Stability, Confusion and a Hope for Clarity of Plan
Treatment Update - Where do we go now?
It has been quite a while since my last update - for a couple reasons. Partly because for a while my treatment was really just status quo. It wasn’t a fun status quo - every two weeks I would get chemo on a Monday, and feel absolutely terrible for about 5 or 6 days. Then I would feel iffy for 2 days or so, then would feel pretty good for about a week. Then we’d repeat. This lasted for 12 cycles, from late February through the end of July. Since then I have hesitated to give much of an update, as we just haven’t been quite sure of my treatment plan going forward.
Loose graphical representation of the status of my lungs
August Scans
In early August, I had my latest CT scans. The results were a combination of confusing, and difficult. On one hand, the existing lung nodules appeared to have been mostly stable from the April scans - and only four were mentioned in the scan and had grown slightly, but the liver results were very different. The August CT reading suggested six new lesions on the right side of the liver, and the prior noted lesion on the left side had no mention. So what the heck happened? As a result of the confusion, a PET scan was ordered.
The PET scan results didn’t provide a whole lot of clarity. It seemed to confirm that there were nodules in the lung, but none of the new supposed liver lesions were confirmed. The prior left side lesion that had no mention on the CT, was noted in the PET scan, indicating that there is most likely an active tumor there. As you may recall, this is a spot that we have had doubts about being a cancerous lesion since it first showed up last December. The PET scan also made mention of a questionable area near the site of my original resection back in December of 2016. So this sent us on quite a roller coaster of thinking.
Loose graphical representation of the status of my liver
Is the liver lesion anything? Maybe both the liver and original resection spots are only lighting up on the PET scan due to continued healing or scarring? Of course using selection bias, we found plenty of scientific articles suggesting that this was a possibility.
These weeks of uncertainty were not easy. There were times where we were very scared about the implications of my scans, and times where we felt like everything was under control, and even a few moments where we pondered the possibilities of false positive scan results.
Regardless, the assumption had/has to be that we should continue to treat it, since it is hard to ignore the lung nodules. If the liver lesion is to be believed to be cancer, it looks like it was reduced by about 50% from February to April, and another 50% from April to August.
So it’s stable - what are my options?
After getting a slightly better understanding of what was going on, we began the journey of determining my next steps for treatment. I knew I didn’t want to continue with the FOLFIRI regimen, regardless if the scans ultimately suggested that things were “stable”. Stable isn’t really what I am shooting for. Could we do a combination of ablation, surgery, or maybe some type of immunotherapy to crush these things?
We looked at a number of clinical trials, with quite a few very interesting and hopeful therapies in the works, there were some worth pursuing if needed. The science behind many of these are very interesting and they could really be the treatment of the future.
Natural Killer Cells are a type of lymphocyte (a white blood cell) and a component of innate immune system. NK cells play a major role in the host-rejection of both tumors and virally infected cells. (Image Source: NIH)
Clinical Trials of Interest
1) Keytruda + Universal Natural Killer Cells - This type of treatment was/is intriguing to us due to our interest in Natural Killer Cell therapies, but also the combination with Keytruda, which has been most successful in CRC patients who are Microsatellite Instability - High (MSI-High), which only represents about 15% of CRC patients overall, and about 5% in the stage IV setting.
MSI-H results when genes that regulate DNA (called Mismatch Repair Genes) don’t work correctly. Mismatch Repair Genes (MMR) work like genetic “spell checkers” by correcting errors in DNA as cells divide, similar to how “spell checkers” correct typos on a computer. (Source: Fight Colorectal Cancer)
Keytruda’s success in MSI-High patients has been very inspiring, and they are now looking for combinations where Keytruda can hopefully be impactful in the Microsatellite Stable (MSS) setting. MSS tumors function differently and do not arise due to errors in mismatch repair genes.
