RU2826820C1 - Method for combined treatment of upper ampullary rectal cancer of ii a-b and iii b stage with negative prognosis factors and absence of mutations in kras genes - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to medicine, more specifically to oncology, and concerns methods of combined treatment of upper ampullary rectal cancer. Preoperative stage involves 2 courses of chemotarget therapy using oxaliplatin in dose of 85 mg/m² intravenously drop-by-drop for 2 hours in 1 day, leucovorin in dose of 400 mg/m² intravenously drop-by-drop for 2 hours in 1 day, 5-fluorouracil in dose of 400 mg/m² intravenously bolus in 1 day and 5-fluorouracil in dose of 2,400 mg/m² intravenously drop-by-drop for 46 hours. That is followed by 4 courses of targeted therapy with cetuximab in dose of 500 mg/m² intravenously for 90 minutes in 1 day in combination with courses of chemotherapy according to the above scheme. Break between the chemotherapy courses is 11 days.

EFFECT: invention provides improved results of combined treatment, reduced toxicity, duration of treatment, increased objective tumour response and frequency of radical operations.

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Description

The invention relates to the field of medicine, specifically to oncology, and concerns methods for the combined treatment of upper ampullary rectal cancer (URC).

Currently, the standard treatment for locally advanced RCC is radiation or chemoradiotherapy (CRT) followed by surgical treatment [1, 2]. Preoperative CRT results in tumor regression (50-60%) and a complete pathological response (10-30%), which leads to a decrease in the incidence of locoregional relapses and improved survival in RCC patients [3, 4].

At the same time, according to data from previously conducted randomized studies [5, 6], it was shown that when using a short course of preoperative radiation therapy, radiation reactions and complications (anal incontinence, sexual dysfunction, etc.) develop, leading to a significant decrease in the quality of life of patients. Similar results were recorded when conducting prolonged preoperative CRT [7, 8].

In this regard, in recent years, only preoperative chemotherapy without radiation therapy has been used in patients with RPC, which has eliminated the negative impact of radiation therapy on the functioning of the anal sphincter and reduced the number of postoperative complications. Preoperative chemotherapy is performed using oxaliplatin and fluoropyrimidines, while according to different authors [9-13], the average number of courses, completion of treatment, frequency of grade III-IV adverse events, timing of the onset of surgical treatment and the level of postoperative complications vary widely. In addition, the frequency of complete pathomorphological tumor responses to preoperative chemotherapy varies significantly, which, combined with the prevalence of the tumor process, directly affects the survival of patients.

In addition to chemotherapy, monoclonal antibodies blocking the endothelial growth factor VEGF (bevacizumab) or epidermal growth factor EGFR (cetuximab or panitumumab) can be used. For the first time, the combined use of chemotherapy and targeted therapy was implemented in patients with metastatic colorectal cancer (mCRC). In particular, it was shown that the addition of bevacizumab to fluoropyrimidine-based chemotherapy led to a significant increase in the time to progression. It should be noted that monoclonal anti-EGFR antibodies (cetuximab and panitumumab) are active only in patients without mutations in the KRAS genes. The combination of cetuximab and panitumumab with chemotherapy regimens based on irinotecan, oxaliplatin and fluoropyrimidines improved immediate and remote results.

The obtained data served as the basis for the use of chemotargeted therapy in operable patients with RCC as a neoadjuvant treatment. Thus, currently there are studies [14, 15] on preoperative treatment using fluoropyrimidines, oxaliplatin and bevacizumab. It was shown that the treatment results varied significantly: the complete pathomorphological response of the tumor was 4.3-25%, and the frequency of distant metastases reached 12.5-27.7%. At the same time, the adverse effects of chemotargeted therapy were predominantly peripheral neuropathy (52%), anemia (44%), neutropenia (28%), including grade III-IV toxicity (28%) [14], as well as cardiovascular toxicity (6.3%) [15]. Thus, in the framework of combined treatment of RCC, the search for new options using preoperative antitumor drug therapy is relevant.

