Natalia Zelenkova, cholangiocarcinoma, stage IV, since 2015

In November 2015, after half a year of trying to figure out the cause of pain, I was finally diagnosed with stage 4 cholangiocarcinoma. It was both a shock and a relief, because at least there was some clarity about what was going on.

Given the neoplasm of hemangioma type I had then according to the description of computer tomography, I was very lucky to be consulted at the Federal State Budgetary Institution «National Medical Research Center of Surgery named after A.V. Vishnevsky» of the Ministry of Health of the Russian Federation. There they announced the verdict to me and immediately sent me to a hospital ward.

To prevent the risk of bleeding, doctors embolized the artery that fed the tumor. This was the preparatory stage for the main surgery: the artery which was feeding the tumor was blocked to prevent bleeding on the days before and during the main surgery. The tumor was large, 12cm x 7cm x 13cm.
During the six months preceding the hospital, I had been «treated», so to speak, by means of acupuncture, currents, magnets, manual therapy, active fitness, etc. All of these just added fuel to the flames and practically provoked an explosion. Various «diagnoses» were made including inflammation of the intercostal cartilage, osteochondrosis, atrophy of the abdominal muscles and so on. When I asked doctors in medical institutions about the causes of my pain and muscle spasms all over my body, they seriously suspected me of doing too little sports after I had given birth to my child and, in general, I was told that «I needed to treat my head, because it was ok that something would hurt at my age, I was way too focused on myself».

Looking back at the surgery in the Federal State Budgetary Institution «National Medical Research Center of Surgery named after A.V. Vishnevsky» of the Ministry of Health of the Russian Federation, I can say that during the surgery, distant metastases were searched for within the chest and the abdominal cavity, everyone was worried about the main neoplasm, later it became clear that a metastasis in the lower leg had probably been there before the surgery. In cases of such a serious lesion, systemic chemotherapy is usually given first, and only after that surgery is performed. First, the malignant process is localized and suppressed and the tumor is compressed as much as possible. Now I understand that, apparently, the doctors did not deem it possible for me to live through at least one course of chemotherapy at that time, so they decided to perform a surgery as soon as possible. I was lucky that the tumor had grown from the left liver lobe in the direction of the heart, which allowed the surgeons to operate and give me time and a chance for further struggle.

On December 7, 2015, Dr Aleksey V. Chzhao and his team performed a surgery. It lasted about 12 hours and was extremely difficult. The situation that the surgeons revealed turned out to be much more serious than it had seemed before on the CT and MRI images.

The tumor in the left liver lobe further had grown into the diaphragm and the pericardium (heart). They had to operate on the open heart. In fact, back then, in November and December 2015, I got very lucky twice: at first, they agreed to do a surgery, and then they didn’t give up on me during the surgery. The surgeons hesitated for a long time after opening the abdominal cavity, gathered all the professors of the division to consult with, but in the end, they began to try to cut out the tumor. They did it.

Given the ingrowth of the tumor, there was no clean tissue left as «reserve», so my borders were identified as R1 (an abbreviation from the postoperative immunohistochemical study). This means that malignant cells were detected at the resection margins under a microscope. Malignant cells remained in my body and another crisis broke out right after the operation in January 2016.

In my case, it was not even a recurrence, but continued growth of malignancy throughout the whole body: in the liver, around the heart, abdominal cavity, the lungs, the arms, the legs... everywhere. At some point, the tumors were no longer counted, but were simply described as conglomerates of lesions of different sizes... in different parts of the body.

According to the immunohistochemical study, I had poorly differentiated cholangiocarcinoma, which means it was very aggressive, as its cells quickly divide and spread to other tissues (in this sense, well or moderately differentiated carcinoma is better, it is considered less aggressive).

In February – March 2016, I underwent 2 cycles of standard chemotherapy: gemcitabine (trade name Gemzar) and oxaliplatin. I underwent chemotherapy at the local hospital. Neither Moscow Scientific Research Oncological Institution named after P.A. Herzen (branch of the Federal State Budgetary Institution «National Medical Research Center of Radiology» of the Ministry of Health of the Russian Federation), nor Federal State Budgetary Institution «National Medical Research Center of Oncology named after N.N. Blokhin» of the Ministry of Health of the Russian Federation, where I had applied for, could admit me for standard chemotherapy, because there were no places for hospitalization, and later the admission of new patients to the hospital was cut short due to influenza quarantine. It was only possible for me to receive chemotherapy at the local place of residence. The influenza in January 2016 was a severe one, I fell seriously ill after the surgery, which probably also affected further negative dynamics.

In January 2016 (after the surgery, but even before the start of chemotherapy) and in March 2016 (based on the results of 2 cycles of chemotherapy), I had a PET CT scan. According to the PET CT, all the existing tumors had grown and a large number of new ones had appeared.