MSS tumors have been referred to as “cold” tumors. In terms of the number of tumor genetic mutations, they are one of the most highly mutated tumor types. In general, non-MSI tumors do not respond to immunotherapies even though cancers with fewer genetic mutations, such as cancers of the stomach and head & neck, have shown responses. (Source: Fight Colorectal Cancer)
Keytruda is one of the more promising new immunotherapy treatments today, and is a programmed cell death protein 1 (PD-1) inhibitor. It works as a checkpoint inhibitor, blocking a signal that would have prevented activated T cells from attacking the cancer, thus allowing the immune system to clear the cancer.
Natural Killer Cells are often only found in short supply in the presence of colorectal cancer tumors. However, under the right circumstances, they are very successful in killing colorectal cancer, and the treatment in combination with Keytruda aims to use checkpoint inhibition as a mechanism for enhancing Natural Killer Cell activity.
Programmed Cell Death Protein 1 - When PD-1 is bound to another protein called PD-L1, it helps keep T cells from killing other cells, including cancer cells. PD-1 Inhibitors such as Keytruda and Opdivo enable T cells to effectively kill cancer cells. (Image Source: Genekor)
2) Keytruda + Navarixin - This trial was interesting to us, once again due to the Keytruda inclusion, but also in the inclusion of Navarixin. Navarixin is a CXCR2 Antagonist originally developed to treat COPD and in particular is intriguing as it was found in preclinical studies to have strong activity against NRAS mutations (of which I have), one study even noted that it completely 'prevented' new lung colony formation.
3) The Stanford Vaccine - This trial was interesting to us due to the astounding success found in the preclinical studies they did using mice - which was noted to completely eliminate tumors in mice. There have been many cases where agents tested on mice don’t translate as well to humans, but this one was particularly striking due to the extreme level of success, and also in that one of the two involved agents was already FDA approved, and the other had been tested in multiple unrelated human clinical trials.
The approach worked startlingly well in laboratory mice with transplanted mouse lymphoma tumors in two sites on their bodies. Injecting one tumor site with the two agents caused the regression not just of the treated tumor, but also of the second, untreated tumor. In this way, 87 of 90 mice were cured of the cancer. Although the cancer recurred in three of the mice, the tumors again regressed after a second treatment. The researchers saw similar results in mice bearing breast, colon and melanoma tumors. - KRISTA CONGER (Source: Stanford University)
The agents used in this combination an Anti-OX40 Antibody (BMS 986178) and a TLR9 Agonist (SD-101)
Image Source: Genetech
Anti-OX40 Antibody
An agonistic monoclonal antibody against receptor OX40 (CD134), with potential immunostimulatory activity. Mimicking the natural OX4 ligand (OX40L), anti-OX40 monoclonal antibody selectively binds to and activates the OX40 receptor. Receptor activation induces proliferation of memory and effector T lymphocytes. (Source: NCI Drug Dictionary)TLR9
Toll-like receptor 9 is a protein that in humans is encoded by the TLR9 gene. (Wikipedia)TLR9 Agonists
Agonists of Toll-like receptor 9 (TLR9) have demonstrated potential for the treatment of cancer. TLR9 agonists directly induce activation and maturation of plasmacytoid dendritic cells and enhance differentiation of B cells into antibody-secreting plasma cells. Preclinical and early clinical data support the use of TLR9 agonists in patients with solid tumors and hematologic malignancies.
(Source: AM Krieg, Toll-like receptor 9 (TLR9) agonists in the treatment of cancer. Oncogene volume 27, pages 161–167 (07 January 2008))
Image Source: Cosmos Magazine
4) VSV-IFNβ-NIS Monotherapy or Combo w/ Avelumab - In this trial, patients are injected with a single vaccination of a Vesicular Stomatitis Virus that is genetically engineered to express NIS and human interferon beta directly into a single tumor. This vaccination would then be co-treated in combination with Avelumab, which is a whole monoclonal antibody of isotype IgG1 that binds to the programmed death-ligand 1 (PD-L1) and therefore inhibits binding to its receptor PD-1.
The theory with this treatment, is that the single injection of virus would lead to widespread deployment of the virus that is selectively targeting tumor cells. The immune system is generally very good at destroying viruses, and this situation would be no different, leading to potentially full eradication of cancer throughout the body.
