Below is a relatively detailed history of Dyanne’s disease and the treatment she got, from her diagnosis in March 2015 and until she died in January 2020.
**Early March 2015
My wonderful wife, Dyanne, was diagnosed with stage IV NSCLC. She has metastasis in the lungs, lymph nodes, bones and brain. She has the EGFR mutation exon 19 deletion. She is 30 years old, ethnic Chinese, Singaporean citizen and we are living in Norway (with our 1 year old daughter).
Treatment that is prescribed: erlotinib (150 mg per day).
**Middle of April 2015
Tumor seems to have responded well to Tarceva (erlotinib). Main tumor has shrunk around 40% in diameter and other metastasis have shrunk as well.
**Early May 2015
To “consolidate” the effect of erlotinib that has been seen on the bone metastasis, she receives radiation on the pelvis (3 Gy x 10 days).
**Middle of May 2015
We visit Care Oncology Clinic in London and they prescribe a protocol of metformin, atorvastatin (which we later change to fluvastatin), mebendazole and doxycycline. The two last medicines should be not be taken at the same time. One medicine one month, and the other the next month, and so on.
A measurement of the vitamin D level shows half the minimum recommended level. Dyanne starts taking around 1600 IU of vitamin D supplements and goes to a tanning studio twice.
**End of May 2015
CT scan show that the main tumor is stable and so are the other metastasis. The first follow-up MRI of the brain show that the largest metastasis there has shrunk and a tiny one has disappeared.
**Middle of August 2015
CT shows that main tumor is growing (from 2.0 x 1.4 cm to 2.6 x 1.7 cm). Other metastasis are either stable or shrinking. MRI of brain shows that the metastasis there continues to shrink. PET scan shows that only the main tumor seems active.
A biopsy is performed and we are waiting for results of this. In addition we start nivolumab in parallell with erlotinib and medicines prescribed by Care Oncology Clinic.
Main tumor in lung is radiated (stereotactic radiation) with 6 Gy x 5. We continue nivolumab (3 mg/kg every second week) and one dose of ipilimumab is also taken (1 mg/kg).
Biopsy done in August showed the following mutations:
-EGFR exon 19 deletion,
-PTEN: “not functional protein”-TP53: “inactivating”
-AR: a mutation in the androgen receptor gene was also found. This has no known significance and later analysis shows this is actually a germline mutation.
Nivolumab every second week and erlotinib is continued, as well as the drugs prescribed by Care Oncology Clinic.
Cough develops, CT scan shows possible pneumonitis. Nivolumab discontinued and two courses of methylprednisolone taken. Symptoms abate.
Both MRI of brain and CT of lungs show progression. During January, some re-purposed drugs are tried for a short period of time: disulfiram, warfarin, itraconazole , celecoxib and auranofin. This drug cocktail eventually gives significant side effects (Dyanne is very tired) and we believe main reason is itraconazole (a potent CYP3A4 inhibitor) is increasing the serum concentration of erlotinib (blood test shows erlotinib level is nearly tripled). Itraconazole is discontinued and the others are also put on hold.
We also decide to participate in a personalized peptide vaccine project in Germany. The project is organized by Professor Bojar of NextGen Oncology Group in Dusseldorf and also involves a professor in Tübingen and a professor in Frankfurt. We send FFPE tissue to be analysed. Estimated time to prepare the vaccine is 2-3 months (it later proved to take 5…).
The lesion that was progressing in the brain was radiated (stereotactic radiation, 25 Gy in one fraction).
We switch from erlotinib to osimertinib (aka Tagrisso aka AZD9291). Osimertinib is obtained on “compassionate use” here in Oslo.
Dyanne develops a severe headache, gets a bit of fever and vomits a lot in early March. An MRI is eventually taken but does not find anything odd. A blood test reveals elevated liver values and all drugs are put on hold. Liver values gradually decline and Tagrisso is eventually restarted. Other drugs (metformin, fluvastatin, mebendazole and doxycycline) are also gradually restarted.
CT scan shows lesions are reduced in size. Brain MRI shows stable.
Celecoxib and auranofin are added to the drug cocktail. Zinc is also started.
PET/CT and MRI scans are good.
Personalized peptide vaccine is finally ready. We travel to Frankfurt (Krankenhaus Nordwest) and get the first injection with the vaccine there. In one arm Dyanne gets the peptides mixed with poly-ICLC and in the other she gets the autologous dendritic cells that have been pulsed with the peptides. We also start low dose nivolumab (~1 mg/kg) and low dose ipilimumab (1 mg/kg). The plan is to get a new vaccine injection every second week (in Frankfurt) and also get low dose nivolumab every second week. Furthermore, ipilimumab is planned to be repeated every 6-12 weeks. Tagrisso and other drugs are also continued in parallel.
