RU2565106C1 - Method of treating prostate cancer permeating through bone - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: treating prostate cancer (PC) permeating through a bone is ensured by segmental radiation and loco-regional and local radiation therapy accompanied by hormone therapy. The segmental radiation is used in a single boost dose of 2 Gy daily 5 times a week to a total boost dose of 30-40 Gy. The amount of radiation is reduced then to the loco-regional exposure on the prostate and regional lymph nodes with reducing the single boost dose to 44-46 Gy. If the tumour stage is N1, whereas a sacral spine, sacral-ileac junctions, pubic and ischial bonesare involved, the loco-regional therapy is additionally conducted to the single boost dose of 50 Gy. That is followed by the local prostate exposure with average single boost dose fractionation of 3 Gy daily, 5 fractions a week in a mobile mode to the isoeffective normally fractionated total boost dose of 69-71 Gy.

EFFECT: complete and stable reduction of pain syndrome in all the treated patients, leaving the length of the treatment and prostate total boost dose unchanged, improved quality and span of life, 67,5% remission.

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Description

The invention relates to medicine, more specifically to oncology and urology, and may find application in the treatment of malignant neoplasms.

Prostate cancer (PCa) is one of the most common neoplasms in men in many countries of the world. In the structure of the incidence of malignant neoplasms of the male population of Russia in 2010, he took third place after lung and skin cancer with melanoma and amounted to 11%, and in 2012 - he already moved to second place and amounted to 12.1% in the structure of cancer incidence.

In Russia, due to poorly developed screening measures, more than 50% of patients with prostate cancer still seek medical help as early as stage 3-4 of the disease, and about 18% in the presence of metastases. In addition, after the treatment, taking into account the “osteophilicity” of prostate cancer, some patients continue to experience progression of the disease with dissemination in the bone.

The standard of treatment for disseminated prostate cancer is currently considered hormone therapy (GT). Remote radiation therapy (DLT) for bone metastases is usually prescribed only for symptomatic local anesthetic treatment of bone metastases in patients with hormone-refractory form of prostate cancer.

Considering the known tropism of prostate cancer dissemination to bone tissue and the anatomical features of venous outflow from the prostate (RV), which contribute to the sedimentation of metastases mainly in the bones of the pelvis, sacro-lumbar spine and the upper third of the femur (in 42-68% of cases), we previously For the treatment of this severe category of patients, a method of segmental irradiation of the pelvic bones (COT) in combination with locoregional and local irradiation of the pancreas against the background of GT was proposed. We could not find other studies in this direction, and the method we developed was widespread in medical practice [V. Metelev et al. “The Efficiency of Radiation Therapy in Patients with Generalized Prostate Cancer” // Medical Radiology and Radiation Safety. - 2005. - T.50 - No. 6 - P.41-46].

This method is taken by us as a prototype [Metelev V.V. The place of radiation therapy in the combined treatment of patients with prostate cancer: Abstract. dis ... doctor. honey. Sciences - St. Petersburg, 2005 - 40 p.].

According to this method, from 1992 to 2005 at the Federal State Budgetary Institution “Russian Scientific Center of Radiology and Surgical Technologies (RSCRHT)” of the Ministry of Health of the Russian Federation (formerly TsNIRRI), palliative DLT was performed for 205 patients with morphologically verified prostate cancer with multiple bone metastases (T1-4N0-1M1v) associated with severe pain. Irradiation was carried out in combination with GT. In addition to the bones of the pelvic girdle, as a rule, the lower lumbar spine and the upper third of the femur, i.e. the areas that are the source of indomitable pain, fall into the radiation exposure zone. Remote irradiation was carried out on linear electron accelerators in the bremsstrahlung mode with a limiting energy of 6 to 18 MeV.

At the first stage, patients underwent irradiation of a body segment with the capture of all the bones of the pelvis (COT). COT was carried out through two open opposite fields (0 ° and 180 °) from the iliac crests (with the capture of L4 according to indications) to the level of the lower edge of the ischial tubercles (or the border of the upper and middle third of the femurs, if interested). Moreover, in a single focal dose (ROD) of 2 Gy daily 5 times a week, 20 Gy were delivered segmentally to the pelvis. Then, the irradiation volume was reduced to a locoregional (second stage), bringing the total focal dose (SOD) to the pancreas and regional lymph nodes to 44-46 Gy. In this case, irradiation was used through two opposite fields (front and back), 15-16 × 16-20 cm in size with the following boundaries: upper - L ₅ -S ₁ , lower - lower edge of the ischial tubercles, lateral - 1.0-1, 5 cm outwards from the pelvic ring on each side. In case of damage to the sacral spine, sacroiliac joints, pubic and ischial bones, as well as stage N1, SOD was brought locally to 50 Gy. Local irradiation of the pancreas was carried out by the third stage by average fractionation in ROD of 3 Gy daily of 5 fractions per week in mobile mode to an SOD of isoeffective 66-72 Gy of conventional fractionation.