Viral immunotherapy is an area that has great potential and could be an amazing option someday. At this point, most options like this trial are in early stages and are not fully proven. But it is very interesting and is a therapeutic area that we’ll be watching closely.
OK, but with all of that said…is the time right to do a trial? Maybe the docs have more up their sleeves that we should consider trying first? With all of these things in mind, we went back to see my oncologist to figure out the plan of attack.
Trials, Ablation, Radiation, Surgery?
All things considered, I knew I didn’t want to continue with FOLFIRI. We also knew we weren’t really interested in 3rd line chemotherapy. So as it stood, my options were one of the many clinical trials, or we could try to ablate them, or maybe even use radiation to treat them. After reviewing all of the scans and talking through all of the options with my oncologist, we were feeling pretty good about the possibility of attacking the lung nodules using a radiation therapy called SBRT, (which is a treatment that Jarod and I hadn’t really been considering prior), and using ablative techniques to attack the liver lesion. Everyone involved agreed that attacking everything hard and fast from here would be a good approach, and could at least provide a clean slate.
Stereotactic Body Radiation Therapy - Image Source: Oncology News Australia
The Lung Nodules - Leveraging SBRT
I haven’t seen my radiation oncologist for a few years, as radiation therapy hasn’t really been a prescribed treatment since my initial neoadjuvant chemoradiation therapy in the Fall of 2016. I was quickly reminded last week though how thorough and patient he is. We talked in great detail about what this treatment would entail, what the benefits were, what the risks were, but also about the things he would do to try to avoid undue damage and side effects.
SBRT
Stereotactic body radiation therapy, or SBRT, is a cancer treatment that delivers extremely precise, very intense doses of radiation to cancer cells while minimizing damage to healthy tissue. (Source: Memorial Sloan Kettering)
The Liver Lesion - Chemoembolization and Microwave Ablation
We only just yesterday met with the interventional radiologist to discuss the options for ablation treatment. It seems my liver lesion is very close to my stomach, which puts it at risk for damage during ablation therapy. That doesn’t mean the treatment can’t be done, just that there are additional techniques that would be required to be as safe as possible. One of these techniques would be a separate procedure called chemoembolization, occurring about two weeks prior to the ablation, which will help to make the lesion and affected area much more visible during ablation, making it easier to avoid impacts to the stomach
Chemoembolization
Transcatheter arterial chemoembolization is a minimally invasive procedure performed in interventional radiology to restrict a tumor's blood supply. Small embolic particles coated with chemotherapeutic drugs are injected selectively through a catheter into an artery directly supplying the tumor. (Wikipedia)
The ablative technique that is planned to be used is Microwave Ablation.
Microwave Ablation
Microwave ablation (MWA), destroys liver tumors using heat generated by microwave energy. With microwave ablation, the surgeon inserts a small laparoscopic port or open incision to access the tumor. A CT scan or ultrasonic guidance is used to pinpoint the exact location of the tumor. A thin antenna, which emits microwaves, is then inserted into the tumor. The probe produces intense heat that ablates (destroys) tumor tissue. - (University of California San Francisco)
Our research on the subject suggests that MWA is often preferable to Radiofrequency Ablation (which is considered standard) due to the speed at which it ablates, and also in its ability to ablate larger tumors and multiple tumors simultaneously.
Off to New York - Again?
So thankful that places like Hope Lodge exist during situations like these! (Image Source: American Cancer Society)
With all of this in mind - I’m planning on going forward with the proposed radiation and ablation approach, but as always, we’re checking on some 2nd opinions. So we’re heading out to New York next week to see my MSK oncologist, as well as my surgeon and hopefully a handful of others. Thank goodness for ACS Hope Lodge and stockpiled Skymiles!
While we feel pretty good about the plan right now, getting confirmation from MSK, or hearing other suggestions from them seems like the prudent approach. This is especially true since it will take a couple weeks for the Fargo team to prepare for SBRT and chemoembolization.
Thanks to everyone for your continued support!
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