A method of treating renal cell carcinoma

 

(57) Abstract:

The invention relates to medicine, more specifically to oncourology, and may find application in the treatment of malignant tumors of the kidney with metastases. How is that a patient with renal cell cancer after establishing the stage of the disease during angiographic studies injected into the renal artery 12 million IU of interferon-alpha and 1 g of 5-fluorouracil with concurrent embolization her avalona, hemostatic sponge and metal spirals. In postembolization period of 2-3 days conducting a course of immunotherapy with interleukin-2 once in 2 days, alternating with intramuscular recombinant interferon-alpha in a dose of 3.0 million IU/m2. As interleukin-2, it is advisable to use Roncoleukin that is administered in a dose of 500 thousand IU intravenous drip in 400 ml of saline solution by adding 8 ml of 10% albumin for 4 h In subsequent patient examination every 3 months and if there is evidence of disease progression or renal artery recanalization, repeat the treatment. When reducing the size of the tumor site and the regression of metastases, it is advisable to conduct the AEB - achieve regression of metastases in regional lymph nodes. 2 C.p. f-crystals.

The invention relates to medicine, more specifically to oncourology, and may find application in the treatment of malignant tumors.

According to the statistical data of various authors renal cell cancer accounts for 2-3% of tumors in the adult population and occurs with a frequency of 5 to 13 persons per 100,000 in Europe and the USA. Prevalence among urological tumors it is on the third place after tumors of the prostate and bladder and is about 85% of all primary tumors of the kidney. In Russia annually 12000 new cases. Most often the tumors are detected at the sixth and seventh decade of life with a mean age of 57 years. Men suffer from this disease twice as often in women.

A feature of the disease is slow growth of primary tumor (growth rate is about 1 cm in diameter for three years) with simultaneous aggressive and unpredictable currents. Most often, the tumor is detected in advanced stages, and the first symptoms are usually: hematuria, pain, fever, palpable tumor masses who immunotherapy, chemotherapy, surgery, radiation therapy.

A known method of surgical treatment of renal cell carcinoma related to radical methods of treatment. The method consists in tumor resection within healthy tissue or nephrectomy (Weigel J. W., et al. Of Urology. 1985; 25:103-5). Resection of the tumor within healthy tissue is possible if the tumor size is less than three inches in diameter, and if it does not invade the capsule and the pelvis of the kidney. The method is applied in stage T1 NO MO, that is, when the tumor size is less than 7 cm in diameter in the absence of germination in capsule or the pelvis of the kidney.

In the presence of metastases in regional lymph nodes or the size of the tumor more than 7 cm in diameter surgical treatment method is also applicable, however, in this case, it is usually combined with prior embolization of the renal artery or high-dose immunotherapy with recombinant interleukin-2 (Dis Kalman. Scand. J. Urol. Nephrol. 33:162-170. 1999; A. M. Granov, M. I. Karelin, P., Taraz. Methodical recommendations N 96/249. Saint-Petersburg. 1997).

In the presence of a single metastasis to lung and tumor-propagating within the renal parenchyma, it is possible to conduct sanitary nephrectomy, the ha Some authors under similar conditions recommended by conducting combined operations, including nephrectomy and coracoid resection of the lung (ithll H. Sokoloff, et al. CA Cancer J Clin. 1996; 46:284-302).

When the small size of the tumor radical nephrectomy is a safe method of treatment with a five year survival rate reaching 80%. On the other hand, in the treatment of tumors of large size disadvantage is the inability to achieve a high degree of elasticnet because of the uncomfortable anatomical localization, which ultimately leads to a high local recurrence rate.

With regard to the methods of combined treatment of locally common and metastatic forms of renal cell cancer, when surgical treatment is combined with immunotherapy or embolization, the question of whether surgical component in their treatment is controversial because the survival rate in the combined treatment with surgical component and without it is roughly the same as the quality of life higher in the absence of a surgical component (Rbrtson CN, et al. J Urol. 1990; 144:614-B18).

There is a method of treatment of renal cell carcinoma by embolis the donkey puncture of the femoral artery by the Seldinger method having a metal or plastic wires with a diameter of 0.035-0.038 and forth, the conductor is led into the abdominal aorta radiopaque catheters (Nook, Cobra, Rosch) to the level of discharge of the renal arteries, and then do 8-10 images, studying the bloodstream to the kidneys and structure of education. If a satisfactory blood supply of the contralateral kidney with sufficient vascularization of the tumor begin to embolization of the renal artery or its branches. As embolisate most often use ethanol, the particles of autologous muscle, avian (microfibrillar collagen), metal spirals, cylinders, gelatin, ivalon (polyvinyl alcohol), leodora, spongostan, thrombin, Willan.

Embolization of renal artery can be performed in the preoperative and palliative modes. Palliative embolization can be used in the presence of life-threatening complications: hematuria, pain caused by the tumor, endocrine activity of the tumor, as well as a component of combined treatment if you cannot surgical removal of the tumor. The main task of preoperative embolization is to reduce blood loss during surgery.

