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MCSC expert told how to reduce the risk of recurrent NSCLC by 80%

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Lung cancer occupies one of the leading places in the structure of morbidity, disability and mortality of the population from malignant neoplasms. 

It is characterized by low detection rates in the early stages and is difficult to treat.

Approximately 30% of patients with non-small cell lung cancer (NSCLC) are diagnosed with an operable tumor. But, the proportion of recurrence of the disease after surgical treatment remains high due to its aggressive course.

On average, NSCLC reappears within 1-2 years after surgery. More than 80% of patients have metastases after surgery.

About the need for additional methods of treatment in patients after radical surgery. Arif Kerimovich Allahverdiyev, MD, Professor, Head of the Department of thoracoabdominal surgery #Mkntsloginova.

Read the interview with the portal "Medvestnik".


NSCLC: relapse risk can be reduced by 80%

Lung cancer – this is a socially significant disease that occupies one of the leading places in the structure of morbidity, disability (10.7% of cases of all disabilities in ZnO) and mortality from ZnO of the population. It is characterized by low detection rates in the early stages, is difficult to treat, and also requires significant financial costs in the provision of medical care to citizens. Approximately 30% of patients with non-small cell lung cancer (NSCLC) are diagnosed with a resectable tumor. However, the proportion of relapses after surgical treatment remains high due to the aggressive course of the disease. On average, relapse develops within 1-2 years after surgery. In more than 80% of patients after surgery, distant metastases are detected at the first relapse. In this regard, there is an urgent need for additional methods of treatment in patients after radical surgery. We asked Arif Kerimovich Allahverdiyev, MD, professor of the Department of Oncology of the Russian Academy of Medical Sciences, head of the Department of thoracoabdominal surgery of the Loginov MCSC State Medical University, to tell about how adjuvant drug therapy of NSCLC with a high risk of relapse is being improved.

High potential for metastasis

- Oncologists are well aware that lung cancer is one of the most common tumor diseases, how common is the surgical method of treatment for these patients?

- Indeed, in recent years, lung cancer has been leading in terms of morbidity and mortality. In the world, this cancer is in first place among men in terms of mortality. According to the latest statistics, about 60 thousand people suffer from lung cancer in Russia, and 1/3 of them are patients with the initial stages of the disease – I – II, and 70% of patients are diagnosed with common forms–III – IV stage. Currently, radical surgical treatment can be planned in 1/3 of patients diagnosed with lung cancer, in our country this is about 15 thousand patients (statistics for 2019).

– In your opinion, after tumor resection, further treatment is required for patients with early NSCLC?

- Traditionally, in recent decades, it was believed that the I–II stages of the disease can be cured exclusively using the surgical method. However, unfortunately, we did not receive any significant improvements in long-term results in this group of patients. This suggests that even in the early stages of the disease, surgery should be supplemented with drug therapy – in order to increase the effectiveness of the operation itself and improve the long-term results of treatment of our patients.

– How high is the risk of recurrence for patients with NSCLC after radical surgery? Can you identify the patient groups that are most at risk for this?

- Non-small cell lung cancer in principle is characterized by early metastasis after radical surgical interventions. The risk of relapse in the initial stages of the disease is quite high. For example, in stage IB of the disease, the frequency of relapses recorded in patients who have undergone surgery is about 45%. As the stage increases, this figure increases: AT II-60% of relapses; at III-76%. Paradoxically, relapses are manifested not only by local progression, i.e. in the area where the operation was performed. Only in 17% of patients with NSCLC, only local relapses are detected, in 39% of patients with local relapse, distant hematogenous metastasis is observed, and in 44% of patients, the progression of the disease is realized exclusively by distant metastases without the presence of local relapse.

There is a group of patients who are most at risk of relapse, and this is influenced by a number of factors: the degree of malignancy of the primary tumor itself, the presence of various pathomorphological invasive characteristics of the tumor, lesions of the capsule of lymph nodes, the presence of metastases in regional lymph nodes. The higher the stage, the higher the likelihood of relapse. And one more proven factor: in patients with glandular tumors (adenocarcinomas) with a mutation in the EGFR gene, hematogenous metastases are more often realized. All this should be taken into account when planning adjuvant drug therapy.