The closest to the proposed method of combination treatment of RCC (prototype) is the method [16], which includes 4 courses of neoadjuvant chemotherapy according to the SAPOX regimen (oxaliplatin at a dose of 130 mg / m ² intravenously by drip on day 1, capecitabine at a dose of 2000 mg / m ² orally in two divided doses from days 1 to 14, every 3 weeks) in combination with targeted therapy (cetuximab at a dose of 400 mg / m ² intravenously by drip 1-hour infusion on day 1, then at a dose of 250 mg / m ² weekly) followed by CRT (irradiation at a total dose of 50.4 Gy in combination with capecitabine at a dose of 1650 mg / m ² /day orally and cetuximab at a dose of 250 mg / m ² intravenous drip weekly), followed by surgical treatment and 4 courses of adjuvant chemotherapy according to the SAROX scheme. This method of combined treatment was carried out in 83 patients, while the results of molecular genetic testing showed that 46 patients had no mutations in the KRAS genes. Negative prognostic factors included criteria determined by magnetic resonance imaging (MRI): tumor prevalence T3c-d (50%), T4 (26%), CRM+ (57%), extramural venous invasion (72%) and low tumor location - at the level of or below the levators (48%). It should be noted that neoadjuvant chemotherapy and targeted therapy were not completed in 5 (6%) patients due to toxic events - 4 (4.8%) and death - 1 (1.2%). In addition, during chemotherapy, the capecitabine dose was reduced from 2000 to 1700 mg/ ^m2 after grade 3 diarrhea requiring hospitalization developed in 4 of the first 14 patients. Adverse events of chemotargeted therapy of ≥grade 3 severity were observed in 31 patients (37.3%) and included skin toxicity (10%), general weakness (10%), diarrhea (8%), hand-foot syndrome (4%), peripheral neuropathy (2%), nausea/vomiting (2%), febrile neutropenia (1%), and stomatitis (1%). When assessing the immediate efficacy of chemotargeted therapy, 5 (11%) cases of complete tumor regression, 27 (59%) cases of partial regression, and 12 (26%) cases of stabilization were recorded. Subsequent CRT was not fully completed in 5 more patients (6%), as 4 (4.8%) patients experienced disease progression and 1 (1.2%) patient refused to continue treatment. Analysis of CRT tolerability revealed grade ≥III adverse events, such as diarrhea (10%), skin toxicity (9%), and palmar-plantar syndrome (4%). Surgical treatment was performed in 45 (97.8%) of 46 patients with the wild type of the KRAS gene (no mutation), including radical surgeries (R0) - 43 (96%) and palliative resections (R2) - 2 (4%). Complete tumor response, confirmed by morphological examination of the surgical material, was recorded in 5 (11%) patients. During the first observation, 1 of 46 patients (2.2%) developed disease progression in the form of hematogenous metastasis, which led to the patient's death. One-year relapse-free and overall survival was 97.8%.

A new technical result is an improvement in the results of combined treatment of upper ampullary rectal cancer stage IIA-B and IIIB with negative prognostic factors and the absence of mutations in the KRAS genes due to a decrease in toxicity, duration of treatment and improvement of its tolerability, an increase in the objective response of the tumor and the frequency of radical operations.

To solve the problem in the method of combined treatment of upper ampullary rectal cancer stage IIA-B and IIIB with negative prognostic factors and no mutations in the KRAS genes, including courses of chemotargeted therapy using oxaliplatin at a dose of 85 mg / m ² intravenously by drip for 2 hours on day 1, a drug from the fluoropyrimidine group and cetuximab intravenously by drip followed by surgical treatment, at the preoperative stage, 2 courses of chemotherapy are carried out using leucovorin at a dose of 400 mg / m ² intravenously by drip for 2 hours on day 1, 5-fluorouracil at a dose of 400 mg / m ² intravenously bolus on day 1 and 5-fluorouracil at a dose of 2400 mg / m ² intravenously by drip for 46 hours, after which 4 courses of targeted cetuximab therapy at a dose of 500 mg/ ^m2 for 90 minutes on day 1 in combination with courses of chemotherapy according to the above scheme, the break between courses of chemotherapy is 11 days.