Dignity embolization is the treatment of tumours with bilateral lesions of the kidneys, in the presence of the tumor site, pervine blood loss during embolization in the preoperative mode and impact on primary tumor, what is needed to prevent further spread of the tumor.

The shortcomings of the method of treatment by embolization of the renal artery are: the impossibility of treating avascular and hypovascular tumors, the possibility of fat embolism in the presence of strong arterio-venous reset, the development of collateral blood supply of the tumor after 1 - 2 months after embolization, which requires constant repetition of the procedure, as well as high frequency of allergic reactions to contrast agents.

There is a method of treatment of renal cell cancer by immunotherapy. Fundamentally there are two groups of methods of immunotherapy: systemic immunotherapy and Loco-regional. The system in turn is divided into active and passive. It is now widely use the following options passive immunotherapy: recombinant cytokines (interleukins-2,4,10,12, interferons alpha and gamma, tumor necrosis factor alpha), adoptive immunotherapy by lymphokineactivated killer cells (LAK-therapy) or lymphocytes infiltrating the tumor (TIL therapy, immunotherapy with the using dendritic cells. As an active immunotherapy uses the effector cells against tumor. At the moment the most effective recognized methods chemoimmunotherapy, which use combinations of cytokines with chemotherapy.

Interleukin-2 is the most studied of all biologics used in the treatment of renal cell carcinoma. In the process of immune response it plays a key role and is actually triggering factor for the synthesis and secretion of other cytokines involved in the immune response.

When using interleukin-2 there are two basic modes: high and low (Angevin E, et al. J Immunother. 1995; 18:188-195).

When high-dose immunotherapy drug is administered in the form of a fifteen-minute intravenous infusion at a dose of 600-700 thousand IU/kg from 1 to 5 and 15 to 18 days of the month. Repeat the treatment usually after dvenadtsatietazhnogo interval. The maximum duration of treatment is 3 courses. The advantage of this method is the relatively high efficiency compared with any variation of chemotherapy. Treatment is effective in approximately 20-25% of patients. The disadvantage is the high toxicity, manifested as fever, chills, myalgias, and liver disease.

When dose immunotherapy is most often used to what about the significant advantage is its low toxicity. To increase the effectiveness of treatment dose immunotherapy with interleukin-2 is most often combined with therapy with interferon-alpha or other cytokines and chemotherapeutic agents.

Interferon-alpha is the second cytokine, which is widely used in the treatment of renal cell carcinoma. This polypeptide with pleiotropic effect, which has antiviral, immunomodulatory and antiproliferative activity. The preparation is applied subcutaneously, intramuscularly, intravenously and topically. The optimal therapeutic dose of interferon-alpha is still not defined. The most frequently used dosage of 5 to 10 IU/m2three to five days subcutaneously.

The frequency of regression of tumors in monotherapy ranges from 12% to 15%, and most often this group includes patients with metastases in the lungs. The disadvantage of this method of treatment, as in the previous example, is the high toxicity of the applied schemes.

In several works are the results of the use of combinations of several interleukins with multiple chemotherapeutic agents and drugs used for differencirovannoe therapy (Atzpodien J., et al. World J. Urol. 1995; 13: 174-177; Jon S. Du Bois, et al. Journal of Clinical Oncology. Vol. 15. N 3. 1997: R. 1052-1062). einevoll acid, and recombinant interleukin-2 soluble component of the receptor of tumor necrosis factor alpha. The response rate in this case was in the range of 32-35%.

Other cytokines, such as interleukin-4,12, inteferon-beta and gamma, tumor necrosis factor alpha, are under consideration, and products created based on them, are phase I and phase II clinical trials (Jun Cheon, et al. Int. J. Urol. 1996; 3:196-201).

Among the methods cellular immunotherapy release therapy lymphokineactivated killer (LAK-therapy), treatment of the tumor infiltrates with lymphocytes (IL therapy) and treatment using dendritic cells. All of these methods have a common name - adoptive immunotherapy (Mitchell H. Sokoloff, et al. CA Cancer J Clin. 1996; 46:284-302; Ruth Whittington, et al. Drugs. January 1993, vol. 46, N 3, p 446-514).

LAK-therapy is a method that is based on the ability of natural killer cells to induce apoptosis of tumor cells regardless of their antigenic structure. The essence of the method consists in the incubation of NK cells obtained from the patient, with interleukin-2 and subsequent introduction into the body of the patient.

When carrying out TIL therapy used lymphocytes isolated from tumor tissue is EIT classes that provides the full flow of antigen specific responses, while at LAK-therapy using so-called natural killer (NK, CD 16), which destroy tumor cells regardless of the availability of tumor antigens.

Dendritic cells - a system of specialized cell populations that recognize and present the antigens to T and b-lymphocytes in Association with antigens of the major histocompatibility complex, co-stimulating molecules and cytokines for the induction of immune responses to foreign antigens or establishment of tolerance to self-antigen (I. A. Balcueva, C. M. Moiseenko, K. P. Hanson. Questions of Oncology, 1999, vol 45, N 5; Gilboa E, et al. Cancer Imunol Immunother. 1998; 46:82-87). Dendritic cells play an important role in the process of tumor progression. When introduced into the body of the patient dendritic cells even at low doses of antigen is synthesized large amounts of antibodies and effector cells. The described method is currently under development, and therefore it is not yet possible to judge its effectiveness.

