RU2800325C1 - Method of diagnosing treatment response in patients with colorectal cancer liver metastases - Google Patents

Abstract

FIELD: medicine, oncology.

SUBSTANCE: invention can be used to evaluate the effectiveness of treatment in patients with colorectal cancer with liver metastases. The method is carried out by determining blood levels of oncomarkers of cancer-embryonic antigen (CEA) and complementary marker CA 19-9 before treatment, the results of which are summarized and then the sum of these indicators is determined after ongoing chemotherapy treatment. After that, a comparative assessment is made of the obtained sum of oncomarker concentration levels after treatment with the sum of oncomarker concentration levels obtained before the treatment. With a decrease in the sum of oncomarker concentration levels by more than 30% relative to the sum of oncomarker concentration levels before chemotherapy, it is assessed as a partial response to this treatment, that is, a decrease in the sum of the diameters of targeted metastatic foci and the appearance of new metastatic foci by more than 30% relative to the indicators before starting chemotherapy treatment. With an increase in the sum of indicators of the concentration levels of oncomarkers by more than 20% relative to the indicators of the sum of the levels of concentrations of oncomarkers before the ongoing chemotherapy treatment, it is evaluated as progression to this treatment, that is, an increase in the size of targeted metastatic foci and the appearance of new metastatic foci by 20% relative to the indicators before the start of the ongoing chemotherapeutic treatment. With a decrease in the sum of indicators of levels of concentration of oncomarkers by less than 30% or an increase by not more than 20% relative to the indicators of the sum of levels of concentrations of oncomarkers before chemotherapy treatment is evaluated as stabilization for this treatment, that is, a decrease in tumor formations by less than 30% or an increase not by more than 20% and the appearance of new lesions relative to the indicators before the start of the chemotherapy treatment. The invention provides an extension of the arsenal of technical means for evaluating the effectiveness of ongoing chemotherapy treatment in patients with colorectal cancer with liver metastases with high reliability at an early stage of chemotherapy treatment.

EFFECT: method allows to improve the overall survival of patients due to the early diagnosis of the progression of the tumor process.

1 cl, 1 tbl, 4 ex

Description

The invention relates to medicine, namely to oncology. It can be used to evaluate the effectiveness of ongoing treatment in patients with colorectal cancer with liver metastases.

The incidence of colon cancer is currently extremely high and tends to increase. Worldwide, colorectal cancer ranks fourth in prevalence and occurs in 9.7% of cases among all malignant diseases [George A T., Aggarwal S., Dharmavaram S., Menon A., Dube M, Vogler M, Foden P., Field A. Regional variations in UK colorectal cancer screening and mortality. Lancet. 2020, 392:277-278]. In 27.2% of patients during the initial visit, already advanced - the fourth stage of colon cancer was diagnosed. Synchronous liver metastases are detected in 15-50% of patients, and metachronous - in 35-45%, even against the background of systemic antitumor therapy [Jennie Engstrand, Henrik Nilsson, Cecilia Stromberg, Eduard Jonas, Jacob Freedman Colorectal cancer liver metastases - a population-based study on incidence, management and survival. BMC Cancer. 2018 Jan 15;18(1):78]. Metachronous metastases are found in 76-85.3% of patients during the first year after removal of the primary tumor, and within three years - in 83-97.5% of patients. At the same time, in 30-40% of patients, the liver is the only organ of metastasis [Jack Martin, Angelica Petrillo, Elizabeth C Smyth et al. Colorectal liver metastases: Current management and future perspectives. World J Clinic Oncol. 2020 Oct 24;11(10):761-808]. The use of systemic anticancer therapy is the standard treatment for unresectable liver metastases and is required in more than 70% of patients, although the effectiveness does not exceed 30%. In addition to systemic chemotherapy, regional chemotherapy methods have been introduced into clinical practice and are actively used in the treatment of patients from this group. However, an extremely important task is to adequately assess the effectiveness of the treatment for timely correction and improvement of treatment outcomes.

