-grade gliomas is the use of the traditional mode of fractionation dose of radiation from a single focal dose of 2 Gy up to a total focal dose of 60 Gy to the tumor (bed of the removed residual tumor) in Grade 4 and Grade 3 - 54 Gy. In patients who underwent radiotherapy using a single focal dose of 3 Gy, overall survival rate was higher as compared to the group of patients, which was carried out using radiotherapy small dose fractionation.

[The role of functional status and recursive partition analysis (RPA) classes for the choice of fractionation regimen in patients with high-grade gliomas].

The treatment results of 396 patients with morphologically verified grade 3-4 malignant brain tumors receiving conventional irradiation regimen and irradiation by medium-sized fractions were analyzed to form institutional guidelines.The standard mode of fractionation with a single dose of 2 Gy and total focal dose (TFD) of 60 Gy is appropriate for patients with initial Karnofsky status of 60-100% and Recursive Partition Analysis (RPA) class I-III. TFD increase to 60-62 Gy in grade 4 gliomas and 54-56 Gy in grade 3 gliomas grants a significant improve in overall survival. An increase of a single irradiation fraction to 3 Gy may be used for patients with initially low functional status (Karnofsky 30-50%) and RPA classes IV-VI. In these cases it is advisable to use the TFD of 45 Gy or more (TFD of equivalent regimen with a dose greater than 54 Gy). The mentioned fractionation regimens could be recommended for the use in clinical practice to improve the results of high-grade gliomas treatment.

[The role of age and tumor grade in the choice of fractionation regimen in patients with high-grade gliomas].

There are currently no conventional guidelines for radiotherapy in gliomas. The treatment program is mainly formed in accordance with tumor morphology and the "golden standard" of irradiation is still the traditional mode of fractionation with a single focal dose of 2 Gy and total focal dose (TFD) of 60 Gy. In this report the treatment results of 396 patients with morphologically verified grade 3-4 malignant brain tumors receiving conventional irradiation regimen and irradiation by medium-sized fractions were analyzed to form institutional guidelines. The standard fractionation mode with a single focal dose of 2 Gy is preferable in patients with grade 3 glioma or elderly patients (over 60 years). TFD increase to 60-62 Gy in grade 4 gliomas and 54-56 Gy in grade 3 gliomas grants a significant improve in overall survival. An increase of a single irradiation fraction to 3 Gy may be used for patients younger than 60 years. In these cases it is advisable to use the TFD of 45 Gy or more (TFD of equivalent regimen with a dose greater than 54 Gy). The mentioned fractionation regimens could be recommended for the use in clinical practice to improve the results of high-grade gliomas treatment.

[The optimal radiation volume after first-line chemotherapy in Hodgkin lymphoma].

Radiation therapy has evolved from extended-field radiation therapy (EFRT) to involved-field radiation therapy (IFRT), reducing toxicity while maintaining high cure rates. Recent publications recommend a further reduction to involved-nodal radiation therapy (INRT); however, this has not been clinically validated. The need for irradiation or optimal radiation volume after chemotherapy are not defined. The treatment results of 296 Hodgkin's disease patients receiving ABVD or BEACOPP-21 chemotherapy with consequent EFRT demonstrate CR/PR > or = 80% and 99% local disease control rate. Beam therapy with EFRT is possible to use if dose levels don't exceed 30 Gy. Higher doses demands reduction of volume of radiating target. In our opinion the optimum program of beam therapy involves 2 stages with maximal possible dose level EFRT followed by additional INRT. Those approaches offer perspectives for Hodgkin's disease treatment.

[Role of response to first-line chemotherapy and of the primary lesion in Hodgkin lymphoma].

Based on the results of combined treatment with inclusion of ABVD and BEACOPP-21 chemotherapy regimens the basic principles of therapy depending on the nodal relaps criterium were developed. The most rational approach to treatment results evaluation concerns the lesions with the least response to chemotherapy. The groups of "adequate" and "inadequate" response to chemotherapy should be formed. The initial lesion localisation doesn't play an important part in the modern chemotherapy settings and should not be concerned while choosing tactics of radiation therapy. The method described should interest oncologists and radiologists involved in the treatment of Hodgkin lymphoma.

[The role of RPA classification in the treatment of high-grade gliomas].

One of the main gliomas treatment programs development criteria is still the morphology, the RPA classification with risk factors developed for high-grade tumors is rarely taken into consideration. In our study shows a high value on the criterion of overall survival identified in the classification of the six RPA classes. The most important factors in the RPA classification are patient's age and the Karnofsky performance scale value. RPA classification can be useful for new treatment strategies development.

[The optimal total focal radiotherapy dosage after first-line chemotherapy in patients with Hodgkin lymphoma].

Based on the treatment results of 300 Hodgkin lymphoma patients the authors formulated the basic approaches for radiation treatment in ABVD and BEACOPP-21 chemotherapy regimens recipients. In patients with complete response to chemotherapy any dose regimen (26 to 44 Gr) leads to 100% local disease control. In patients with major response to chemotherapy (PR> or =80%) the 36 Gr total focal dose allows an adequate local control, more intensive local control doesn't yield better results. In patients with PR 0-79% the implication of total focal doses less than 40 Gr leads to statistically significant increase of nodal relapse rate. These treatment approaches may be implied by specialists conducting chemotherapy and radiation therapy in Hodgkin lymphoma patients.