The advantage of the methods of cellular immunotherapy is the treatment of activated effector cells, neposredno compared with other methods of immunotherapy.

A common shortcoming of these methods is a complex technology of obtaining cells that require special equipment, and TIL therapy, in addition, the need for removal of the tumor before treatment, which limits the application of this method in stage IV disease. A positive effect can be reached in 20-25% of patients, less than cytokines.

Vaccine therapy relates to methods of active specific immunotherapy of tumors (Gilb E, et al. Cancer Imunol Immunother. 1998; 46:82-87; Simons JW, et al. Cancer Research 57: 1537-1546, 1997). The essence of the method is the introduction into a patient of tumor antigens, modified in one way or another, with co-stimulating molecules or other factors that enhance the production of antibodies and effector cells. Methods of vaccine therapy are under study, but at the moment it is already evident that the main disadvantage of these methods is the absence of antigens in tumors that were significantly different from the antigens of normal cells, and therefore very difficult to achieve active production of effector molecules.

Currently, immunotherapy is recognized as the most effective method of treatment of renal cell carcinoma.

The proposed method of treatment, refers to methods nonspecific passive immunotherapy and is intended primarily for the treatment of locally advanced and metastatic forms of renal cell cancer.

Closest to the present invention is a method of treating renal cell cancer, in which patients with metastatic renal cell cancer were treated with recombinant interleukin-2, recombinant interferon-alpha and 5-fluorouracil scheme: interleukin-2 subcutaneously three times per week at a dose of 20 million IU/m21 and 4 weeks of treatment and 5 million IU/m2on the 2nd and 3rd weeks. Recombinant interferon-alpha was administered intramuscularly at a dose of 6 million IU/m2once a week for 1 and 4 weeks of treatment, three times a week in the same dosage at 2 and 3 weeks at a dose of 9 million IU/m2three times a week for 5-8 weeks of the eight week cycle. 5-fluorouracil in this scheme was introduced in the form of a bolus intravenous injection at 5-8 weeks of treatment at a dose of 750 mg/m2(Van Herpen C. M. , Jansen R. L., W. H. Kruit, K. Hoekman, et al. Imunochemotherapy with interleukin-2, interferon-alfa and 5-fluorouracil for progressive metastatic renal cell carcinoma: a multicenter phase II study // Br. J Cancer, 2000 Feb; 82(4):772-6.23).

The treatment cycle was repeated in the presence of at least minimal effect from protestations foci - 2 (1 to 5). The average life of patients after treatment was 16.5 months. The average duration of recurrence-free period averaged 8.3 months. Partial positive answer, i.e. stabilization or a slight decrease in the size of metastatic foci were obtained from 11.8% of patients. Complete response to treatment, i.e. a complete regression of metastases was not obtained in any patient.

The disadvantages of this treatment are, first, the high incidence of toxic reactions of III-IV degree (55.8%) in the form of anorexia, nausea, vomiting, fever, toxic radiation; and secondly, the almost complete absence of the effect of treatment by a primary lesion, local recurrence and lymph node metastases.

In their study, the authors do not indicate the reason why they used such a complex scheme, but, apparently, the alternation of high and low doses of the drugs they wanted to avoid the synthesis of neutralizing antibodies inactivating recombinant interleukin-2 and interferon-alpha. However, the use of this method did not achieve significant results.

The technical result of the present invention is to UDL the system anaesthesia and locoregional anaesthesia immunotherapy.

According to the invention this result is achieved by the fact that the patient renal cell cancer produce embolization of renal artery particles avalon, hemostatic sponges and metal spirals with the simultaneous introduction of its 5-fluorouracil at a dose of 1 g and interferon-alpha in a dose of 12 million ME. And postembolization period, after two or three days, intravenously administered recombinant interleukin-2, alternating with intramuscular interferon-alpha in a dose of 3 million IU/m2within three weeks. As recombinant interleukin-2 it is advisable to use the drug Roncoleukin that is administered in a single vine 500 thousand IU intravenous drip in 400 ml of physiological solution with 8 ml of 10% albumin. When reaching the regression of metastases and reduce tumor size appropriate for the nephrectomy.

Doing professionally for many years the treatment of renal cell cancer, we have performed different regimens of immunotherapy with the use of Roncoleukin, interferon-alpha and 5-fluorouracil in different dosages. In particular, one group of patients received recombinant interferon-alpha is the most commonly used dosage to 9 million IU/m23 times in nedelki, nausea, vomiting, and, in addition, failed to obtain a significant effect on primary tumor and regional lymph nodes.