If there is a pain syndrome or the threat of pathological fractures in the area of bone metastases outside the pelvis, their irradiation was carried out in parallel with locoregional or local exposure to enlarged fractions in the ROD of 3-6 Gy daily to an SOD of isoeffective 30-65 Gy, depending on the location of the metastases.

Irradiation of the primary focus to significant therapeutic doses was justified to exclude further “overseeding” of distant bone metastases, prevention of local relapses. In addition, it improved the quality of life of patients suffering from aggravating local manifestations of the disease.

The effectiveness of the COT technique in patients with generalized prostate cancer in combination with locoregional and local pancreatic irradiation was evaluated by studying the immediate and long-term results of treatment.

The immediate effect was evaluated by comparing the need for analgesic drugs, ultrasound data, the level of specific prostatic antigen (PSA) and alkaline phosphatase in the blood before treatment and after it. To assess the long-term results of treatment, the weather direct direct survival of the patients and the average life expectancy of the dead patients were calculated.

An immediate positive effect was achieved in the majority (93.2%) of patients. It was manifested by a marked reduction or disappearance of bone pain, which led to a significant reduction in the need for the vast majority of patients, including the complete abolition of analgesic drugs in 73.2% of patients. A significant decrease in pancreatic volume by an average of 34.7 ± 2.43% according to the results of ultrasound was observed in 75.6% of patients, stabilization (volume did not change significantly) - in 13.7%, and an increase in gland volume was recorded in 10.7% of cases .

When assessing the objective direct effect on the dynamics of the PSA level: PSA normalized (complete answer) in 107 (52.2%) cases; significantly decreased (by more than 50% - a partial answer) in 76 (37.1%) cases; decreased by less than 50% (partial response) in 12 patients (5.9%) and increased compared with the initial (progression) in 10 (4.8%) cases.

Thus, the response rate (biochemical remission) was 95.2%. Moreover, complete remission was observed in 52.2% of cases.

Evaluation of long-term results, therefore, showed that with generalization of prostate cancer, palliative and symptomatic DLT not only improved the quality of life of patients, but also increased its duration.

Long-term indicators of 3- and 5-year survival were 61.5% and 31.7%, respectively. At the same time, the 8-year survival rate is 10.2%, and the 10-year survival rate is 3.9%.

As our observations showed, the tolerance of COT to SOD of 20 Gy in combination with locoregional and local pancreatic irradiation was satisfactory.

Our further observations of patients treated by this method showed that with SOT the addition of SOD 20 Gy nevertheless did not always lead to a complete relief of bone pain in patients, namely in 73.2%.

The technical result of the present invention is to relieve pain in the bones of a significantly larger number of incurable patients by increasing the total focal dose during their segmental irradiation.

This result is achieved by the fact that in the known method of treating prostate cancer with dissemination in the bone, including segmental irradiation and local and local radiation therapy with hormone therapy, and in the presence of pain or the threat of pathological fractures in the area of bone metastases outside the pelvis - their irradiation in parallel with locoregional or local irradiation of aggregated fractions in ROD of 3-6 Gy daily to an SOD of isoeffective 30-65 Gy of conventional fractionation depending on the location of metastases, according According to the invention, segmental irradiation is carried out to achieve a total focal dose of 30-40 Gy, bringing SOD in the pancreas to an isoeffective 69-71 Gy of conventional fractionation.

Engaged in the professional treatment of prostate cancer, including inoperable patients with bone metastases, and having extensive experience with segmental irradiation of such patients and long term monitoring of their condition, we decided to try to completely eliminate the pain syndrome to try to increase the total doses with SOT first to SOD 30 Gy, and depending on patient tolerance and up to 40 Gy. The increase in SOD at the stage of COT, in our opinion, is justified by the fact that, according to our observations, the further progression of the disease is almost always associated with a metastatic process in the bones. And therefore, an increase in the focal dose to the area of bone metastases in the pelvis leads to a more frequent elimination of bone pain and a longer stabilization of the tumor process. In this case, the duration of treatment and the total radiation load on the patient do not increase, because the local-regional and local zones are included in the volume of COT.