To date, for an objective assessment of the results of the effectiveness of drug therapy in patients with liver metastases, the RECIST (Response Evaluation Criteria in Solid Tumors), mRECIST (modified RECIST) criteria, which are proposed by the American Association for Liver Disease Research, are used. Less commonly used criteria are EASL (European Association for the Study of the Liver), developed by the European Association for the Study of Liver Diseases. The RECIST scale is based on the assessment of changes in the size and number of tumor formations; since 2009, the RECIST 1.1 version has been used [Jordan Levy, Jesse Zuckerman, Richard Garfmkle et al. Intra-arterial therapies for unresectable and chemorefractory colorectal cancer liver metastases: a systematic review and meta-analysis. HPB (Oxford). 2018 Oct; 20(10):905-915].

The criteria for evaluating mRECIST and EASL are based on the assessment of necrosis zones detected after chemotherapy in malignant liver tumors using computed tomography (CT) or magnetic resonance imaging (MPT) [Bruix J. Clinical Management of Hepatocellular Carcinoma. Conclusions of the Barcelona-2000 EASL Conference / J. Bruix, M. Sherman, J.M. Llovet et al. // J. Hepatology. 2001. - Vol. 35, no. 3. - P. 421-430]. In 2018, a group of domestic X-ray endovascular surgeons used the Choi criteria, which are based on the assessment of changes in the X-ray (densimetric) density of liver metastases on CT images, as an assessment of the results of regional chemotherapy. The authors concluded that the Choi criteria are more effective than the RECIST criteria in assessing treatment outcomes for colorectal liver metastases. The authors also noted that the size of lesions before treatment was not a prognostic factor, and that an initially higher density of liver metastases was associated with a more favorable treatment prognosis.

The disadvantages of the presented rating scales are the description of macroscopic changes in the size and number of liver metastases, and the values of biochemical blood parameters are not taken into account, which excludes early diagnosis of progression at the microscopic (subclinical) level and the possibility of a timely change in the line of chemotherapy, which entails a worse prognosis and a reduction in the life expectancy of patients.

Closest to the proposed invention is a method for evaluating the effectiveness of ongoing chemotherapy treatment according to the mRECIST scale. The mRECIST system (Modified Response Criteria for Solid Tumors to Treatment) assesses the degree of arterial blood supply in the tumor node. Target formations should have a linear size of more than 1 cm and even contours for reproducible measurements and accumulate a contrast agent in the arterial phase of the scan. The mRECIST criteria apply to CT and MRI. Non-target formations include nodes with uneven, fuzzy contours, including those after local therapy (embolization, ablation, destruction). The following criteria for different responses to ongoing treatment are distinguished: complete response to ongoing treatment - elimination of intratumoral accumulation of a contrast agent in the arterial phase of scanning in targeted foci; partial response to the treatment; decrease in the sum of diameters of viable (contrast-accumulating) tumor tissue >30%; stable disease - no changes classified as partial response or disease progression; disease progression - an increase in the smallest sum of diameters of viable (contrast-accumulating) tumor tissue> 20% [Fedash A.V., Lomovtseva KN., Kondrat'ev E.V., Blohin I.A., Galchina Yu.S. Treatment Response Evaluation in Hepatic Tumors using CT and MRI: Road Map for Radiologist MEDICAL VISUALIZATION 2017, V. 21, N6, pp. 49-62]. As in previous cases, the disadvantage of the known method is the visual determination of the effectiveness of ongoing drug therapy without taking into account the level of tumor markers, which makes it difficult to early diagnose the progression of the tumor process.

The technical result consists in expanding the arsenal of technical means for evaluating the effectiveness of ongoing chemotherapy treatment in patients with colorectal cancer with liver metastases with high reliability at an early stage of chemotherapy treatment.

