Patients with large headaches and inoperable headaches
In 2009, on the basis of the Research Institute of Neurosurgery named after.
N.N. Burdenko completed the work “Chemotherapy in the treatment of patients with inoperable supratentorial malignant astrocytic gliomas.” According to this work, in 37 patients with inoperable large headaches, who received only chemotherapy after STB, three schemes were used: PCV - in 15 (40.5%) patients, TMZ - in 5 (13.5%), TMZ +cisplatin - in 17 (54%) patients. MTDP was 5, 4 and 8 months, median OS was 8.5, 6.0 and 10.5 months, respectively. In the case of chemotherapy alone, the highest immediate effectiveness was obtained using the TMZ + cisplatin regimen: complete response in 2 patients, partial response in 10, stabilization in 7, progression in 7. When using TMZ in monotherapy, the maximum effect was stabilization [ 14]. The prerequisite for studying the combination of TMZ + cisplatin was a number of studies performed in patients with relapses of G.B. The first and largest series of observations showing the effectiveness of the combination of TMZ + cisplatin in recurrent hypertension in patients who had not previously received chemotherapy was a study by A. Brandes et al. [15]. Based on in vitro
, which showed that cis-platinum can not only reduce the activity of MGMT, but also enhance the effectiveness of TMZ in this direction. The effectiveness of the combination of TMZ + cisplatin has also been shown in patients who have already used TMZ and subsequently had PROP [16]. S. Balana et al. [17] showed the effectiveness of using TMZ + cisplatin as the first line of treatment in patients with verified inoperable headaches.
In this group of patients with hypertension, we used carboplatin instead of cis-platin in combination with TMZ. Carboplatin has less nephrotoxicity and significantly less emetogenicity.
In 792 patients with advanced ovarian cancer, the combination of carboplatin + paclitaxel was no less effective than the combination of cisplatin + paclitaxel, had fewer side effects and a more convenient administration regimen [18]. In 598 patients with testicular germ cell tumors, when comparing the effectiveness of combinations of bleomycin + etoposide + carboplatin or cisplatin (BEC/BEP), it was shown that BEC was significantly inferior to BEP in terms of relapse-free and overall survival [19]. The experience of treating 618 patients with advanced non-small cell lung cancer with carboplatin + paclitaxel or cisplatin + paclitaxel regimens showed that with the same number of responses to treatment, patient OS was longer when using the combination of cisplatin + paclitaxel, and the combination of carboplatin + paclitaxel is a reasonable alternative, with similar response rates, good safety profile, acceptable toxicity and ease of use [20]. A comparative assessment of the effectiveness of the combination of temozolomide + cisplatin and TMZ + carboplatin in patients with inoperable gliomas has not been carried out.
In our series, 12 patients received chemotherapy alone as first-line therapy. Primary multiple headaches were present in 4 patients, one of them underwent STB, the rest had one of the tumor nodes removed. Widespread diffuse headache was present in 8 patients. In 2 cases, STB was performed, in 6 cases, partial tumor removal was performed. In all cases, the size of the existing or remaining tumor after removal prevented L.T. These 12 patients received chemotherapy in the T.K. regimen. After tumor size reduction, 6 patients underwent RT. MTDP in the entire group was 8.1 months.
Based on the available data on the effectiveness of the combination of TMZ with platinum drugs for large headaches, we prescribed TC after completion of CRT to patients with partially removed headaches. There were 20 such patients. Of these, tumor progression was detected in 16 patients before completion of 6 courses of chemotherapy. 4 people continued treatment for more than 6 courses, of which 3 patients had progression after 8, 9 and 12 courses, respectively. Treatment was stopped after 10 courses in 1 patient. The median time to progression in this group was 7.2 months.
Retrospective data show that patients with inoperable headaches live for about 3 months with only symptomatic therapy, and 6-7 months with RT [21]. Thus, temozolomide + cisplatin and TMZ + carboplatin regimens can be recommended for use in patients with advanced diffuse glioblastoma. However, despite the achieved benefits in OS, the results of treatment of patients with large headaches remain unsatisfactory.
Early tumor progression in these patients indicates a relatively low effectiveness of the therapy and the need to use more effective drugs, for example, using BEV.