– Does a modern oncologist have the ability to reduce the risk of relapse? Which of them are used in the treatment of patients with NRML? How effective do you think they are?

– It should be noted that the risk of relapse is influenced by the nature of the surgical intervention performed. We can hope to reduce the risk of relapse only in the group of patients who underwent radical surgery, i.e. resection in the volume of R0 – removal of the tumor itself with anatomical resection of the part of the lung in which the tumor is localized, and complete removal of regional lymphatic collectors, where relapses can often occur. This approach minimizes the recurrence of the disease. But, despite the radicalism of the operation performed in compliance with the oncological principles of surgical treatment of patients, we often encounter a relapse of the disease. Traditionally, adjuvant therapy has been used to reduce this risk in recent years – postoperative chemotherapeutic treatment in patients with Stage II–IIIA of the disease. However, large randomized trials demonstrate that the prescribed chemotherapy (platinum duplets) has low effectiveness, increasing the 5-year overall survival rate by only 5%. Obviously, the situation requires significant improvement.


"Breakthrough Therapy" status

-In the last decade, enormous research work has been carried out in the field of creating new drugs for the treatment of oncological diseases, including lung cancer. One of the recent and encouraging works is the ADAURA study, the results of which were presented as part of the plenary session at the annual congress of the American Society of Clinical Oncology ASCO-2020. Please tell us about the results obtained during the study.

- With the advent of the first generation of EGFR tyrosine kinase inhibitors a decade and a half ago, oncologists have hope for improving the situation in patients with metastatic NSCLC. Drugs of this group became the standard first line of systemic therapy, increasing life expectancy from 8-10 months to 24-36. But the results of prescribing tyrosine kinase inhibitors as adjuvant therapy in patients with NSCLC with an activating mutation of the EGFR gene were not so optimistic. And now there is a representative of the third generation of tyrosine kinase inhibitors-osimertinib, which can block the activity of EGFR both in the case of activating mutations in exons 19 and 21, and in the event of a mutation of resistance to first-second generation inhibitors – T790M.

ADAURA is an international randomized, double-blind, placebo-controlled Phase III trial aimed at investigating the efficacy and safety of osimertinib in the adjuvant treatment of patients with stage IB, II and IIIA NSCLC with activating EGFR mutations (ex19del or L858R) after radical surgery. It is important to note that patients before randomization into study groups could receive adjuvant chemotherapy at the doctor's discretion. Last year, the US Food and Drug Administration (FDA) awarded osimertinib the status of "Breakthrough Therapy" – this status is assigned to accelerate the development and consideration by regulatory authorities of new promising drugs intended for the treatment of serious diseases and satisfying a significant medical need. This happened just after the results of the ADAURA study were announced at ASCO-2020.

The study demonstrated a statistically and clinically significant benefit of osimertinib in terms of disease–free survival when used as adjuvant therapy: the risk of disease recurrence or death decreased by 80% compared with the observation group in the group of patients with stage IB-IIIA of the disease. Two-year disease-free survival rates were 89% and 52% in the osimertinib group and the follow-up Group, respectively. The Independent Data Monitoring Committee recommended that the company conduct the disclosure of the study data 2 years ahead of schedule. Basis-strong evidence of efficacy has been obtained in connection with achieving its primary endpoint – disease-free survival. This is a very high result. However, it is important to clarify that, despite the early analysis, the study is ongoing, blindness at the level of researchers and study participants was not carried out, and in the future we will be able to see the final results of the study, including data on overall survival.

– It should be noted that osimertinib has already been approved for use for a new indication in Russia and at the beginning of this year was included in the national clinical recommendations of the Ministry of health of the Russian Federation as an adjuvant therapy for stage IB–IIIA NSCLC in patients with EGFR mutations after complete surgical resection of the tumor. In your opinion, the use of a new drug can affect clinical practice and the quality of life of patients?