In addition to the medicines mentioned above, Dyanne takes vitamin D, probiotics, fish oil, calcium, iron and zinc.
CT scan in August showed that the main tumor in Dyanne’s lungs may have increased a bit in size. Some lymph nodes also seemed a bit larger than on the previous scan. No new lesions and all other metastasis seem unchanged. MRI of brain was all good.
We did a PET-CT scan to follow up in September. The main tumor in the lungs did NOT light up which was good news. The lymph nodes did seem to light up a bit, but the reason for this is unknown. We follow the lymph node just above Dyanne’s right collar bone with ultrasound every second week. The first two ultrasound scans measure the lymph node is stable at 1.1 cm. The third scan indicates it is 1.0 cm.
Dyanne travels to Frankfurt every second week to get new vaccine injections, as well as low dose nivolumab (0.7 mg/kg every second week) and low dose ipilimumab (1 mg/kg every 12 weeks).
CT and MR scans in October generally showed everything is stable. Some changes in lesion in brain which has been radiated (SRS), but the changes are believed to be a result of the radiation itself.
Dyanne continues to travels to Frankfurt every second week to get new vaccine injections, as well as low dose nivolumab (0.7 mg/kg every second week) and low dose ipilimumab (1 mg/kg every 12 weeks).
CT and MR scans in January 2017 are generally good. No new lesions and no growth. The lession which had some changes in it at the previous MR scan has changed further. However, it is still believed to be a radiation after effect.
CT and MR scans in March 2017 show that there is no new lesions and no growth. Still some further change (i.e. increase) in the area that has received stereotactic radiation. However, they still believe it is “only” a result of radiation, i.e. not cancer.
In March Dyanne has also started on tetrathiomolybdate (TTM), a drug which reduces copper in the body and which studies indicate may be able to slow or stop cancer growing. She has some fatigue, which may be due to TTM, or perhaps some of the other medication.
Dyanne starts to feel her balance is not as good as it has been before. And she feels a bit more clumsy than before. A new MRI scan is done and this shows that the area in the brain which has received stereotactic radiation is yet larger than it was on the March-17 MRI. Doctors now believe the growth is cancer and not only radiation changes. Surgery is planned.
Brain surgery to remove the suspicious lesion in the brain. Pathologist can’t find any cancer cells in the resected tissue. Changes on MRI were, hence, most likely due to the stereotactic radiation Dyanne received in February 2016. Dyanne recovers well from surgery, except balance which is still an issue.
In the end of May Dyanne develops shortness of breath. We visit ER and she spends a night in hospital. Turns out it was most likely triggered by some infection, and hence nothing too serious.
Dyanne starts a new version of the personalized peptide vaccine in Germany. The new version contains some of the old peptides (which she had a response to) as well as a number of new peptides. The peptides are, generally, also a bit longer than the peptides used in the previous two vaccine versions. The vaccine is split into four cocktails and she gets two injections in each arm.
Together with the vaccine, she gets low dose nivolumab (0.7 mg/kg every second week) and low dose ipilimumab (~1 mg/kg every 12 weeks).
Both MR and CT scans are good. We experiment with tetrathiomolybdate (TTM) to reduce copper. However, side effects (stomach) are quite annoying and we eventually stop this.
Dyanne is generally in good shape, but still has some balance issues.
We have added one new peptide to the vaccine: a peptide matching the EGFR T790M mutation (amino acid sequence: IMQLMPFGC).
Both MR and CT scans are good. Everything stable and no new lesions.
Dyanne is in good shape and balance issue has gotten better.
CT scan showed that one metastasis in the lung had grown and most likely it is cancer. The size is 13 x 7 mm, vs 8 x 5 mm in September. MR scan of brain shows all is good there.
Radiation of the one lesion in the lung that has grown. Due to its proximity to the stomach, the dose is reduced compared to what would have been normal . The delivered dose was 4.3 Gy x 4 for part of the lesion closest to the stomach and 6.45 Gy x 4 for the part further away from the stomach.
Dyanne has some fatigue, nausea and stomach issues, most likely due to the radiation.
CT scan shows that the radiated lesion has shrunk significantly. MR scan of the brain is good.
Dyanne is generally in good shape.
CT scan shows that there are 2, perhaps 3, metastasis that have grown in size. They are all still small: the two biggest are 8 x 5 mm and 7 x 6 mm.
We plan to do ablation of the growing lesions.