As mentioned above, according to the results of randomized phase III studies, BEV is not indicated in the first line of treatment for G.B. However, the analysis of data by O. Chinot established that the use of BEV in the first line of therapy has a different effect on survival in different subtypes of G.B. Thus, for patients with the proneural type of headache and the absence of the IDH1 gene mutation, when using BEV in the first line of treatment, the OS was 17.1 months, and in the placebo group it was 12.8 months ( p
=0.002) [22]. It was also shown that the use of BEV provided a significant increase in the time until deterioration in the status of general health, physical, social functioning, motor and communication deficits. The ability of BEV to effectively reduce cerebral edema has been described [23].
It should also be noted that the inclusion criteria for patients in Avaglio and RTOG 0825 required patients to have a Karnofsky score of 70 or more, whereas the majority of patients in our series who received TC had a lower score. Thus, taking into account the high immediate effectiveness of BEV, detected both clinically and with MRI, it makes sense to study its effectiveness in the first line of treatment in patients with diffuse widespread G.B. It is necessary to search for factors that predict the benefit of using BEV, for example, the HD subtype, the content of matrix metalloproteinase in the blood plasma, and the methylation status of the MGMT gene.
Pharmacological properties of the drug Bevacizumab
bevacizumab is a recombinant hyperchimeric (humanized, close to human) monoclonal antibody that selectively binds to and neutralizes biologically active vascular endothelial growth factor (VEGF). Bevacizumab inhibits the binding of vascular endothelial growth factor to its receptors on the surface of endothelial cells, which leads to decreased vascularization and inhibition of tumor growth. Bevacizumab contains fully human frameworks with mouse hyperchimeric antibody complementarity-determining regions that bind to VEGF. Bevacizumab is produced using recombinant DNA technology in an expression system represented by Chinese hamster ovary cells. Administration of bevacizumab suppresses metastatic disease progression and reduces microvascular permeability in a variety of human tumors, including colon, breast, pancreas and prostate cancer. Bevacizumab in combination with irinotecan, fluorouracil and leucovorin (IFL) as first-line therapy in patients with metastatic colorectal cancer statistically significantly increases the overall survival period (from 15.6 to 20.3 months) in all subgroups of patients, regardless of age, gender, general condition, location of the primary tumor, number of organs affected and duration of metastatic disease. The addition of bevacizumab to IPF chemotherapy increases progression-free survival, improves overall response rates, and increases the median duration of response. A lower risk of mortality was observed in the group receiving bevacizumab in combination with IFL compared with the group receiving IFL chemotherapy alone. When prescribing bevacizumab (5 mg/kg, every 2 weeks) in combination with fluorouracil/leucovorin (FU/LV) as first-line therapy in patients with metastatic colorectal cancer and the presence of contraindications to irinotecan therapy (age over 65 years, previous radiation therapy abdomen and pelvis) or with a lower likelihood of benefiting from irinotecan therapy (PS 1, baseline albumin ≤3.5 g/dL) had a higher objective response to treatment and a trend toward increased survival compared with FU chemotherapy alone /LV. When bevacizumab is administered intravenously in a dose range of 1–10 mg/kg over 90 minutes, its pharmacokinetics are linear. When bevacizumab is administered once a week every 2 weeks or every 3 weeks in doses of 1 to 10 mg/kg, its volume of distribution is 2.66 L and 3.25 L in women and men, respectively. Following a single IV administration of bevacizumab, its metabolic characteristics are similar to those of the naturally occurring IgG molecule. The clearance of bevacizumab is 0.207 L/day in women and 0.262 L/day in men. The volume of distribution and clearance corresponds to an initial half-life of 1.4 days and a terminal half-life of 20 and 19 days in women and men, respectively. This half-life corresponds to the terminal half-life of human endogenous IgG, which is 18–23 days. After dose adjustment for body weight, bevacizumab clearance was 26% higher in men than in women. In patients with low albumin (≤29 g/dL) and high ALP levels (484 U/L) (both markers of disease severity), bevacizumab clearance is approximately 20% higher than in patients with average laboratory values. There were no significant differences in the pharmacokinetics of bevacizumab depending on age.
Ports for targeted and chemotherapy
A central venous catheter, or port, is a convenient solution for cancer patients who need to regularly receive intravenous treatment and donate blood. Over time, the condition of their blood vessels worsens due to constant punctures, and attempts to administer drugs turn into torture for both patients and medical staff. An almost invisible device, usually installed under the skin just below the collarbone, solves this problem - its owners do not experience problems with taking tests and delivering drugs to the body.
Ports have many advantages: they allow you to reduce the number of injections, avoid discomfort during chemotherapy or targeted therapy, and reduce the risk of drugs getting on the skin, and therefore irritation. Their disadvantages include the possibility of clogging the catheter, the appearance of blood clots in it, and its kinking or displacement. It is not difficult to avoid unpleasant consequences - just strictly follow the cleaning instructions, wash your hands thoroughly, try to avoid hitting it and do not engage in contact sports.