The technical result is achieved by the fact that the evaluation of the effectiveness of ongoing chemotherapy treatment in patients with liver metastases of colorectal cancer is carried out by determining in the blood the concentration levels of oncomarkers of cancer-embryonic antigen (CEA) and complementary marker CA 19-9 before treatment, the results of which are summed up and then the sum of the concentration levels of oncomarkers of cancer-embryonic antigen (CEA) and complementary marker CA 19-9 is determined after of the ongoing chemotherapy treatment, after which a comparative assessment is made of the obtained sum of oncomarker concentration levels after the ongoing chemotherapy treatment with the sum of the oncomarker concentration levels obtained before the ongoing chemotherapy treatment and when the sum of the oncomarker concentration levels is normalized, provided that the sum of elevated levels before the start of the ongoing chemotherapy treatment is evaluated as a complete response, that is, the disappearance of all metastatic foci, to the ongoing chemotherapy treatment, with a decrease in the sum of oncomarker concentration levels by more than 30% relative to indicators of the sum of oncomarker concentration levels before the ongoing chemotherapy treatment is evaluated as a partial response to this treatment, that is, a decrease in the sum of the diameters of targeted metastatic foci and the appearance of new metastatic foci by more than 30% relative to the indicators before the onset of chemotherapy, with an increase in the sum of oncomarker concentration levels by more than 20% relative to the sum of oncomarker concentration levels before the ongoing chemotherapy treatment, it is evaluated as progression to this treatment, that is, an increase in the size of targeted metastatic foci ov and the appearance of new metastatic foci by 20% relative to the indicators before the start of the ongoing chemotherapy treatment and with a decrease in the sum of the levels of oncomarker concentrations by less than 30% or an increase by no more than 20% relative to the sum of the levels of the concentrations of oncomarkers before the ongoing chemotherapy treatment is evaluated as stabilization for this treatment, that is, a decrease in tumor formations by less than 30% or an increase by no more than 20% and the appearance of new foci relative to the indicators before the start of the ongoing chemotherapy treatment .

The method is carried out as follows

Before the start of chemotherapy treatment in patients in the blood, the concentration levels of oncomarkers of cancer-embryonic antigen (CEA) and complementary marker CA 19-9 are determined. The results obtained are summarized. For example, one month after the ongoing chemotherapy treatment, the levels of CEA tumor markers and the complementary marker CA 19-9 in the blood are again determined. Then the results are summarized and a comparative assessment is made with the obtained sum of the concentration levels of these tumor markers before chemotherapy treatment. The criteria for assessing the tumor response to ongoing chemotherapy treatment according to the total concentration of tumor markers in the patient's blood are as follows:

When normalizing the sum of indicators of levels of concentration of oncomarkers, subject to the sum of elevated indicators before the start of the ongoing chemotherapy treatment, it is evaluated as a complete response, that is, the disappearance of all metastatic foci, to the ongoing chemotherapy treatment.

With a decrease in the sum of oncomarker concentration levels by more than 30% relative to the sum of oncomarker concentration levels before chemotherapy, it is evaluated as a partial response to this treatment, that is, a decrease in the sum of diameters of targeted metastatic foci and the appearance of new metastatic foci by more than 30% relative to the values before the start of chemotherapy.

With an increase in the sum of oncomarker concentration levels by more than 20% relative to the sum of oncomarker concentration levels before chemotherapy treatment, it is evaluated as progression to this treatment, that is, an increase in the size of targeted metastatic foci and the appearance of new metastatic foci by 20% relative to the indicators before the onset of chemotherapy.

With a decrease in the sum of indicators of the concentration levels of tumor markers by less than 30% or an increase by no more than 20% relative to the indicators of the sum of the levels of concentration of tumor markers before the ongoing chemotherapy treatment, it is evaluated as stabilization for this treatment, that is, a decrease in tumor formations by less than 30% or an increase by no more than 20% and the appearance of new foci relative to the indicators before the start of the ongoing chemotherapy treatment.

These criteria for evaluating the effectiveness of the treatment are reliable and provide timely correction and improvement of treatment outcomes. Such an assessment can be carried out at any stage of chemotherapy treatment.

To develop the method, data from 64 treated patients with liver metastases of colorectal cancer who received systemic and/or regional chemotherapy were used. For the biochemical assessment of the therapeutic response, the value of the cancer-embryonic antigen (CEA) and the complementary marker CA 19-9 were determined before the ongoing chemotherapy treatment. The results obtained were summarized. After 3 months, in these patients, the concentration levels of CEA tumor markers and the complementary marker CA 19-9 in the blood were determined, the results were summed up, and a comparative assessment was made with the initial data of tumor marker values.

Evaluation of the effectiveness of the treatment was carried out according to the developed method and according to the mRECIST scale after 3 months, the results are presented in Table 1.