Apart from some fatigue, a bit of nausea and stomach issues, Dyanne has been in good shape.
After having researched options, we decide to go to Frankfurt to treat the lesions with microwave ablation (MWA) with Prof Thomas Vogl. He treats one of the metastasis successfully and without any complications.
We also find out that there is a place in Norway that can do MWA of lung metastasis. We hence go there to get treat the remaining metastasis. During the procedure there, Dyanne gets a pneumothorax, a well-known complication. She is bed-ridden for 5 days and loses two kilos of weight. After being checked out of the hospital, she develops a fever and is readmitted for another 2 days.
**May and June 2018
MRI scan of brain is clear. However, there are signs of slow progression. The activating EGFR mutation was found in a liquid biopsy and a CT scan in June shows there is slow growth of a lesion in the lung. The lesion has grown from 4 mm in January to 6 mm in April to 7 mm in June.
The tumor marker CEA is, furthermore, slowly creeping upwards. Having been below 2 for the past couple of years, it reached 3 in the end of June.
**July and August 2018
Summer holiday is good and Dyanne gains some further weight. CEA keeps creeping upwards, however, and CT scan in August confirms growth in the lungs. 3 metastasis in the lungs are each 8-9 mm in diameter.
In the end of August Dyanne also did a fecal microbiota transplant (FMT). The idea was both to reduce gastro-intestinal (GI) side effects from immunotherapy and other treatments, and maybe also to increase the chance immunotherapy will be effective.
Brain MRI done in August is a bit unclear, but no obvious growth.
2 of 3 lesions in the lungs are radiated (6 Gy x 3). The third is planned biopsied.
FMT seems to have reduced GI side effects of the last immunotherapy infusion.
Dyanne receives an experimental oncolytic virus in Heidelberg. The virus is a parvovirus and is given intravenously over a few days.
CEA reaches 9 in the end of September.
A brain MRI shows things are pretty stable. No certain growth.
A biopsy is done from the hilus in the right lung. Cancer cells are found. DNA and RNA from the biopsy material is extracted immediately after the biopsy is performed, frozen and then shipped on ice to Cegat GmbH in Germany. They will analyze it using a tumor panel (~700 cancer related genes) and will also do whole exome sequencing of both tumor tissue and normal blood, and RNA sequencing of RNA from the tumor. Finally, they will look for mutations in cell free DNA (cfDNA) from the blood.
CEA was 20 in the end of October.
The lymph node conglomerate in the hilus of the right lung (i.e. the lesion that was biopsied and where they found cancer cells) was radiated. However, due to the lesion’s proximity to the right bronchus, which received some radiation back in 2015 when the primary tumor in the right lung was radiated, the radiation dose that can be delivered is very small. The part of the lesion that is closest to the bronchus received only 2.8 Gy x 3, while the part that is further away received 6 Gy x 3. A peripheral lung lesion received 6 Gy x 3.
Initial results from analysis of biopsy from right hilum shows no easily targetable mutations. High level of MUC1 and CEA expression is found, however. And PD-L1 expression of around 20%.
We travel to Singapore/Malaysia for holiday and while we are there we discover an enlarged lymph node above Dyanne’s right collar bone. The location is the same as the enlarged lymph node that was discovered in February 2015 and then got Dyanne diagnosed with NSCLC. We thus panic, get a PET scan done in Penang (Malaysia) and this confirms there is progression in several places: lymph nodes, liver and probably also lungs and in the bones.
We also receive results from the analysis done by Cegat GmbH. Their more comprehensive analysis reveal the following mutations:
-EGFR exon 19 deletion is found, but the EGFR T790M mutation is gone.
-PIK3CA mutation (E542K)
-PTEN frameshift (inactivating the gene)
-RB1 homozygous deletion (inactivating the gene)
-TP53 mutation (V272L)
In addition it is found that the tumor mutational burden is low (2.2 variants/megabase), there are no signs of MSI and a high level of chromosomal instability is found.
The combination of RB1 loss and a TP53 mutation signals the tumor may have transformed into small cell lung cancer. However, the pathologist does not find any signs of small cell transformation when looking at the biopsy in the microscope.
Dyanne is generally in good shape, but starts to experience some numbness in the right chin, teeth and tongue.
CEA appears to keep rising still.
Upon return from Singapore, a brain MRI is done. This shows two metastasis at, or near, the base of the skull. These are the likely cause of the numbness of the chin. These are radiated with 6 Gy x 3.
A CT scan shows progression in lymph nodes, lung and liver (4 metastasis). Whether there is any progression in the bones is more uncertain.
An MR scan of the brain shows two metastasis at the base of the skull, pressing on a nerve, and likely the cause of the numbness in the chin.