[Risk factors and long-term results of radiotherapy in grade-3 and -4 brain neoplasms].

Data on the treatment of 278 patients with brain tumors grade III-IV were evaluated, end-results compared and relevant prognostic factors identified. In our view, average fractionated radiotherapy is not inferior to standard fractionation modalities. It offers an advantage of using different single target doses. In primary patients with high-grade malignancies, an index (Karnofsky) of less than 60% appeared to be the most significant practical factor of prognosis. Both age and tumor size proved significant.

[Risk factors for hematologic toxicity and multifaceted analysis of blood in Hodgkin's disease: a model for hematologic toxicity].

Basic hematological features of CEA/ABVD medication for Hodgkin's disease were studied. An effective model was worked out on the principle of data discrimination for predicting different leukocytic toxicities induced by cytostatics-1 administration, once in two weeks. It might predict individual limits (dosage and intervals) of a chemotherapy course unless a colony-stimulation technique is used.

[The role of adjuvant radiotherapy in the complex treatment of stage III-IV aggressive non-Hodgkin's lymphoma].

Immediate and end results of chemoradiotherapy of 225 patients (average age--43 years) with primary aggressive non-Hodgkin's lymphomas stage III-IV were evaluated. Stage 1 of treatment included 4-8 cycles of chemotherapy (ACOP and other standard protocols); stage 2--irradiation of residual foci with 20-50 Gy, or 20-36 Gy for originally extensive and extralymphatic foci when in full remission. The latter's rate rose from 24 to 65% (p < or = 0.05) following adjuvant radiotherapy although that of failures remained unchanged. The disease is specific, so relapse-free survival in cases of generalized primary aggressive lymphoma in full remission remained unchanged too whatever the stage at which full remission emerged.

[Multivariate analysis of risk of cardiac complications in Hodgkin's lymphoma].

A computer database was created to take care of a wide range of protocols for combined treatment of Hodgkin's disease stage I-IV (n=1,573). Early-onset radiation-related injuries (pneumonitis) and exposure of lung tissues to radiation were identified as the main risk factors for cardiopathology development. It is suggested that total focal dosage used after chemotherapy be reviewed since total dosage for the entire lymph collector in excess of 30 Gy might contribute to hazards of cardiopathology. However, a locally administered TTD ranging 36-44 Gy to deal with residual tumor offers best advantage in preventing local relapse. Nor does it increase the risk of future complications. Our approach might promote individualization of prognosis as far as cardiac complications involved in Hodgkin's lymphoma are concerned.

[Prognostic models for Hodgkin's disease].

A prognostic model for Hodgkin's disease was worked out using the data on disease-free survival among patients receiving 4-8 courses of COOP(MOPP)/ABVD plus (sub)total irradiation. Patients with stage I-II Hodgkin's disease (less then 4 lesions) without large involved mediastinal masses, intoxication symptoms and focal splenic involvement were referred to the favorable prognosis group. The poor prognosis group featured stage III(2)-IV tumor as well as large masses of involved mediastinal tissue, focal splenic involvement at any stage plus 7 or more lesions. An assessment of tumor advancement across lesions is more significant for radiotherapy planning rather than that of organ involvement. It is reasonable to distinguish two substages--III(1) and III(2). Our model was compared with GHSG and it was suggested that ways be found to use both of them in prognosing of disease outcome.

[Five-year outcome of a new combination chemotherapy with CEA/ABVD for advanced Hodgkin's disease with poor prognosis].

Data are presented on our 5-year experience with combination chemotherapy of stage II-IV Hodgkin's disease (110), the unfavorable prognosis group, using a novel regimen of chemotherapy--CEA/ABVD (belustin, etoposide, doxorubicin, bleomycin, vinblastine, dacarbazine). Complete remission after 4 courses of CEA/ABVD chemotherapy was reported in 31.8%, unconfirmed complete remission--45.5%, objective effect--100% and an 80% regression of tumor mass--93.2%. No chemo-resistant forms were identified. Five-year actuarial relapse-free survival was 96.4%; overall 5-year survival--97.7%. Death from complications recorded during medication period occurred in 2.3% (1 out of 44), recurrence--2.3% (1 out of 44). Recurrence-free survival rose by 25% (p < 0.05) while overall survival--by 20% (p = 0.04 in year 3), as compared with COOP(MOPP)/ABVD (179 patients with poor prognosis). Our regimen opens up new vistas in managing Hodgkin's disease.

[Novel approaches to combination therapy of Hodgkin's disease].

Data on 668 patients receiving 4-8 cycles of chemotherapy were used to suggest the following approach to complex therapy of Hodgkin's disease: devise a simplified model for Hodgkin's disease, develop a new modality of chemotherapy, demonstrate feasibility of only four chemotherapy cycles in the poor prognosis group, partial response as the ultimate goal of chemotherapy as well as the importance of subtotal dosage under 26-36 Gy sufficient for irradiation of the entire lymphatic collector. Said measures will, in their totality, offer fresh opportunities in treatment of Hodgkin's disease.