In the future, we conducted a combined therapy, including oily chemo-embolization of the renal artery and systemic immunotherapy with interferon-alpha in dosages 9,6,3 million IU/m2entered according to the scheme described for the first group. As preparation for chemoembolization we have chosen 5-fluorouracil. For gimigiano embolization of this drug was not used because, first, he does not possess both the properties of oil and water solubility, which is one of the main requirements to the drug used for these purposes, and secondly, it was traditionally thought that the active metabolites of 5-fluorouracil are formed only in the liver. Despite the above limitations, we decided to try to enter in the renal artery it is 5-fluorouracil, since it is known that he was at least minimal activity in tumors that are resistant to other types of chemotherapy, but as embolisate to use a non-fat basis, as when gimigiano embolization, and avalon, hemostatic sponge and metal spiral.

In the result of commersonia size of primary tumour by 50% or more and in some cases reduce the size of regional lymph nodes, and found no significant differences in treatment effectiveness in the use of high and low doses of interferon-alpha. In the further part of the interferon-alpha we have introduced directly into the renal artery, at the same time embolizarea her.

In the group of patients who were treated by the above method was able to achieve a significant reduction in the size of the primary lesion, the regression of metastases in regional lymph nodes and tumor necrosis 90% or more in patients who were subsequently operated.

For doing in the renal artery, we used different dosages, however, according to our observations the combination of 12 million IU of interferon-alpha and 1 g of 5-fluorouracil is an optimum ratio for maximum therapeutic effect with minimal toxicity.

In the process immunochemotherapy all patients we investigated the performance of immunological indexes, in particular, CD3 - the total number of lymphocytes, CD4 T-helper cells, CD8 - cytotoxic lymphocytes, CD 16 - natural killer cells, CD95 - apoptotic cells, and IFN-alpha interferon-alpha, TNF-Alfa - tumor necrosis factor alpha. According to our observations, conducting immune the surrounding key role in antitumor protection. At the same time, we have shown that the introduction of the scheme of Roncoleukin compensates for the negative impact of interferon-alpha and 5-fluorouracil on the immune system. Roncoleukin we used in the recommended dosage, there are 500 thousand ME intravenously over 4 hours Introduction to the patient on immunity and interferon-alpha in one day lead to severe toxic reactions in the form of fever and myalgias, we went to the interchange of these drugs. The total dose of Roncoleukin also chosen empirically. We have shown that the greatest efficiency of the product is determined by its impact on the indicators of immunity is achieved using a total dose of 5-6 million ME. Further increase in dose leads to severe side effects and does not increase the effectiveness of treatment.

Thus, having analyzed the results of treatment of patients, we concluded that the optimum treatment scheme is the introduction in the renal artery of 5-fluorouracil at a dose of 1 g and interferon-alpha in a dose of 12 million ME with simultaneous embolization in combination with systemic interferon-alpha in a dose of 3 million IU/m2and Roncoleukin in a single dose of 500 thousand ME to a total dose of 5.5 million ME on cerebus is and tumor tissue more than 90% and the regression of regional lymph nodes.

The method consists in the following.

A patient with a tumor on admission to the clinic is made obscenites examination, including computer tomography, ultrasound, isotope and x-ray examination, resulting in a set stage of the disease. Next, produce diagnostic angiography and if a satisfactory blood supply to the tumor site produce embolization of renal artery avalona, hemostatic sponge and metal spirals with the simultaneous introduction of its 5-fluorouracil and interferon-alpha. In postembolization period, 2-3 days, begin the introduction of Roncoleukin (recombinant interleukin-2) in a dose of 500 thousand IU, alternating with intramuscular interferon-alpha in a dose of 3 million IU/m2In the future, patient check-up examination every three months and if there is evidence of disease progression or renal artery recanalization, repeat the treatment. When reaching the regression of metastases and tumor shrinkage patient produce nephrectomy.

The essence of the method is illustrated by examples.

Example 1. Patient S., 1960 R. the History N 101. He entered clino place of residence, where by ultrasound had revealed a tumor of the right kidney, and therefore was sent to cnerry for further evaluation and treatment.

When the medical examination revealed the following changes:

12.01.1999. Ultrasonography. In the right kidney in the upper third is determined by education h cm beyond the contour of the kidney. At the gate right kidney is rendered increased to 2 cm in diameter lymph node. Left kidney: parenchyma is not changed, cavitary system is not extended. Bladder - without pathological changes. The liver is homogeneous. The bile ducts are not dilated. Pancreas - without features. Prostate HH mm homogeneous density.

12.01.1999. Radiograph of the lungs. Without pathology.

14.01.1999. Computed tomographic study. The left kidney is without features. In the right kidney is determined by education dimensions HH cm, heterogeneous density, located at the lateral edge of the outside contour of the body. The lower Vena cava is not extended. At the gate of the kidneys is determined by the node about 2.5 cm in diameter. At the level of L1-L2 (the first and second lumbar vertebrae) is defined chain of lymph nodes up to 1.5 cm in diameter.

15.01.1999. Osteocrin ezotericheskogo type. The left kidney - without a pathology.

18.01.1999. Indirect lymphoscintigraphy. Not visible iliac and paraaortal lymph nodes on the right. The rest - without a pathology.