So, on March 15, 2016 after 2 cycles of standard chemotherapy, I received the results of PET CT showing significant negative dynamics, and exactly on that same day I learned about the recruitment of patients with cholangiocarcinoma in a clinical trial of pembrolizumab (trade name Keytruda)!

The clinical trial gave me a great hope. It was obvious to me that I had to participate in this clinical trial.

Firstly, because the standard chemotherapy did not work for me at all.

Thirdly (and it was the decisive reason), it was immunotherapy, which meant a chance «to reload» my immune system, involve it in the combat, it was a hope for long-term prospects and hope to survive... By that time, I had already found information about pembrolizumab, including a clinical trial of patients with cholangiocarcinoma (at cholangiocarcinoma.org). I actively studied the patients’ board on this website and saw the results of the 2nd phase of the clinical trial of this drug: the so-called «success stories» — successful treatment cited by individual patients.

Secondly, I had already consulted remotely with doctors in Israel, the USA, Germany, Finland remotely using my tomography images and medical documents, and all the doctors unanimously said that I had no option but to undergo standard systemic chemotherapy. Neither radiation, nor any other treatment options were offered to me.

I read online about pembrolizumab and its incredible effectiveness in melanoma, the diagnosis for the therapy of which this drug had already been approved officially. With the help of some kind pharmacists I learnt about the international database of clinical trials on clinicaltrials.gov, there I found there a planned clinical trial of the drug pembrolizumab which was already in the 3^rd phase in Russia and I was actively asking all the doctors I met on my way, where and how I could find this clinical trial. I really wanted to participate in it.

Eventually, Dr Yuliya V. Vakhabova, the oncologist – chemotherapist, who I had consulted at the Federal State Budgetary Institution «National Medical Research Center of Oncology named after N.N. Blokhin» of the Ministry of Health of the Russian Federation back in January 2016 and ardently questioned her at the consultation where to find this clinical trial (especially since I saw Federal State Budgetary Institution «National Medical Research Center of Oncology named after N.N. Blokhin» of the Ministry of Health of the Russian Federation on the list of the centers participating in that clinical trial on clinicaltrials.gov), remembered about me when the clinical trial started recruiting patients in Russia in March 2016, and reached out to inform me about it. I am infinitely grateful to her!

The doctor responsible for this clinical trial in the Department of Clinical Trials and Biotechnologies (currently Chemotherapy Department №17) of the Federal State Budgetary Institution «National Medical Research Center of Oncology named after N.N. Blokhin» of the Ministry of Health of the Russian Federation, Dr Valeriy V. Breder, was able not only to confirm the possibility of my participation in this clinical trial, but also to answer another question that had long tormented me: where and how to do molecular profiling of the tumor to identify the targets for targeted therapy.
I found the information about the molecular profiling of the tumor on the same website cholangiocarcinoma.org. At the Board, patients abroad were actively discussing the possibility of searching for mutations (genetic disorders) in a tumor and selecting targeted therapy. In Russia I was in a tight corner, receiving such responses as «don’t even try, it’s impossible in Russia, only somewhere far away in America, at the level of experiments, but with your diagnosis it is definitely not possible».

Dr Valeriy V. Breder himself, before I even asked him, suggested doing this molecular genetic testing of the tumor tissue.

I started examinations as part of the clinical trial with pembrolizumab and at the same time submitted my paraffin blocks with the tumor tissue to Andrey R. Zaretskiy at scientific laboratory «Evrogen» to find mutations (today Andrey R. Zaretskiy is the head of the Molecular Group of the Department of Molecular Technologies of the Scientific Research Institution for Translational Medicine of Federal State Autonomous Educational Institution of Higher Education «Russian National Research Medical University named after N.I. Pirogov» of the Ministry of Health of the Russian Federation).

It is important to highlight that the molecular profiling of the tumor was not related to my participation in the clinical trial, it was, so to speak, my «own initiative».

On April 5 and May 5, 2016, I was put on two pembrolizumab infusions. The immunotherapy was well tolerated with no particular side effects. But at that time, my general condition was deteriorating significantly each day due to the growth of tumors.

In the last days of April, I was rushed to the State Budgetary Institution of Health «Scientific Research Institution for Emergency Care named after N.V. Sklifosovskiy» of the Moscow Department of Health to have a stent placed in the bile ducts. One of the tumors compressed the bile ducts, which could be seen on the MR (magnetic resonance) cholangiopancreatography images, the bile could not pass, and as a result, I had a sharp increase in bilirubin, obstructive jaundice, and intoxication of the body.