The proposed method meets the criterion of “novelty”, since, unlike the prototype, it has the following significant distinctive features:

1) treatment is carried out in patients with lesions of the upper ampullary part of the rectum of stage IIA (mrT3dN0M0, CRM+), IIB (mrT4aN0M0) and IIIB (mrT3-4aN1M0) in the absence of mutations in the KRAS genes;

2) preoperative CRT is not used, as a result of which the duration of preoperative treatment is reduced by ≈ 4 weeks;

3) the total number of chemotherapy courses was reduced from 8 to 6, and targeted therapy – from 9 to 4;

4) all courses of chemotherapy are used at the preoperative stage, with the first 2 courses of chemotherapy being carried out without targeted therapy, and the subsequent 4 courses of chemotherapy being combined with targeted therapy;

5) 5-fluorouracil is used as a fluoropyrimidine according to the following regimen: leucovorin at a dose of 400 mg/m2 intravenously ^by drip over 2 hours on day 1, 5-fluorouracil at a dose of 400 mg/ ^m2 intravenously by bolus on day 1, and 5-fluorouracil at a dose of 2400 mg/ ^m2 intravenously by drip over 46 hours;

6) cetuximab infusion is administered at a dose of 500 mg/ ^m2 over 90 minutes on day 1;

7) the break between courses of preoperative chemotherapy is 11 days.

Due to the presence of the specified features in this method, as well as their use in combination and a certain sequence of actions, it is possible to draw a conclusion about the compliance of the claimed method with an “inventive step”.

The invention meets the criterion of “industrial applicability” since it can be used in clinical practice for the combined treatment of patients with stage IIA-B and IIIB upper ampullary rectal cancer with negative prognostic factors and no mutations in the KRAS genes.

The method is carried out as follows: before the start of treatment, based on an examination including magnetic resonance imaging of the pelvic organs (MRI-OMT), video colonoscopy with tumor biopsy, spiral computed tomography of the chest and abdominal organs (SCT-OCG and OBP), diagnostic laparoscopy, the initial prevalence of the tumor process is determined. If stage IIA (mrT3dN0M0, CRM+), IIB (mrT4aN0M0) and IIIB (mrT3-4aN1M0) lesions of the upper rectum are detected with no mutations in the KRAS genes, 6 courses of preoperative chemotherapy are administered using oxaliplatin at a dose of 85 mg/ ^m2 intravenously by drip over 2 hours on day 1, leucovorin at a dose of 400 mg/ ^m2 intravenously by drip over 2 hours on day 1, 5-fluorouracil at a dose of 400 mg/ ^m2 intravenously by bolus on day 1 and 5-fluorouracil at a dose of 2400 mg/ ^m2 intravenously by drip over 46 hours, while courses 3-6 of chemotherapy are combined with targeted therapy with cetuximab at a dose of 500 mg/ ^m2 intravenously by drip for 90 minutes on day 1, the break between chemotherapy courses is 11 days. After completion of preoperative treatment, a control examination is carried out in the same volume to assess the objective response of the tumor, after which a radical operation is performed.

Rationale for the approach: Preoperative radiotherapy or fluoropyrimidine-based CRT followed by surgery is the standard treatment strategy for patients with locally advanced CRC [17]. However, preoperative CRT has been shown to negatively affect the rate of postoperative complications, including anastomotic leakage [18] and anal sphincter dysfunction [7], and to increase the incidence of late complications, such as sexual, urinary, and defecation dysfunction [6, 19].