20.01.1999. Scintigraphy of the liver and spleen. Without pathology.

As a result of the examination diagnosed with a tumor of the right kidney T2 N1 MO, i.e. the patient has a tumor more than 7 cm in diameter in the presence of metastases in regional lymph nodes and no distant metastases.

Given the patient has a tumor of the right kidney of the big sizes, it was decided to perform diagnostic angiography and when a satisfactory blood supply to the lesion to perform embolization of the right kidney with the simultaneous introduction of 5-fluorouracil and interferon-alpha and postembolization period to a course of immunotherapy Ronkoleykin and interferon-alpha.

25.01.1999. Aortography. Arteriography and embolization of the right kidney.

On angiograms revealed: the projection of the medial third of the right kidney is determined hypervascular education dimensions htm containing abnormal blood vessels and extravasate. The accumulation of contrast agent in this area is uneven. The Venosa is SUP>3avalon and one metal spiral with simultaneous introduction into the renal artery of interferon-alpha - ME 12 million, 5-fluorouracil - 1, control angiograms of blood supply in the projection of the right kidney is missing.

With 27.01.1999 on 17.02.1999 was conducted immunotherapy course Ronkoleykin and interferon-alpha. The patient's height 172 cm, weight 78 kg body - 2.2 m - indicator, calculated according to the nomogram given the growth and mass. The dose of interferon-alpha for a single injection - 6.6 million IU (3 million IU/m2). Roncoleukin was introduced by ME 500 thousand intravenous drip in 400 ml of saline solution by adding 8 ml of 10% albumin for 4 hours every other day, alternating with intramuscular 6.6 million IU of interferon-alpha. Immunotherapy course satisfactorily.

19.02.1999. Discharged with recommendations for follow-up examination after three months.

20.05.1999. Re-hospitalization in cnerry. The history N 958.

When the medical examination revealed the following changes:

21.05.1999. Ultrasonography. In the right kidney in the upper third is determined by education 5x6 cm beyond the contour of the kidney. Left kidney: parenchyma is not changed, cavitary system is not extended. Limpet the AI. Prostate HH mm, homogeneous density. Bladder - without pathological changes. Compared with ultrasound from 12.01.1999 - decrease in size with h cm to 5 × 6 cm, and reducing the size of the lymph node at the gate of the right kidney.

21.05.1999. Radiograph of the lungs. Without pathology.

24.05.1999. Computed tomographic study. The left kidney is without features. In the right kidney is determined by education dimensions HH cm, heterogeneous density, located at the lateral edge of the outside contour of the body. The lower Vena cava is not extended. Compared with the data from CT 14.01.1999 - HH cm - shrinking education.

26.05.1999. Osteointegrated - without a pathology.

26.05.1999. Angioprotective. The left kidney normal shape and position. The right is also accumulates RN, but less (saved in the bloodstream Ambrosiano kidney). In angiopathy: left - the inflow and outflow of normal, right inflow and outflow is less than three times.

28.05.1999. Indirect lymphoscintigraphy. Not visible iliac and paraaortal lymph nodes on the right. The rest - without a pathology.

31.05.1999. Scintigraphy of the liver and spleen. Without pathology.

Given that according to ang is alizatio right kidney and repeat the course of treatment.

7.06.1999. Arteriography and demonizacija right kidney.

Control angiograms compared with angiograms from 25.01.1999 the size of the tumor of the right kidney decreased with him to 7x7 see In the lateral part of the tumor vascularization is missing. The right renal artery recanalization.

Performed demonizacija right kidney 0.5 cm3avalon, 0.5 cm3hemostatic sponges and two metal spirals with the introduction renal artery 1.0 g of 5-fluorouracil and 12.0 million IU of interferon-alpha. Control angiograms of blood supply in the projection of the right kidney is missing.

With 9.06.1999 on 30.06.1999 was conducted immunotherapy by Ronkoleykin and interferon-alpha according to the method described above. Immunotherapy course satisfactorily.

5.07.1999. Discharged with recommendations for follow-up examination after three months.

7.10.1999. Hospitalized in cnerry. The history N 1127. When the medical examination revealed the following changes:

7.10.1999. Ultrasonography. In the right kidney in the upper third is determined by education 5x5 cm beyond the contour of the kidney. Lymph nodes are not enlarged. The liver is homogeneous. The bile ducts are not dilated. Pancreas - Bena system is not extended. Bladder - without pathological changes. Compared with ultrasound data from 12.01.1999 and 21.05.1999 - determined size reduction education right kidney with h cm up to 5x5 cm, as well as reducing the size of the lymph node at the gate of the right kidney.

7.10.1999. Radiograph of the lungs. Without pathology.

11.10.1999. Computed tomographic study. The left kidney is without features. In the right kidney is determined by education dimensions HH.5 cm, heterogeneous density, located at the lateral edge of the outside contour of the body. The lower Vena cava is not extended. Compared with the data from CT 14.01.1999 and 24.05.1999 is a small decrease in the size of the formation and regression of enlarged lymph nodes.