–Patients with stage IB-IIIA NSCLC with EGFR mutation are characterized by hematogenic distant metastases, including CNS damage. This is the most difficult group of patients, which requires serious financial investments in therapy, as well as solving social issues. Administration of osimertinib in adjuvant mode will reduce the risk of relapse in NSCLC with EGFR mutation, including long-term relapses, including brain metastases. Prevention / prevention of disease progression will affect the quality of life of this group of patients and, of course, our clinical practice. Hopefully we'll get better results, both immediate and remote.

Molecular genetic testing (MHT), which is necessary to determine the status of a tumor and select a treatment strategy, has already become routine in the management of patients with advanced NSCLC. Can it be argued that testing for a mutation in the EGFR gene should be performed in all patients with NSCLC regardless of stage?

"Today, we can safely say that testing for the presence of a mutation in the EGFR gene should be carried out in all patients with NSCLC, with lung adenocarcinoma, regardless of the stage of the disease. The drug osimertinib has been clinically tested and approved for a new indication. And all patients with a mutation in the EGFR gene after radical surgical treatment should be recommended adjuvant therapy with osimertinib.

– How, in your opinion, to optimally organize the routing of patients with early-stage NSCLC to obtain MHT results? How is this process organized in your institution? At what stage should Testing be done?

- In most specialized clinics, comprehensive treatment is carried out and there is a possibility of MHT, which in Russia is carried out within the framework of compulsory medical insurance. This does not present any technical or financial difficulties, so this type of testing can be planned for all patients operated on for NSCLC at the clinic. In institutions where there is no MGT, patients must necessarily be sent to laboratories where such studies are performed.

In our institution there is a modern pathomorphological laboratory with the capabilities of MHT. All operated patients with stage IB–IIIA lung adenocarcinoma were sent for testing to detect mutations in the EGFR gene. After surgery, it is about two weeks after discharge, the patient is referred for consultation to the chemotherapist of our clinic. If the patient was operated not in our clinic, then he with form 057-Y and with morphological preparations, paraffin blocks can apply to our laboratory, where he will be given MHT.

Testing can be performed at the postoperative stage. We have a sufficient amount of biological material that will allow us to perform all the molecular genetic tests planned for each specific patient.

This analysis can be carried out at the clinical stage, i.e. before surgery. And, in my opinion, this approach (obtaining biomaterial from the primary tumor) allows you to speed up the process of obtaining MHT results and reduce the time before the start of treatment. In this case, after surgery, we will already have an idea of the presence or absence of a mutation in the EGFR gene and the ability to plan adjuvant therapy with osimertinib in advance.

Adjuvant administration of osimertinib after radical surgery in the ADAURA study is recommended for up to 10 weeks from the date of surgery. Today, minimally invasive operations come out on top, which allow the patient to be discharged on the 3-5 day after surgical treatment. In reserve after surgery, the patient and the doctor have 7-8 weeks to prescribe targeted therapy.

– What should the doctor explain to the patient in order for the treatment to be most effective?

- The patient should understand that, despite the fact that NSCLC is a malignant neoplasm with a sufficiently high potential for metastasis, today, thanks to the successes achieved in the field of surgery, it is possible to receive surgical treatment with minimal trauma. And thanks to the successes that have been achieved in the field of drug therapy, it is possible to consolidate the results of surgical treatment and reduce the likelihood of a return of the disease. With the possibilities of modern oncology, NSCLC ceases to be a sentence. There is a prospect to increase the chances of healing patients in the early stages, significantly improve the duration and quality of life in patients with advanced forms of the disease.

EGFR mutation, on the one hand, is bad, because in such patients distant hematogenous metastasis is more often realized, but on the other hand, we have osimertinib, the timely administration of which can significantly reduce the likelihood of disease progression. The doctor should explain to the patient the possibilities of adjuvant treatment and talk about the results that can be achieved. The patient must adhere to all the recommendations given by specialists who are part of a multidisciplinary consultation – a surgeon, a chemotherapist and a radiotherapist. The patient should trust their opinion and on the basis of their conclusion, taking into account all the pros and cons of treatment, make decisions. Only this approach can guarantee the best results.

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