Use of the drug Bevacizumab
Administered only intravenously; It is forbidden to administer intravenous fluids! Standard dosage regimen: 5 mg/kg 1 time every 14 days as an intravenous infusion, long-term. If signs of disease progression appear, bevacizumab therapy should be discontinued. The required amount of bevacizumab is diluted to a total volume of 100 ml with sterile pyrogen-free 0.9% sodium chloride solution. The initial dose is administered over 90 minutes as an IV infusion after chemotherapy, and subsequent doses may be administered before or after chemotherapy. If the first infusion is well tolerated, the second can be given over 60 minutes. If the infusion over 60 minutes is well tolerated, then all subsequent infusions can be carried out within 30 minutes. It is not recommended to reduce the dose of bevacizumab due to adverse events. If necessary, treatment with bevacizumab should be stopped completely or temporarily.
How is targeted therapy taken?
Today, there are several forms in which such drugs are produced. They can be taken orally, like regular tablets, capsules or syrups, or intravenously.
Medicines are delivered to the body through regular
catheter - a thin soft plastic tube in a blood vessel, or
central venous
, the so-called port - a device installed under the skin. They are administered by a specialist in a few minutes or hours.
Oral targeted therapy is usually taken on a regular schedule at home. Each patient receives clear instructions about how much, when and how to do it. Doses of the drug are calculated in such a way that the required amount of these substances that destroy cancer cells is constantly present in the body. Any slightest failure or deviation from the scheme can affect the effectiveness of treatment. Any omission or delay in taking the drug should be reported to the doctor, who will decide how to act in this situation.
Side effects of the drug Bevacizumab
The most serious side effects: gastrointestinal perforation, hemorrhage, arterial thromboembolism. In patients receiving only bevacizumab or combination treatment with chemotherapy, asthenia, anorexia, diarrhea, constipation, nausea, nosebleeds, hypertension (arterial hypertension) and pain of various localizations are most often observed. The following are side effects of any severity that occurred in patients receiving bevacizumab in combination with IFL or FU/LV. From the cardiovascular system - hypertension (arterial hypertension), arterial thromboembolism (including myocardial infarction, stroke, transient ischemic attack and other arterial thromboembolic complications); deep vein thrombosis, chronic heart failure. From the blood system: leukopenia, neutropenia, anemia. From the gastrointestinal tract: abdominal pain, diarrhea, constipation, rectal bleeding, stomatitis, bleeding gums, perforation. From the respiratory system: nosebleeds, shortness of breath, rhinitis. Skin: dry skin, exfoliative dermatitis, change in skin color. From the central nervous system: taste disturbance, anorexia, syncope, cerebral ischemia. From the organ of vision: visual impairment. Local reactions: pain at the injection site. Laboratory parameters: proteinuria, hypokalemia, hyperkalemia, hyponatremia, hypophosphatemia, hyperglycemia and increased alkaline phosphatase activity in the blood serum. Other: asthenia, abscess, sepsis, fever, vaginal bleeding.