14.10.1999. Osteointegrated - without a pathology.

14.10.1999. Angioprotective. The left kidney normal shape and position. The right function is missing.

18.10.1999. Indirect lymphoscintigraphy. Without pathology.

20.10.1999. Scintigraphy of the liver and spleen. Without pathology.

Considering that the patient was able to reduce the size of the tumor and regional lymph nodes, decided to make nephrectomy.

26.10.1999. Operation: pravesh lymph nodes were found. The kidney is dramatically reduced in size, thick consistency.

2.11.1999. The histological conclusion. 0-144604-611. Tumor size 4.HH see Renal cell cancer. About 95% of the tumor necrotization.

17.11.1999. Discharged with recommendations for follow-up examination after three months.

18.02.2000. The patient at the outpatient reception in cnerry.

During the examination in outpatients revealed the following changes:

14.02.2000. Ultrasonography. Left kidney: parenchyma is not changed, cavitary system is not extended. Lymph nodes are not enlarged. The liver is homogeneous. The bile ducts are not dilated. Pancreas - without a pathology. Prostate HH mm, homogeneous density. Bladder - without pathological changes. In the area of the bed right kidney pathological entities is not defined.

Osteointegrated 15.02.2000, angioprotective 15.02.2000, lymphoscintigraphy 17.02.2000, scintigraphy of the liver and spleen 18.02.2000, chest x-ray lung 14.02.2000 is unchanged.

Recommended re-examination after three months.

19.05.2000. The patient at the outpatient reception in cnerry.

During the examination in outpatients revealed the following change in tegrate liver and spleen 19.05.2000, computer tomography 17.05.2000, chest x-ray lung 15.05.2000 - without dynamics.

Recommended re-examination after three months.

28.08.2000. The patient at the outpatient reception in cnerry.

During the examination in outpatients revealed the following changes:

Ultrasound 21,08.2000, osteointegrated 25.08.2000, angioprotective 25.08.2000, lymphoscintigraphy 23.08.2000, scintigraphy of the liver and spleen 24.08.2000, chest x-ray lung 21.08.2000 is unchanged.

Recommended re-examination after three months.

27.11.2000. The patient at the outpatient reception in cnerry.

During the examination in outpatients revealed the following changes:

Ultrasound 20.11.2000, osteointegrated 24.11.2000, angioprotective 24.11.2000, lymphoscintigraphy 23.11.2000, scintigraphy of the liver and spleen 21.11.2000, chest x-ray lung 20.11.2000 is unchanged.

Recommended re-examination after three months.

2.03.2001. The patient at the outpatient reception in cnerry.

During the examination in outpatients revealed the following changes:

Ultrasound 23.02.2001, osteointegrated 28.02.2001, angioprotective 28.02.2001, lymphoscintigraphy 26.02.2001, scintigraphy of the liver and spleen 1 month.

Thus, embolization of the renal artery with simultaneous introduction of 5-fluorouracil, interferon-alpha and subsequent systemic immunotherapy reduced the size of primary tumor, regional lymph nodes and to achieve a 95% tumor necrosis. The patient is kept under observation until the present time. Remission period is 29 months. The duration of recurrence-free period of 20 months.

Example 2. A patient 1933 R. for the First time he entered the urology Department of cnerry 7.04.1999. The history N 985. From the anamnesis it is known that in the last three months have pointed to the rise in body temperature to 38oPredominantly in the evening, and therefore appealed to the district hospital, where, according to ultrasound examination revealed a tumor of the left kidney. Sent to cnerry for further evaluation and treatment.

When the medical examination revealed the following changes:

8.04.1999. Ultrasonography. The left kidney is determined by education h cm with an area of decay in the center. Determined increased paraaortal lymph nodes in level LI-L2 (the first and second lumbar vertebrae) to 1.5 cm in diameter. Bladder - without pathological changes. The liver is homogeneous. Gall FR is CCA: parenchyma is not changed, abdominal system is not extended.

8.04.1999. Radiograph of the lungs. On survey radiographs of the chest in the left lung, there are two rounded education with a diameter of 3 cm and 0.3 cm, with a fairly clear boundaries, not related to the pleura and mediastinum. In the right light - the single node at the apex of about 4 cm in diameter, with clear contours, rounded shape. Enlarged lymph nodes at the root and the mediastinum is not defined. The sinuses are free.

12.04.1999. Computed tomographic study. The right kidney is without features. Is determined by a giant (HC cm) heteroplasmy hilly tumor of the left kidney, pushing back the spleen and tail of the pancreas. The lower Vena cava is not extended. At the level of L1-L3 is determined by the chain of lymph nodes up to 3.0 cm in diameter. Fatty liver.

14.04.1999. Osteointegrated - without a pathology.

14.04.1999. Isotope renography. The right kidney - without a pathology. The left function is missing.

16.04.1999. Indirect lymphoscintigraphy. Not visible paraaortal lymph nodes on both sides. The rest - without a pathology.