A complete response to the ongoing chemotherapy treatment according to the developed evaluation criteria based on a comparative assessment of the total concentration of oncomarkers in the blood of patients after chemotherapy and before chemotherapy was diagnosed in two cases - in one case, the results coincided with the mRECIST scale data, and in the second case, the data obtained were confirmed by re-evaluation of the effectiveness of the treatment two months later according to abdominal CT with intravenous contrast. A partial response to ongoing chemotherapy according to the developed evaluation criteria was detected in 4 cases, stabilization of the tumor process - in 44 cases, and according to mRECIST data - in 5 and 46 cases. Subsequently, in the course of ongoing chemotherapy treatment and repeated determinations of the concentration levels of CEA tumor markers and the complementary marker CA 19-9 in the blood of these patients, the effectiveness of the selected chemotherapy treatment was confirmed precisely on the basis of the developed evaluation criteria by the claimed method. The progression of the tumor process according to our method was detected in 14 patients, in contrast to mRECIST - in 12 patients. The progression of the tumor process in two cases was proven during a re-examination after 2 months, in which the progression of the tumor process was confirmed in patients according to the results of CT of the abdominal organs with intravenous contrast. In this connection, our proposed method for evaluating the effectiveness of treatment more reliably evaluates the effectiveness of this chosen treatment in patients with colorectal cancer with liver metastases and at an early stage of ongoing treatment, since such a determination can be carried out at any stage of treatment.

Method implementation examples

Clinical example 1

Patient Zh., 55 years old, diagnosed with T3N2aM0 caecal cancer, right-sided hemicolectomy on April 23, 2020. In March 2021, progression was diagnosed - four bilobar metastatic nodes up to 8 mm in diameter. Prior to the start of chemotherapeutic treatment in the patient's blood, the sum of the concentration of CEA tumor markers and the complementary marker CA 19-9 was determined. After 6 months from the start of chemotherapy treatment, the effectiveness of the treatment was evaluated. According to the mRECIST scale and the developed criteria for the biochemical assessment of the tumor response to the ongoing chemotherapy treatment, namely, according to the comparative assessment of the obtained sum of the concentration levels of these tumor markers after and before the chemotherapy treatment, a complete response was revealed. Prior to the start of the ongoing chemotherapy treatment, the sum of the indicators was 59.3. Then, after 6 months of treatment, the sum of the concentrations of tumor markers was 12.2. That is, the sum of the concentrations of these onocomarkers returned to normal, although it was increased to the ongoing chemotherapy treatment, and CT scan data of the abdominal organs with IV contrast showed the disappearance of all metastatic foci, in response to the ongoing chemotherapy treatment.

Clinical example 2

Patient A., 56 years old, diagnosed with cancer of the rectosigmoid colon T3N0M0, laparoscopic anterior resection of the rectum on October 3, 2019. Prior to the start of chemotherapy treatment, the sum of the concentration of CEA tumor markers and the complementary marker CA 19-9 was determined in the patient's blood before the start of chemotherapy treatment. He received chemotherapy treatment for the progression of the main oncological disease - liver metastases. After the fourth course of drug therapy, the patient was assessed the effectiveness of the treatment. According to the mRECIST scale, stabilization of the tumor process was diagnosed. According to the developed criteria for the biochemical assessment of the tumor response to ongoing chemotherapy treatment, the patient was diagnosed with a partial response. Namely, before the start of the ongoing chemotherapy treatment, the sum of the indicators was 296.3. After the fourth course of treatment, the sum of oncomarker concentrations was 103.7. That is, in a comparative analysis, the sum of the concentration levels of tumor markers after chemotherapy treatment decreased by more than 30% relative to the sum of the concentration levels of tumor markers before the ongoing chemotherapy treatment. Abdominal CT scan data showed a decrease in the sum of the diameters of targeted metastatic foci and the appearance of new metastatic foci by more than 30% relative to the values before the start of chemotherapy.