An important problem associated with preoperative treatment is that surgical treatment in some cases may not be performed due to tumor progression during treatment. At the same time, the use of new cytostatic drugs in combination with targeted therapy can significantly increase the frequency of objective tumor response and improve the prognosis in patients with RCC. The results obtained served as the basis for preoperative chemotargeted therapy without radiation [14, 15]. At the same time, depending on the chemotherapy regimen (based on 5-fluorouracil or capecitabine), there are differences in the implementation of targeted therapy: bevacizumab is used every 2-3 weeks, panitumumab is used after 2 weeks, and cetuximab should be administered once a week.

In the proposed method, in contrast to the prototype [16], in patients with RCC with damage to the upper ampullary region at stage IIA (mrT3dN0M0, CRM+), IIB (mrT4aN0M0) and IIIB (mrT3-4aN1M0) and the absence of mutations in the KRAS genes, in order to reduce toxicity, duration of treatment and improve its tolerability at the preoperative stage, radiation therapy is not performed and the total number of chemotherapy courses is reduced from 8 to 6, and targeted therapy - from 9 to 4, which makes it possible to reduce the time of preoperative treatment by ≈ 4 weeks. However, reducing the number of courses of drug antitumor therapy and refusing radiation from the standpoint of ensuring better tolerability of the treatment and maintaining the quality of life of patients with RCC at the proper level can lead to negative oncological results in the form of reduced resectability and the frequency of radical operations (R0), an increased risk of local relapses and / or hematogenous metastases [14]. In order to intensify treatment and implement the maximum objective response of the tumor in the claimed method, all 6 courses of chemotherapy are used at the preoperative stage and the interval between them is reduced to 11 days. In this case, the first 2 courses of chemotherapy are carried out without targeted therapy, and the next 4 courses of chemotherapy are combined with targeted therapy with cetuximab. In addition, to achieve the above goals, parenteral form (5-fluorouracil) is used instead of oral form (capecitabine) as fluoropyrimidines, and the dose of cetuximab is increased to 500 mg/ ^m2 with an infusion duration of 90 minutes. All this ensures the maximum damaging effect on the tumor at the preoperative stage with an acceptable level of adverse events and increases the frequency of radical surgical interventions (R0).

Thus, in the claimed method, on the one hand, the reduction in the total number of chemo- and targeted therapy courses and the refusal to perform radiation are aimed at reducing the frequency of adverse events, increasing the completeness of preoperative treatment and reducing its duration, on the other hand, the transfer of chemotherapy courses from the postoperative to the preoperative stage, reducing the interval between them, replacing the tablet form of fluoropyrimidines with an injection form and increasing the dose of targeted therapy should provide a pronounced carcinocidal effect in the form of an increase in the objective tumor response, including complete pathomorphological regression, and the frequency of radical operations (R0). Improved tolerability and efficacy of combined treatment of upper ampullary rectal cancer stage IIA-B and IIIB with negative prognostic factors and the absence of mutations in the KRAS genes due to the use of the proposed method is confirmed by the following data:

Clinical example 1

Patient D., 63 years old, diagnosis: Upper rectal cancer. Stage IIB, mrT4aN0M0. Histological conclusion: Highly differentiated adenocarcinoma. There are no mutations in the KRAS genes (wtKRAS). According to MRI-OMT (02/18/2022), a tumor formation in the form of an uneven circular thickening of the rectal walls (from 7 to 12 mm) up to 38 mm long is noted at a distance of 10 cm from the anal sphincter. Lymph nodes are not visualized in the pararectal tissue and along the branches of the rectal artery. Video colonoscopy (02/16/2022): a tumor is determined in the upper ampullar section of the rectum along the left semicircle, which reaches 4 cm in length. CT-OGK and OBP (02/17/2022) did not reveal any data on distant metastasis. For the purpose of surgical staging, diagnostic laparoscopy was performed on 02/21/2022. In the period from 22.02.2022 to 04.05.2022, combination treatment was carried out using the declared method: 6 courses of preoperative chemotherapy using oxaliplatin at a dose of 150 mg intravenously by drip for 2 hours on day 1, leucovorin at a dose of 700 mg intravenously by drip for 2 hours on day 1, 5-fluorouracil at a dose of 700 mg intravenously by bolus on day 1 and 5-fluorouracil at a dose of 4320 mg intravenously by drip for 46 hours, while 3-6 courses of chemotherapy were combined with targeted therapy with cetuximab at a dose of 900 mg intravenously by drip for 90 minutes on day 1, the break between courses of chemotherapy was 11 days. The patient tolerated preoperative chemotargeted therapy satisfactorily, no adverse effects were noted. A follow-up examination revealed partial regression of the tumor. According to MRI-OMT (06/15/2024), delicate non-structurality and thickening of the intestinal wall due to minimal edema are determined at a distance of 10 cm from the anal sphincter, there is no exophytic component. Lymph nodes are not visualized in the pararectal tissue and along the branches of the rectal artery. Video colonoscopy (06/20/2022): a flat ulcerative defect is determined in the upper ampullary part of the rectum along the left wall. On 06/21/2022, laparoscopic anterior resection of the rectum was performed as planned. Histological examination of the postoperative material recorded complete therapeutic pathomorphosis of the tumor (TRG 1 according to Mandard). The postoperative period was uneventful. The patient was discharged from the hospital in a satisfactory condition. During dynamic observation over 18 months, no data on local recurrence or progression of the tumor process were found.

Clinical example 2

Patient K., 42 years old, diagnosis: Upper rectal cancer. Stage IIIB, mrT4aN1M0. Histological conclusion: Moderately differentiated adenocarcinoma. There are no mutations in the KRAS genes (wtKRAS). According to MRI-OMT (05/16/2022), a space-occupying lesion is determined at a distance of 8 cm from the anal sphincter, which extends in the proximal direction by 75 mm in the form of an uneven circular thickening of the intestinal wall (up to 13 mm). Lymph nodes up to 7 mm in diameter are determined in the pararectal tissue and along the upper rectal vessels. Video colonoscopy (05/17/2022): there is a tumor in the upper ampullar section of the rectum that circularly affects the intestine for 8 cm. According to CT-OGK and OBP (05/19/2022), there is no data on distant metastases. For the purpose of surgical staging, diagnostic laparoscopy was performed on 05/25/2022. In the period from 05/26/2022 to 08/03/2022, combined treatment was carried out using the declared method: 6 courses of preoperative chemotherapy using oxaliplatin at a dose of 135 mg intravenously by drip for 2 hours on day 1, leucovorin at a dose of 630 mg intravenously by drip for 2 hours on day 1, 5-fluorouracil at a dose of 630 mg intravenously by bolus on day 1 and 5-fluorouracil at a dose of 3840 mg intravenously by drip for 46 hours, while 3-6 courses of chemotherapy were combined with targeted therapy with cetuximab at a dose of 800 mg intravenously by drip for 90 minutes on day 1, the break between courses of chemotherapy was 11 days. The patient tolerated preoperative chemotargeted therapy satisfactorily, no adverse effects were noted. A follow-up examination revealed a complete clinical and radiological response of the tumor. According to MRI-OMT (09/05/2022), there are no obvious space-occupying lesions in the rectal wall. No lymph nodes are detected in the pararectal tissue or along the upper rectal vessels. Video colonoscopy (09/07/2022): there is an irregularly shaped scar in the upper ampullary part of the rectum, 10 cm from the anal sphincter. On September 08, 2022, a laparoscopic anterior resection of the rectum was performed as planned. Histological examination of the postoperative material confirmed complete therapeutic pathomorphosis of the tumor (TRG 1 according to Mandard). The postoperative period was uneventful. The patient was discharged from the hospital in a satisfactory condition. During dynamic observation over 16 months, no data on local recurrence or progression of the tumor process were found.