Surgery of the enlarged lymph node above the right collar bone is conducted, primarily to get hold of tissue that can be used for analysis and more. Surgery goes well, but only 3/4 of tumor is cut out. Tumor seems to be sitting in the “soft tissue”, is attached to blood vessels and goes down towards the mediastinum.
Part of the tumor that was removed with surgery was sent to StoreMyTumor, a biobank that cryopreserves tumors so they can be used for a range of purposes in the future.
Another part of the tumor tissue is sent for drug sensitivity testing. This produces a number of interesting findings: disulfiram and auranofin seem to be able to kill cancer cells. So does panobinostat. One of the chemo drugs that are being planned, pemetrexed (Alimta), does not seem to have much effect. Another chemo drug, etoposide, does seem to wipe out cancer cells effectively.
Based on the results from the drug sensitivity testing, and also other factors, the planned chemo regime, carboplatin and pemetrexed, is switched to carboplatin and etoposide. Dyanne starts this just before Christmas.
She also does stereotactic radiation (6 Gy x 3) of the two metastasis at the base of the skull.
The pathology report from the surgically removed tissue shows that the tumor has transformed into large cell neuroendocrine carcinoma (LCNEC) and that it has a “very aggressive behaviour”. There is very strong staining of synaptophysin. TTF1, Ecadherin, CKpan and chromogramin A are positive. Ki-67 is 100%. PD-L1 is 15% on tumor cells and surrounding immune cells are mostly positive. Vimentin and SSRT2 are negative.
Bioinformatics analysis of the whole exome sequencing data from Cegat GmbH shows that most of the mutations found in the tumor (~80%) belong to what is called “mutational signature 3”. This is, coincidentally, the type of mutations found in BRCA mutant breast, ovarian and pancreatic cancer. Dyanne does not, however, have any BRCA mutations.
Just before chemo, CEA reaches 99. NSE has also risen exponentially in the past months, rising from around 10 in August to 75 in the middle of December. On 31st December CEA has fallen to 47 and NSE has fallen to 11 (within the normal range).
A bit of a rocky start on the new year: landed in hospital with delirium. Probable cause was disulfiram. Disulfiram was started in December due to research suggesting it has promising anti-cancer activity and results from drug sensitivity testing.
CT, MR and PET scans show very good response to chemo treatment. Tumors everywhere have shrunk. Tumor markers have also fallen dramatically. CEA is 9 in the end of January, down from a peak of 99 in December.
The PET scan done in January showed that 2, or maybe 3, spots were lighting up, suggesting still active cancer. One place in the iliac bone and one place on the neck. We had both places radiated. In addition, the neck metastasis was treated with an intratumoral immunotherapy injection.
CEA plateaued at around 7-8 and various treatments (including mifepristone) were attempted, unsuccessfully, to push it down further.
Analysis done by BC Cancer Agency in Canada suggested ALK could be important, prompting testing for ALK by IHC. This was positive and crizotinib initiated (in addition to osimertinib).
CEA started increasing exponentially: from 8.9 in the end of February to 21 on 14th March. Crizotinib did not seem to impact CEA curve any. Dasatinib, which came out well in drug sensitivity testing that was done at University of Augusta, was also tried a few days, but with no noticeable impact on CEA curve.
CT scan showed growth in several places in lung. Lesions still small (<1cm) and growth quite limited (a couple of mm). One lesion in liver had also grown, but one lesion had disappeared as well. Bone mets hard to evaluate on CT scan. Neck metastasis that was treated with radiation and intratumoral immunotherapy shrank further, as compared to January scan.
MR scan showed 3-4 new small brain mets. Largest was 2 x 2 x 2 mm.
A new round of chemotherapy (carboplatin and etoposide) was given in the end of March. The dose used was 75% of the dose given in December last year.
The brain mets that appeared on the March MRI scan were treated with stereotactic radiation (18 Gy in one fraction). The liver metastasis that had grown on the March CT scan was radiated with 4 Gy x 3.
Additional pathology analysis of the surgery specimen removed in Finland in December 2018 showed that the initial assessment, which concluded the cancer cells were large cell neuroendocrine carcinoma (LCNEC) probably was wrong. The new analysis shows the cells consist of two separate tumor cell populations: one that consists of small cell lung cancer (SCLC) cells, and one that consists of squamous cell carcinoma (SCC) cells.
CT scan shows mixed results. Improvement of some lesions, stability other places and possibly some places with a bit of growth. MR scan of brain is good.