Clinical Case 3

Patient M., 57 years old, diagnosed with T3N1aM0 transverse colon cancer, left-sided hemicolectomy on August 2, 2018, 6 courses of chemotherapy in the XELOX mode. Prior to the start of chemotherapeutic treatment in the patient's blood, the sum of the concentration of CEA tumor markers and the complementary marker CA 19-9 was determined. He received chemotherapy treatment for progression - bilobar mts in the liver from 12/15/2021. After 6 months of ongoing chemotherapy, the patient was diagnosed with a complete response according to the mRECIST scale. According to the developed criteria for the biochemical assessment of the tumor response to ongoing chemotherapy treatment, the patient was diagnosed with stabilization of the tumor process, which requires the continuation of drug therapy, rather than a complete withdrawal of treatment. Namely, before the start of the ongoing chemotherapy treatment, the sum of the indicators was 168.4. Then 6 months of ongoing treatment, the sum of the concentrations of tumor markers was 37.0. That is, the sum of indicators of levels of concentration of tumor markers decreased by less than 30% relative to the indicators of the sum of levels of concentration of tumor markers before the ongoing chemotherapy treatment. The results of CT scan of the abdominal cavity with intravenous contrast showed a decrease in tumor formations by less than 30% or an increase by no more than 20% and the appearance of new foci relative to the indicators before the start of chemotherapy.

Clinical Case 4

Patient N., 69 years old, with a diagnosis of sigmoid colon cancer T3N1aM0, resection of the sigmoid colon on 10/18/2020, 6 courses of chemotherapy in the FOLFOX mode, progression was diagnosed - bilobar metastatic liver damage. Prior to the start of chemotherapeutic treatment in the patient's blood, the sum of the concentration of CEA tumor markers and the complementary marker CA 19-9 was determined. Further, the patient underwent chemotherapy treatment due to the progression of the process. After 3 months of treatment (XT in FOLFIRI mode), according to the mRECIST scale, the patient was diagnosed with stabilization of the tumor process and continued drug therapy was recommended. Based on the results of the developed criteria for the biochemical assessment of the tumor response to the ongoing chemotherapy treatment of the proposed method, the patient was diagnosed with biochemical progression, which required a change in the line of chemotherapy. Namely, before the start of the ongoing chemotherapy treatment, the sum of the indicators was 263.5. Then, after 3 months of treatment, the sum of oncomarker concentrations was 339.9. That is, the sum of indicators of levels of concentration of oncomarkers increased by more than 20% relative to the indicators of the sum of levels of concentration of oncomarkers before the chemotherapy treatment. The results of CT scan of the abdominal cavity with IV contrast showed an increase in the size of targeted metastatic foci and the appearance of new metastatic foci by 20% relative to the indicators before the start of chemotherapy.

The method compared with known analogues has a number of significant advantages:

1. Allows using a clear algorithm to determine the effectiveness of ongoing chemotherapy treatment.

2. Allows you to determine the effectiveness of drug therapy at the laboratory level before macroscopic changes.

3. Allows to improve the overall survival of patients due to early diagnosis of the progression of the tumor process.

Claims (1)

A method for evaluating the effectiveness of ongoing chemotherapy treatment in patients with liver metastases of colorectal cancer, including determining in the blood the concentration levels of oncomarkers of cancer-embryonic antigen (CEA) and complementary marker CA 19-9 before treatment, the results of which are summarized and then the sum of the concentration levels of tumor markers of cancer-embryonic antigen (CEA) and complementary marker CA 19-9 after chemotherapy is determined , after which a comparative assessment is made of the obtained sum of oncomarker concentration levels after treatment with the sum of oncomarker concentration levels obtained before the treatment, and with a decrease in the sum of oncomarker concentration levels by more than 30% relative to the sum of oncomarker concentration levels before chemotherapy treatment, it is evaluated as a partial response to this treatment, that is, a decrease in the sum of diameters of targeted metastatic foci and the appearance of new metastatic foci by more than 30% relative to the indicators before the onset of chemotherapy treatment, with an increase in the sum of oncomarker concentration levels by more than 20% relative to the sum of oncomarker concentration levels before ongoing chemotherapy treatment, it is evaluated as progression to this treatment, that is, an increase in the size of targeted metastatic foci and the appearance of new metastatic foci by 20% relative to the indicators before the start of chemotherapy treatment and with a decrease in the sum of oncomarker concentration levels by less than 30% or an increase by no more than 20% relative to the sum of oncomarker concentration levels before the ongoing chemotherapy chemotherapy treatment is assessed as stabilization for this treatment, that is, a decrease in tumor formations by less than 30% or an increase by no more than 20% and the appearance of new foci relative to the indicators before the start of the ongoing chemotherapy treatment.