This method was used to treat 22 patients with upper ampullary rectal cancer without mutations in the KRAS genes (wtKRAS), including 9 men (40.9%) and 13 women (59.1%). The average age of the patients was 60 years (42-76). The initial prevalence of the tumor process: stage IIA (mrT3dN0M0, CRM+) - 1 (4.5%), stage IIB (mrT4aN0M0) - 1 (4.5%) and stage IIIB (mrT3-4aN1M0) - 20 (90.9%). Preoperative antitumor drug therapy was fully administered to 20 patients (90.9%). Adverse events were noted in 12 patients (54.5%), including grade III-IV toxicity in the form of neutropenia (9.1%) and skin rash (4.5%). According to MRI data, the objective tumor response was as follows: complete regression - 2 (9.1%), partial regression - 15 (68.2%) and stabilization - 5 (22.7%). Thus, the overall radiographic tumor response reached 77.3% (complete and partial regression). Surgical treatment in all cases (100%) was performed in a radical volume (R0). Postoperative complications occurred in 3 (13.6%) patients: grade I (Clavien-Dindo) - 2 (9.1%) and grade IIIA - 1 (4.5%). Complete therapeutic pathomorphosis (Mandard TRG 1) was diagnosed in 3 (13.6%) patients. The median follow-up of patients was 14 (2-24) months. Progression was detected in 2 (9.1%) patients: local relapse - 1 (4.5%) and distant metastases to the lungs - 1 (4.5%). The relapse-free and overall one-year survival rates of patients were 90.9% and 100%, respectively.

Currently, there are a number of studies in the world literature evaluating the efficacy and tolerability of preoperative chemotherapy in patients with rectal cancer. Thus, in the study by M. Koizumi [10], in patients with lower and mid-ampullary rectal cancer, after 6 courses of preoperative chemotherapy using a combination of 5-fluorouracil/oxaliplatin, the complete pathomorphological tumor response was 6.7%. In general, adverse events during chemotherapy were noted in 80% of cases. The most common complications were peripheral neuropathy (53.3%), leukopenia (36.7%), nausea (33.3%), increased ALT (13.3%) and AST (13.3%), and palmar-plantar syndrome (10%). In 23.3% of cases, leukopenia had grade III-IV toxicity. Postoperative complications (grade ≥2 according to Clavien-Dindo) accounted for 20%, including anastomotic failure (13.6%), intestinal obstruction (6.6%), wound suppuration (6.6%), stoma necrosis (3.3%) and intra-abdominal abscess (3.3%), which required reoperations. The median follow-up of patients was 31.1 months, during which 2 (6.7%) local recurrences and 5 (16.7%) hematogenous metastases were detected.

According to the study by J. Hasegawa [14], in which 4 courses of preoperative chemotherapy with capecitabine/oxaliplatin + bevacizumab were administered to patients with high-risk progression RCC (T4 or N+), the planned antitumor drug treatment was fully completed in 72% of patients. In 28% of cases, the reasons for refusing preoperative treatment were toxic reactions and tumor progression. In addition, 16.7% of patients required dose reduction of cytostatics during chemotherapy. During chemotherapy, both hematological (anemia - 44% and neutropenia - 28%) and non-hematological adverse events (peripheral neuropathy - 52%, arterial hypertension - 20% and bleeding - 16%) were observed, while grade III-IV toxicity was registered in 28% of patients. Radical operations (R0) were performed in 92% of patients. Postoperative complications were recorded in 26.1% of patients and included: wound suppuration (17.4%), anastomotic insufficiency (4.3%), intestinal obstruction (4.3%) and bleeding (4.3%), for which repeated surgical interventions were performed. Analysis of postoperative material showed that complete pathomorphological regression of the tumor did not exceed 4.3%. The observation period for patients was 31 months, while the frequency of local relapses and distant metastases was 4.5% and 22.7%, respectively.