Short periods where various treatments were tried and evaluated using tumor makers CEA and NSE. Drugs tried included mifepristone, tetrathiomolybdate, PI3K+PARP inhibitors and auranofin, disulfiram and celecoxib.
PET-CT scan done early in the month shows progression in multiple lesions. A new chemo infusion was given: carboplatin and etoposide at 90% of the normal doses. Pembrolizumab (100 mg, around 2 mg/kg) was done a bit less than two weeks after the chemo. CEA and NSE fall nicely following the chemo and pembrolizumab.
At the end of the month, a new version of the personalized neoantigen peptide vaccines was ready. This was injected subcutaneously together with Montanide ISA 51 and XS15, two adjuvants.
One week of fever therapy done with Dr Ralf Kleef in Vienna. Fever was induced by IL2.
Cryoablation of the main lesion in the lungs and one liver lesion was done. Immunotherapy was injected in both lesions and also into a metastasis on the neck.
A few days of fever induced by Coley’s toxin was done. Fever reached around 39 degrees Celsius.
A CT scan showed progression, and tumor markers (CEA and NSE) exhibited exponential growth. Dyanne had back pain and a “pins and needles” feeling in three last fingers on left hand. Due to this, another chemo infusion was done (carboplatin and etoposide at 90% of normal doses) and radiation (4 Gy x 5) was done of the lesion in the spine suspected of causing the back pain. The radiation eliminated the back pain.
An MRI scan of the brain showed 13 new brain mets. All were very small (largest was 4x3x4 mm) and Dyanne was asymptomatic. Pulsed dosing of afatinib (150-200 mg once per week) was started due to the brain mets.
A new brain MRI showed that all 13 brain mets found in August have shrunk or disappeared, most likely thanks to the pulsed afatinib. The scan unfortunately showed two new brain mets. The largest was 3 mm, and the other was just described as a “point”.
A CT scan showed there was slow growth in the lungs, and a bit more rapid progression in the liver (including a couple of new metastasis).
The CT scan did not show any remarkable changes in the bones. However, Dyanne started having pain in the left hip, and we suspected it was due to cancer. The pain was a bit on and off.
Dyanne started a more frequent chemo regime, consisting of weekly, low, doses of carboplatin and gemcitabine. She had two infusions of this in September.
The two new brain mets identified on the September brain MRI were radiated with stereotactic radiation (18 Gy in one fraction). And the hip was radiated as well (6 Gy in one fraction).
Pulsed afatinib is continued. In second half of the month, the weekly carboplatin and gemcitabine infusions were dose reduced to 55-65% of the previous doses.
As tumor markers (CEA, NSE) suggested the low dose carboplatin and gemcitabine was not working as hoped for, chemo was switched to nab-paclitaxel and one infusion of this was given in the end of the month (30th October).
Chemo was switched again to carboplatin and etoposide (75% of regular dose). Main reason was uncertainty of benefit from nab-paclitaxel. The chemo reduced both CEA and NSE significantly.
CT scan shows growth in lungs, liver and lymph nodes, as well as metastasis (not mentioned previously) in kidney and pancreas.
Dyanne was hospitalized twice during November: first she had surgery to drain an epidural hematoma (bleeding in the dura, a membrane between the brain and the skull). Then she got Clostridium difficile and was hospitalized a few more days.
Dyanne’s shape has been poor and declining over the past weeks and following the hospitalizations in November. Symptoms from the cancer also develop: a bad cough and back pain and then also constipation due to oxycodone (a morphine type of pain killer). A CT scan done to plan radiation treatment shows significant progression in the liver.
Dyanne was in again hospitalized for a couple of days due to fever. Antibiotics seemed to help.
The whole liver was radiated in December (4 Gy x 2) and also a spot in the lungs (3 Gy x 2). Then she also got radiation to the spine to try to control the back pain.
She increasingly suffers from shortness of breath and is on 25th December admitted to the hospital and put on oxygen. They also find her platelets are very low.
One last shot at trying to treat the disease is tried and Dyanne gets an infusion of low dose irinotecan in the end of December.
** January 2020
Another infusion of low dose irinotecan is given in early January. The chemo seems to help a bit and Dyanne is allowed to leave hospital and go back home. She is, however, on continuous oxygen and mostly bedridden. A new problem also develops: difficulty swallowing liquids and also pills (dysphagia).
We measure CEA and NSE again. Two infusions of low dose irinotecan reduced CEA by around 60%. Sadly, NSE was not affected: it increased by around 60%.
After some days at home, Dyanne’s situation deteriorates and she has increasing shortness of breath. She is brought to the hospital in an ambulance on the night of 16th January. On the 18th January 2020 she died.