20.04.1999. Scintigraphy of the liver and spleen. Without pathology.

In resultr, not germinating in neighbouring authorities, with the presence of metastases in regional lymph nodes and multiple metastases in the lungs.

Given the presence of the patient tumor of the left kidney of large size and multiple metastases in the lungs, it was decided to hold embolization of the kidney with the introduction in the renal artery of 5-fluorouracil and interferon-alpha on the basis of satisfactory blood supply to the tumor site with subsequent systemic immunotherapy order effects on metastatic lesions.

26.04.1999. Aortography. Selective angiography and chemoembolization left kidney.

On angiograms revealed: the left kidney krovosnabzhayutsya one artery. In the upper and middle thirds of it, the pathological formation of mixed vascularization beyond the upper and lateral contours, with the centers of extravasation, tumor vessels, uneven accumulation of contrast agent. The size of the tumor I see there has been a sharp expansion of the left renal vein.

Performed embolization of the left kidney 0.5 cm3avalon, 0.5 cm3hemostatic sponge, 2 metal spirals. Introduced in the renal artery: interferon-alpha 12 million ME, 5-fluorouracil - 1, the pin is 60 kg The surface of the body 2 m2. The dose of interferon-alpha for a single injection - 6.0 million to ME.

With 28.04.1999 on 19.05.1999 was conducted immunotherapy by Ronkoleykin and interferon-alpha according to the method described in the previous example. Immunotherapy course satisfactorily.

24.05.1999. Discharged with recommendations for follow-up examination after three months.

30.08.1999. Re-hospitalized in SPERRY. The history N 3619.

When the medical examination revealed the following changes:

31.08.1999. Ultrasonography. The left kidney is determined by education 8h9 see Right kidney: parenchyma is not changed, cavitary system is not extended. Bladder - without pathological changes. The liver is homogeneous. The bile ducts are not dilated. Pancreas - without features. Spleen - without pathological changes. Paraaortal lymph nodes are not enlarged. Compared with ultrasound data from 8.04.1999 a decrease in education h cm to 8h9 cm, and decrease paraaortal lymph nodes.

31.08.1999. Radiograph of the lungs. On survey radiographs of the chest in the left lung, there are two rounded education with a diameter of 2.0 cm and 0.3 cm, apex, about 1.5 cm in diameter, with clear contours, rounded shape. Enlarged lymph nodes at the root and the mediastinum is not defined. The sinuses are free.

Compared with x-rays from 12.04.1999 positive changes.

2.09.1999. Computed tomographic study. The right kidney is without features. Defined tumor of the left kidney HH cm, pushing back the spleen and tail of the pancreas. The lower Vena cava is not extended. Fatty degeneration of the liver. Lymph nodes at the level of research is not increased. Compared with the data from CT 12.04.1999 is determined by the reduction in tumor size (HH cm to HH cm) and the disappearance of the chain increased limtations nodes.

3.09.1999. Osteointegrated - without a pathology.

3.09.1999. Angioprotective. Is determined by the blood flow in both kidneys. Left - three times less.

6.09.1999. Indirect lymphoscintigraphy. Not visible paraaortal lymph nodes on both sides. The rest - without a pathology.

8.09.1999. Scintigraphy of the liver and spleen. Without pathology.

Due to the fact that according to engineerintegration opredelaetsa the blood flow in the left kidney, recommended conducting diabolical with the introduction of 5-fluorouracil and interfer the control angiograms compared with angiograms from 26.04.1999 the size of the tumor of the left kidney decreased with h cm to see h Recanalization of the left kidney and capsular arteries. Performed embolization of the left kidney hemostatic sponge 0.5 cm3, avalona 1 cm3two metal spirals to the left and renal capsular artery. Introduced: interferon-alpha - ME 12 million, 5-fluorouracil - 1, control angiograms of blood supply in the projection of the left kidney missing.

With 16.09.1999 on 7.10.1999 were immunotherapy by the method described above. Immunotherapy course satisfactorily.

11.10.1999. Discharged with recommendations for follow-up examination after three months.

17.01.2000. The patient on Aboltina cnerry.

During the examination in outpatients revealed the following changes:

11.01.2000. Ultrasonography. Right kidney: parenchyma is not changed, cavitary system is not extended. The left kidney is determined by education 9x9 see the Liver is homogeneous. The bile ducts are not dilated. Pancreas - without features. Spleen - without pathological changes. Paraaortal lymph nodes are not enlarged. Bladder - without pathological changes. Without dynamics compared with ultrasound from 31.08.1999.

11.01.2000. Radiograph of the lungs. Review of rencheng is freely clear boundaries, not related to the pleura and mediastinum. In the right light - the single node at the apex, about 1.5 cm in diameter, with clear contours, rounded shape. Enlarged lymph nodes at the root and the mediastinum is not defined. The sinuses are free.

Compared with x-rays from 31.08.1999 without dynamics.

13.01.2000. Computed tomographic study. The right kidney is without features. Defined tumor of the left kidney HH cm, pushing back the spleen and tail of the pancreas. The lower Vena cava is not extended. Fatty degeneration of the liver. Lymph nodes at the level of research is not increased. Without dynamics compared to CT from 2.09.1999.