In the study by A. Dewdney [16], 4 courses of neoadjuvant chemotherapy using the capecitabine/oxaliplatin + cetuximab regimen followed by CRT (external beam irradiation with a total dose of 50.4 Gy in combination with capecitabine and cetuximab) were used as part of the combined treatment of RCC, followed by surgical treatment and 4 courses of adjuvant chemotherapy using the capecitabine/oxaliplatin regimen. Neoadjuvant chemotargeted therapy was fully administered to 94% of patients. Adverse events of chemotargeted therapy grade ≥III were 37.3%. It should be noted that due to grade III diarrhea, 28.6% of patients required a reduction in the capecitabine dose. After chemotargeted therapy, the overall radiological response of the tumor was 71%, including complete (11%) and partial regression (59%). Chemoradiotherapy could not be completed in another 6% of patients, while adverse events of grade ≥III accounted for 23%. Thus, the overall completion of preoperative treatment did not exceed 88%, dose reduction of cytostatics was required in 28.6%, and the level of adverse events of grade ≥III in total reached 60.3%. Surgical interventions were performed in 97.8% of patients, including radical (96%) and palliative resections (4%). In the postoperative period, a complete pathomorphological response of the tumor was detected in 11% of cases. One-year relapse-free and overall survival of patients was 97.8%. Disease progression occurred due to distant metastases (2.2%) and ended in death.

According to the literature, to enhance the antitumor effect of preoperative chemotherapy, it is necessary not only to administer potent cytostatics, but also to maintain a high intensity of drug doses. However, as indicated above [14, 16], full preoperative treatment (4 courses) was possible in 72-94% of patients, while in 16.7-28.6% it was necessary to reduce the drug dose. In the method we propose, the completion rate of preoperative treatment (6 courses) was 90.9% and no reduction in the dosage of chemotherapy drugs was required. At the same time, the level of grade III-IV adverse events was significantly lower (13.6%) compared to the results of other studies (23.3-37.3%) [10, 14, 16]. In turn, the objective tumor response according to MRI data after chemotargeted therapy was higher and amounted to 77.3% versus 71% [16], as well as the frequency of radical operations (R0) - 100% versus 92-96% [14, 16] and the achievement of complete pathomorphological tumor regression (pCR) - 13.6% versus 4.3-11% [10, 14, 16]. It should be noted that the duration of preoperative treatment when using the proposed method was reduced by ≈ 4 weeks relative to the study of A. Dewdney [16] due to the rejection of CRT without loss of control over the tumor process.

Thus, the proposed method allows achieving a new technical result, namely, improving the results of combined treatment of upper ampullary rectal cancer stage IIA-B and IIIB with negative prognostic factors and the absence of mutations in the KRAS genes by reducing toxicity, duration of treatment and improving its tolerability, increasing the objective response of the tumor and the frequency of radical operations.

Sources of information taken into account when compiling the description:

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Claims (1)

A method for the combined treatment of stage II A-B and III B upper ampullary rectal cancer with negative prognostic factors and no mutations in the KRAS genes, including courses of chemotargeted therapy using oxaliplatin at a dose of 85 mg/ ^m2 intravenously by drip over 2 hours on day 1, a drug from the fluoropyrimidine group and cetuximab intravenously by drip, followed by surgical treatment, characterized in that at the preoperative stage, 2 courses of chemotherapy are administered using leucovorin at a dose of 400 mg/ ^m2 intravenously by drip over 2 hours on day 1, 5-fluorouracil at a dose of 400 mg/ ^m2 intravenously by bolus on day 1 and 5-fluorouracil at a dose of 2400 mg/ ^m2 intravenously by drip over 46 hours, after which 4 courses of targeted therapy are administered cetuximab at a dose of 500 mg/ ^m2 for 90 minutes on day 1 in combination with courses of chemotherapy according to the above scheme, the break between courses of chemotherapy is 11 days.