I am grateful to Dr Oleg D. Olisov, a surgeon at the Moscow City Center for Liver Transplantation at the State Budgetary Institution of Health «Scientific Research Institution for Emergency Care named after N.V. Sklifosovskiy» of the Moscow Department of Health and Dr Yuriy S. Teterin, an endoscopist at the State Budgetary Institution of Health «Scientific Research Institution for Emergency Care named after N.V. Sklifosovskiy» of the Moscow Department of Health for the successful stenting of the bile ducts which resembled a miracle.

By mid-May 2016, the situation had reached its peak. I could neither eat nor drink, I had endless debilitating pains, numerous tumors all over my body, a metastasis on my abdomen was bleeding. Pembrolizumab did not give me an obvious instant effect. This did not mean that it would not happen at all, it is typical of immunotherapy that in the short term, tumors grow due to the influx of the patient’s own immune lymphocyte cells of to the tumor, and then tumors decrease (destroyed by these immune cells). The computer tomography as part of the clinical trial showed a significant negative dynamics.

On April 19, 2016, the laboratory «Evrogen» sent a report with the results of the molecular profiling of the tumor. BRAF V600E mutation was detected. This disorder had a target therapy: BRAF inhibitors, but they were approved for another diagnosis: melanoma.

Nobody excluded me from the clinical trial. But I was in position where I didn’t have any obvious effect from pembrolizumab and there was «no more than a week» left until the irreversible terminal stage. At the same time a decrease in bilirubin level was acheived (!) due to successful stenting, and at least obstructive jaundice and intoxication from bilirubin receded. At the beginning of May 2016, Dr Valeriy V. Breder suggested not missing this «window of opportunity» in my condition and trying targeted therapy against the detected disorder. The decision was made in consultation with the tumor biologist Andrey R. Zaretskiy, who took into consideration the potential sensitivity of my tumor.

On May 18, 2016, I began targeted therapy with BRAF inhibitors. Despite the difficulties of the first days of taking the medicine, i.e. a sudden unexpected and a severe adverse side effect to ultraviolet, as a result, fever, high temperature, rash; the need for antibiotics, most likely due to the inflammatory process associated with the stent, that targeted therapy had an immediate positive effect. All tumors were reducing before our eyes.
An adverse reaction to ultraviolet occurred while I was taking vemurafenib, BRAF inhibitor (trade name Zelboraf), which I had to start with because dabrafenib, BRAF inhibitor (trade name Tafinlar) was not available in pharmacies. That adverse side effect to ultraviolet is typical of vemurafenib and is described in the package leaflet. I had to stop taking it due to severe rash and uncontrollable fever.

After switching to dabrafinib, the adverse side effects were managed, and my condition returned to normal. Dabrafinib was taken in combination with trametinib, MEK inhibitor (trade name Mekinist). That scheme was the initial goal of the targeted therapy.

Then there had to be taken certain steps in order «to convince» local Authorities of the Ministry of Health that the targeted therapy in my case was «not my personal experiments and creativity», but the treatment I needed. Six months later I was able to arrange the provision of the necessary drugs (see more detailed information below).

At the end of May 2016, I also sent a paraffin block with the tumor tissue to the American Foundation Medicine laboratory for test of 315 genes. They confirmed the presence of the BRAF V600E mutation and also found CDKN2A/B. I suspect that in 2016 I was one of the first Russian patients to send them tumor tissue for testing. Now the organizational process has become much simpler and more accessible, since there are Russian medical institutions and laboratories that process documents and send biomaterials.

Then there was a long correspondence with the Moscow Department of Health about PET CT. Finally, on July 18, 2018, patients with cholangiocarcinoma were included in the Order for state-funded PET CT.

The stent placed in my bile ducts in April – May 2016 was removed in November 2016.

Currently, there are no evidence of disease progression. The targeted therapy was canceled due to serious adverse side effects to dabrafenib (fever, high temperature that was difficult to bring down, severe joint pains), these did not occur immediately, but after a complete response to the targeted therapy was achieved.

This is a topic that requires special attention. The results of the molecular profiling of the tumor helped to establish the target for the therapy of which there are drugs. These drugs were approved in Russia, but they were approved for a completely different diagnosis. While I was actually diagnosed with cholangiocarcinoma, these drugs were approved for melanoma. As a result:

What could be done in this situation:

Of course, the first packages were bought with the money raised. Here I must cordially thank my friends, colleagues, acquaintances, and even strangers. They always took interest in helping me.

Then there was «Novartis», a pharmaceutical company, the manufacturer of Tafinlar and Mekinist drugs. I turned to the Russian representative office, showed all the medical documents, conclusions, tests, prescriptions — the whole story. The pharmaceutical company provided me with drugs for 3 months. It definitely took some effort to tackle all the necessary formalities. Here a huge role was played by the Federal State Budgetary Institution «National Medical Research Center of Oncology named after N.N. Blokhin» of the Ministry of Health of the Russian Federation and my attending Dr Valeriy V. Breder. They organized consultations, correspondence and communication with the pharmaceutical company. That was mostly due to the fact that I actually could not get the drugs from the hands of the pharmaceutical company for obvious reasons. The company «Novartis» allocated them to the Federal State Budgetary Institution «National Medical Research Center of Oncology named after N.N. Blokhin» of the Ministry of Health of the Russian Federation for my treatment. The charitable support of the pharmaceutical company was not limited to 3 months, it was most likely pronounced just as a formal set period. They were monitoring the dynamics and were ready to provide the drugs further.