Special instructions for the use of Bevacizumab
Use with caution for hypertension (arterial hypertension), a history of arterial thromboembolism, wound healing, bleeding, gastrointestinal perforation, and in patients over 65 years of age. Patients with metastatic colorectal cancer treated with bevacizumab in combination with chemotherapy have an increased risk of developing gastrointestinal perforation. Severe cases of gastrointestinal perforation with the development of peritonitis, including fatal ones, were noted. Although the causal relationship of perforation and peritonitis resulting from gastric ulcers, tumor necrosis, diverticulum or colitis to bevacizumab has not been established, caution should be exercised when treating patients at risk. If perforation develops, treatment with bevacizumab should be discontinued. Bevacizumab may negatively affect wound healing. Treatment with bevacizumab should not be started within 28 days of surgery or until the surgical wound has completely healed. If complications associated with wound healing develop during treatment, bevacizumab should be temporarily discontinued until the wound is completely healed. Bevacizumab should also be temporarily discontinued if undergoing elective surgery. An increased incidence of hypertension (arterial hypertension) was noted in patients receiving bevacizumab. Clinical safety data suggest that the incidence of hypertension (arterial hypertension) is independent of the dose of bevacizumab. There is no information on the effect of bevacizumab during initiation of treatment in patients with uncontrolled hypertension (arterial hypertension). When prescribing bevacizumab to such patients, caution should be exercised and blood pressure should be regularly monitored. In patients with hypertension (arterial hypertension) requiring drug therapy, it is recommended to temporarily discontinue bevacizumab therapy until adequate blood pressure control is achieved. If it is impossible to establish drug control of blood pressure and/or the development of a hypertensive crisis, bevacizumab should be discontinued. The risk of developing proteinuria is increased in patients with a history of hypertension (arterial hypertension). Urine testing for proteinuria is recommended before and during bevacizumab therapy. If nephrotic syndrome develops, bevacizumab should be discontinued. Patients with metastatic colorectal cancer have an increased risk of tumor-related bleeding. If severe bleeding occurs during treatment, bevacizumab should be discontinued. In patients with congenital bleeding diathesis, acquired coagulopathy, or receiving full-dose anticoagulants for thromboembolism, caution should be exercised before prescribing bevacizumab. Serious bleeding, some fatal, has been reported in patients with non-small cell lung cancer (squamous cell carcinoma or centrally located tumor close to large blood vessels) treated with bevacizumab. Bleeding occurred suddenly and proceeded like massive hemoptysis. In most cases, it was preceded by the formation of a cavity and/or tumor necrosis. Bleeding was also rarely observed in other types of tumors (hepatoma with metastatic damage to the central nervous system, hip sarcoma with necrosis). A history of arterial thromboembolism or age over 65 years are associated with an increased risk of arterial thromboembolism during treatment with bevacizumab. Caution must be exercised when treating such patients. If arterial thromboembolism occurs, bevacizumab therapy should be discontinued. A history of anthracycline therapy and/or radiation therapy to the chest may contribute to the development of congestive heart failure. In patients with such risk factors, caution should be exercised when prescribing bevacizumab. When prescribing bevacizumab to patients over 65 years of age, there is an increased risk of arterial thromboembolism (including stroke, transient ischemic attack, myocardial infarction) and leukopenia. An increase in the incidence of other adverse events, including gastrointestinal perforation, wound healing disorders, hypertension, proteinuria, bleeding and congestive heart failure associated with the use of bevacizumab, was not observed in elderly patients. Men and women of childbearing potential should use reliable methods of contraception during treatment with bevacizumab and for at least 6 months after treatment. Breastfeeding is not recommended for at least 6 months after completion of bevacizumab therapy.
How does targeted therapy work?
Targeted drugs are designed to target specific substances in cancer cells: an excess of certain proteins, as well as compounds or changes in genes that are absent in normal tissues.
Such medicines can:
- block or turn off signals that stimulate cell growth and division;
- stop the growth of new blood vessels that the tumor needs for nutrition;
- change the proteins contained in tumor cells, due to which they stop multiplying and die;
- activate a person’s own immune system - direct it to fight cancer;
- transfer toxins into cancer cells - toxic substances that kill them, but are not dangerous to healthy tissues.
Drug interactions Bevacizumab
Patients receiving bevacizumab in combination with IFL experienced a 33% increase in concentrations of the active metabolite irinotecan SN38 compared to patients receiving IFL alone. The association of increased SN38 levels with bevacizumab has not been established. In patients treated with IFL + bevacizumab, there was a slight increase in the incidence of adverse events such as diarrhea and leukopenia (known side effects of irinotecan), as well as a more frequent need for irinotecan dose reduction. If severe diarrhea, leukopenia or neutropenia develops during combination therapy with bevacizumab and irinotecan, a dosage adjustment of irinotecan is necessary. Current data suggest that bevacizumab does not affect the pharmacokinetics of fluorouracil, carboplatin, paclitaxel and doxorubicin. With the combined use of warfarin (treatment of venous thrombosis) and bevacizumab, no increase in the incidence of serious bleeding was noted. Pharmaceutically incompatible with dextrose solutions.
What is targeted therapy?
Targeted therapies are special medications that destroy specific types of cancer cells.
They act exclusively on substances due to which some types of cancer grow and spread throughout the body. The name of the method comes from the English word “target” - goal or target. This is exactly how it works – precisely against altered tissues.
How is targeted therapy different from chemotherapy?
These substances, like other drugs used to treat cancer, are technically considered chemotherapy, but the way they work is different:
- Due to their targeted action, these agents affect cancer cells and practically do not damage healthy ones. Standard “chemistry” is cytotoxic – poisonous not only for tumor cells, but also for normal cells.
- Conventional drugs destroy already formed altered cells, while targeted drugs block their copying, prevent division and the creation of new ones.