Our results of such therapy exceeded our expectations. Over the past 4 years (2011-2014) with the use of SOD 30 Gy while performing SOT, we treated 33 patients, 2 patients received 34 Gy at this stage, 1 patient 36 and 38 Gy and 3 patients 40 Gy . 33 out of 40 patients are alive. In this case, an increase in SOD from 30 to 40 Gy in the case of satisfactory tolerance of such irradiation was carried out until the pain was completely relieved. Due to the differentiated increase in SOD at the stage of SOT to 30-40 Gy, it was possible to stop pain in the pelvic bones in all 40 patients. When assessing the objective direct effect on the dynamics of the PSA level, a complete response (PSA normalized) was achieved in 27 (67.5%) cases, a partial response (PSA decreased) in 7 (17.5%) cases, and the response rate (biochemical remission) amounted to 85%. In this case, complete remission was observed in 67.5% of cases (in the prototype - in 52.2%). Obtaining such unexpected positive treatment results for us was the subject of the present invention.

The essence of the method is as follows.

At the first stage, against the background of traditional hormone therapy, patients with prostate cancer with dissemination of bone undergo irradiation of a body segment with capture of all pelvic bones through two large open opposite fields (0 ° and 180 °) from the iliac crests (with capture of L4 according to indications) to the level of the lower edge sciatic tubercles (or the borders of the upper and middle third of the femur, if interested), sizes 30-34 × 21-24 cm in the genus 2 Gy daily 5 times a week, depending on tolerance to SOD 30-40 Gy. At the second stage, the volume of exposure is reduced to locoregional with bringing SOD to the pancreas and regional lymph nodes to 44-46 Gy. In this case, irradiation is used through two opposite fields (front and back), measuring 15-16 × 16-20 cm with the following boundaries: the upper one is L ₅ -S ₁ , the lower one is the lower edge of the ischial tubercles, the lateral ones are 1.0-1, 5 cm outwards from the pelvic ring on each side. In case of damage to the sacral spine, sacroiliac joints, pubic and ischial bones, as well as stage N1, SOD is brought up to 50 Gy locally. The third stage is the local irradiation of the pancreas by average fractionation in ROD of 3 Gy daily of 5 fractions per week in a mobile mode to an SOD of an isoeffective 69-71 Gy of conventional fractionation.

If there is a pain syndrome or the threat of pathological fractures in the area of bone metastases outside the pelvis, their irradiation is carried out in parallel with locoregional or local exposure to enlarged fractions in the ROD of 3-6 Gy daily to an SOD of isoeffective 30-65 Gy, depending on the location of the metastases.

The essence of the method is illustrated by examples.

EXAMPLE 1. Patient F., born in 1956, has been observed at the Federal State Budget Scientific Center of the Russian Center for Science and Technology with the diagnosis of prostate cancer of the IV st.

From the anamnesis: Considers himself ill since July 2011, when pain in the cervical spine and then in other parts of the skeleton first appeared. Examination in the oncospacer at the place of residence on osteoscintigrams revealed multiple pathological hyperfixation of the radiopharmaceutical in the bones of the skeleton, and on MRI and CT revealed metastases in the thoracic, lumbosacral spine, ribs, and pelvic bones. PSA from 09/01/2011 - 23.43 ng / ml.

In 122 MSC (St. Petersburg), on September 15, 2011, a pancreatic biopsy was performed. The histological conclusion No. 111468: pancreatic adenocarcinoma. Gleason score 9 (5 + 4). According to the results of the examination (MRI, ultrasound, TRUS, CT, osteoscintigraphy, chest and bone x-ray), stage T3bNXM1b (oss) G3-4 - stage IV with severe pain in the bones of the skeleton was established.

In October 2011, GT was started in the regime of maximum androgen blockade (Casodex 50 mg - 1 tablet 1 time daily + 45 mg eligard subcutaneously), from 11.24.2011 - bone resorption inhibitors (zoledronic acid 4 mg monthly) with a recommendation Consult a radiologist at the Russian Science and Technology Center.