12.01.2000. Osteointegrated - without a pathology.

12.01.2000. Angioprotective. Right - without a pathology. The left kidney function is not defined.

14.01.2000. Indirect lymphoscintigraphy. Not visible paraaortal lymph nodes on both sides. Otherwise - without pathology

Recommended re-examination after three months.

17.04.2000. The patient at the outpatient reception in cnerry.

When surveyed in amolatina mode revealed the following changes:

Ultrasound 10.04.2000, osteointegrated 12.04.2000, onlineproscar survey radiographs of the chest in the left lung, there are two rounded education with a diameter of 1 cm and 0.3 cm, with a fairly clear boundaries, not related to the pleura and mediastinum. In the right light - the single node at the apex of about 1 cm in diameter, with clear contours, rounded shape. Enlarged lymph nodes at the root and the mediastinum is not defined. The sinuses are free.

Compared with x-rays from 11.01.2000 positive trend (decrease in the size of metastatic lesions in both lungs about 0.5 cm in diameter).

Recommended re-examination after three months.

28.08.2000. The patient at the outpatient reception in cnerry.

When surveyed in amolatina mode revealed the following changes:

Ultrasound 25.08.2000, osteointegrated 25.08.2000, angioprotective 25.08.2000, indirect lymphoscintigraphy 23.08,2000, the roentgenogram of lungs 23.08.2000 - without dynamics.

Recommended re-examination after three months.

27.11.2000. The patient at the outpatient reception in cnerry.

When surveyed in amolatina mode revealed the following changes:

Ultrasound 21.11.2000, osteointegrated 23.11.2000, angioprotective 23.11.2000, indirect lymphoscintigraphy 24.11.2000, scintigraphy of the liver and spleen 24.11.2000, chest x-ray lung 21.11.2000 no change.) - Rev. Mr. cnerry.

When surveyed in amolatina mode revealed the following changes:

Ultrasound 26.02.2001, osteointegrated 28.02.2001, angioprotective 28.02.2001, indirect lymphoscintigraphy 1.03.2001, scintigraphy of the liver and spleen 1.03.2001, chest x-ray lung 26.02.2001, computed tomography 2.03.2001 no change

Recommended re-examination after three months.

Thus, as a result of chemoimmunotherapy by the proposed method was able to reduce the size of the kidney tumor, to reduce the volume of lung metastases, as well as to reduce the size of regional lymph nodes. The duration of remission of the disease is 25 months.

To date, the proposed method treated 31 people. 10 people had isolated metastatic lung damage. As a result of treatment 1 person showed complete regression of metastases, and 4 had a decrease in the size of metastatic foci and 4 - stabilization process. All patients from this group observed a reduction of primary tumor size by 50% or more. 10 people to date operated. Of these, 6 to the beginning of treatment was not determined well as regional and distant metastases, and 4 was suspected Macartney embolization in our technique was able to achieve reduction in size of lymph nodes, therefore, patients were considered resectable. All operated patients were able to achieve necrosis of more than 90% of the tumor site. In this group the average duration of remission was 22 months. 5 patients were noted to have metastatic lymph nodes. These patients are under observation from 8 to 29 months. As a result of the treatment they have managed to achieve the stabilization process. 4 people were found to have metastatic lungs and bones at the same time. Three of them are the result of the treatment was able to stabilize the process. One notes the progression of bone metastases. 2 patients had a metastatic lesion of the liver. They both are under the supervision of 7 months. Both slow the progression of the process.

The method of treatment in comparison with analogues has the following advantages:

1) lengthening remission and duration of recurrence-free period of up to 24 months or more, while in the known analogues of this period was 14-16 months;

2) achieve necrosis of tumor tissue, comprising 90% or more, while in other types of embolization, the average is a maximum of 30-40%;
LINEITEM surgical treatment of these patients, while in the known analogues was achieved recourse only pulmonary metastases.

The method is developed and has been clinically tested at the urology Department of cnerry in 31 patients with a positive result.

1. A method of treating renal cell carcinoma by recombinant interferon-alpha, recombinant interleukin-2 and 5-fluorouracil, wherein the interferon-alpha and 5-vorurteil injected directly into the renal artery with simultaneous embolization her, and interferon-alpha is used in a dose of 12 million IU, 5-fu at the dose of 1 g, and 2-3 days after embolization of intravenously administered recombinant interleukin-2 once in two days, alternating with intramuscular interferon-alpha in a dose of 3 million IU/m2within three weeks, and if necessary, repeat the treatment.

2. The method according to p. 1, characterized in that as recombinant interleukin-2 drug use Roncoleukin that is administered in a dose of 500 thousand IU intravenous drip in 400 ml of saline solution by adding 8 ml of 10% aqueous solution of albumin for 4 h

3. The method according to p. 1, characterized in that at achieving regression of metastases and the

 

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< / BR>
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< / BR>
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< / BR>
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