On the other hand, it was obvious that that was the «to the tee» therapy for me. In the conditions when standard chemotherapy did not work, everyone kept saying that I had to be provided with those drugs by the healthcare system and I had to fight. I applied to the local Authorities of the Ministry of Health - Moscow Department of Health. I contacted them in the written form. I found their website. In the «Electronic Reception: Citizens’ Appeals» section, I wrote a request to provide me with the drugs attaching all the medical documents that proved 1) the disease progression on standard approved schemes, 2) the prescription of the Federal Institution, 3) the conclusion of the molecular profiling, 4) the positive dynamics from the required drugs. I waited for their official response for 30 days, after which I received a letter with the recommendation to make an appointment with the Chief oncologist of Moscow. The conclusion of the Chief oncologist was the following: «it is recommended to continue the therapy with those drugs». Further, on the basis of that conclusion, the local dispensary assembled consultations and wrote the prescriptions. I got my medicine at the pharmacy in a standard way for free.

It was 2016. Starting from 2019, practical recommendations for the drug therapy of biliary cancer of the Russian Society of Clinical Oncology include the possibility of prescribing BRAF inhibitors if BRAF V600E mutation is detected in the tumor and receiving treatment for free, under the compulsory medical insurance. In Summer 2022, the Food and Drug Administration (FDA) in the USA approved the dabrafenib + trametinib scheme for all patients over 6 years old with unresectable or metastatic solid tumors with BRAF V600E mutation after progression on the prior therapy.

In conclusion, I would like to say a few words about how we had fight when there were no drugs available in Russia. It would be absolutely impossible without friends who were willing to spend their time on visiting places, learning the information, making decisions. The problem was that to buy the drug abroad, a local oncologist's prescription was required. Without being embarrassed, my friends went to the Embassy of the Russian Federation abroad to ask for help, they explained everything, the certificate from the Federal State Budgetary Institution «National Medical Research Center of Oncology named after N.N. Blokhin» of the Ministry of Health of the Russian Federation on the official blank form with the prescription and its translation into English were of great help. Our diplomats (I am very thankful to them) reacted to my misfortune, promptly helped me find a local oncologist who made a prescription based on the available medical documents, the drug was ordered to a local pharmacy and purchased. Everything was done by my friends without my presence, only according to the medical documents. The drugs were brought to Russia. Mostly such a complicated solution was caused by a cumbersome procedure of purchasing those drugs. Even in Russia, the sale of Tafinlar and Mekinist is possible only after the patient provides the pharmacy with all the necessary medical documents, they are confirmed by the pharmaceutical company, and shipped to the pharmacy for a specific patient.

In May 2016, with the start of the targeted therapy and further until the complete response was obtained, I did blood tests to track the dynamics of BRAF V600E circulating in the blood plasma. The positive dynamics according to PET CT was in line with the decrease of circulating tumor DNA with BRAF V600E mutation in the blood until its complete disappearance.

In March 2017 (in the abdomen) and in April 2019 (in the lungs), when a recurrence (negative dynamics) was suspected according to PET CT, I also did a blood test first thing in order to detect BRAF V600E in the plasma. This made it possible to obtain additional information either confirming the suspicions about the negative dynamics in PET CT, or not. In case of BRAF V600E presence in the blood plasma, I would have had the information about the recurrence before the appearance of clearly visible tumors. Everything was done by Andrey R. Zaretskiy (at that time working in the laboratory «Evrogen»).

In the summer of 2020, during the pandemic I took advantage of discounts on tests at the Foundation Medicine and sent blood for a comprehensive genomic profiling.

After achieving a complete response at the end of 2016, all the subsequent blood tests never detected circulating tumor DNA with BRAF V600E mutation.

The suspicions of recurrence on PET CT in March 2017 and April 2019 were not confirmed by alternative examinations either MRI of the abdominal cavity (March 2017) or chest CT (April 2019) followed by PET CT. No therapy was undergone in connection with these suspicions.

FSBI «NMRC of Oncology named after N.N. Blokhin» of the Ministry of Health of the Russian Federation:

FSBI «NMRC of Surgery named after A.V. Vishnevsky» of the Ministry of Health of the Russian Federation:

Source:
«Experimental and Clinical Gastroenterology» journal, publication Ed. 144, №8 2017

Source:
Journal of Gastrointestinal Oncology