From 07/02/2012 to 03/19/2012, at the clinic of the Federal State Budget Scientific Center of the Russian Center for Science and Technology, against the background of GT and bone resorption inhibitors, a palliative course of DLT in SOD was performed at the SOT stage - 30 Gy, locoregional - 40 Gy and locally on the pancreas in SOD isoeffective 71 Gy. The patient underwent satisfactory treatment with complete relief of the pain syndrome and a decrease in the PSA level from 03/19/2012 to 1.66 ng / ml.

Currently, the patient is alive, no complaints, according to the results of osteoscintigraphy from 05/22/2014 - stabilization of multiple metastases in the bones of the skeleton.

EXAMPLE 2

Patient R., born in 1962, is under observation at the Federal State Budget Scientific Center of the Russian Center for Science and Technology with 04.04.2012 with a diagnosis of Prostate Cancer, IV st.

From the anamnesis: Considers herself ill since February 2012, when severe back pain appeared, for which he turned to a neurologist at the Scandinavia clinic. According to the results of MRI of the thoracic and lumbosacral spine, multiple metastases with signs of spinal cord compression were revealed. Directed to the urologist. In connection with the increase in PSA to 300 ng / ml (dated 03.03.12), a biopsy of the pancreas was performed on 13.03.2012. The histological conclusion No. K-310595-612: Pancreatic adenocarcinoma in 16 of 18 micropreparations. Gleason score 8 (4 + 4). Immediately after the biopsy, the patient's legs were taken away, signs of lower paraparesis appeared, and therefore the patient was forced to use a gurney. According to the results of the examination (MRI, ultrasound, TRUS, osteoscintigraphy, chest and bone x-ray), stage T4N1M1b (oss) G3 - stage IV was established.

On March 13, 2012, HT was started in the regime of maximum androgen blockade (Casodex 50 mg - 1 tablet 1 time daily + zoladex 3.6 mg subcutaneously) and bone resorption inhibitors (zoledronic acid 4 mg monthly). The patient was recommended to consult a radiologist at the Russian Center for Science and Technology.

From 10.04.2012 to 05.29.2012, against the background of GT and bone resorption inhibitors, a palliative course of DLT in the SOD at the stage of the SOT - 40 Gy, locoregional - 50 Gy and locally in the pancreas in the SOD of isoeffective 69 Gy was performed at the clinic of the Federal State Budget Scientific Research Center for Chemistry and Chemistry. At the same time, local irradiation of metastases in the thoracic spine (Th2-11 inclusive) was performed in an SOD of isoeffective 34 Gy of conventional fractionation.

The patient underwent satisfactory treatment, with a complete relief of the pain syndrome, the reverse development of the phenomena of lower paraparesis (he began to walk on his own) and a decrease in the PSA level from 05/28/2012 to 0.11 ng / ml.

The patient is observed to date, in a stable condition, no complaints.

To date, the proposed method has treated 40 patients with a diagnosis of prostate cancer with dissemination in the bones of art. T2-4N0-1M1b (oss) G3-4 - stage IV with severe pain. All patients underwent SOT, while 33 received SOD 30 Gy, 2 - 34 Gy at this stage, 1–36 and 38 Gy and 3 patients — 40 Gy. 33 out of 40 patients are alive. The pain syndrome was stopped in all patients. During the observation of them in the period 2011-2014. of the 33 survivors to date, only three patients have pain outside the irradiation zones, for which additional DLT was performed.

The proposed method in comparison with the known has several advantages:

1. Complete and persistent relief of pain in all treated patients.

2. The method does not require an increase in the duration of treatment and SOD in the pancreas.

3. Significantly improves the quality of life of this severe category of patients with an increase in life expectancy.

The method was developed in the radiation therapy group of oncological urological diseases of the Federal State Budget Scientific Center of the Russian Center for Cardiology and Chemistry and passed clinical testing in 40 patients with a positive result.

Claims (1)

A method for treating prostate cancer with dissemination in bone, including segmental irradiation and local and regional and local radiation therapy with hormone therapy, characterized in that segmental irradiation is performed in a single focal dose of 2 Gy daily 5 times a week to a total focal dose of 30-40 Gy, further reduce the volume of exposure to locoregional with bringing the total focal dose to the prostate gland and regional lymph nodes to 44-46 Gy, and with tumor stage N1, damage to the sacral spine, cr stso-iliac joints, pubic and sciatic bones, additionally bring locoregionally to a total focal dose of 50 Gy, then the prostate gland is locally irradiated by medium fractionation in a single focal dose of 3 Gy daily of 5 fractions per week in mobile mode to a total focal dose of isoeffective 69-71 Gr ordinary fractionation.