Will Immunotherapy do the magic?
MissionBTB: Time for a clinical trial for my prostate cancer
Clinical Trials
In dealing with a life-threatening disease (stage 4 Prostate Cancer in my case) with no cure, one of the tools in the medical team’s toolkit is to consider a clinical trial for the patient. In my journey right from the beginning, I was advised that there are many ongoing clinical trials for prostate cancer that may make sense for me to get into at some point. As mentioned in the last blog, my PSA (Prostate Specific Antigen marker) was getting high enough by the summer of 2021 that we needed to change my treatment again. This was the time when my collective medical team (at Kaiser Permanente & University of California, San Francisco) and we agreed to consider enrolling in a medical trial.
In medicine, new treatments or new diagnostics move forward by conducting controlled trials that are designed by medical researchers in academia and in pharmaceutical companies. A search of a central database at http://clinicaltrials.gov lists ongoing worldwide trials by medical condition. When I searched it for prostate cancer clinical trials that are active/ongoing, it yielded 1849 entries worldwide, of which 1011 entries are listed in the US alone. The effective number of truly unique trials may be less, as slight variants of the trials are listed separately in this database. This gives you a sense of the magnitude of research going on just in the prostate cancer field — that’s not even the highest funded cancer research area. The top 5 funding recipients typically are breast cancer, lung cancer, brain and central nervous system cancer, leukemia, and colorectal cancer, ahead of prostate cancer. Since there are many government and charitable organizations funding cancer research, it is hard to get a comprehensive aggregate number, but the above is a reasonable assessment based on data from the National Cancer Institute and the American Cancer Society.
This may give you a scope of the collective number of clinical trials ongoing across all cancer types — and we have not yet found cures for so many cancers and sub-types. While we can debate the efficiency and type of funding available (or lack there off), and the influence of drug companies in steering what is actually funded, we cannot deny that cancer is a very complex beast. Let’s see what the renewed focus on Cancer Moonshot Program by the Biden administration does in accelerating the research and closing the gaps in the types of funding available to the researchers. As a cancer patient on the receiving end of available treatments, all I can say is that the research and approval of new treatments are not moving fast enough, there are too many people suffering for a very long time and dying of the disease while waiting for treatment.
Why and when does a clinical trial make sense?
For stage 4 metastatic prostate cancer (and other cancers) that cannot be dealt with by surgical removal of the tumor/impacted organs, there are less than a handful of total available approved treatments. So, the oncology team strategically figures out how to sequence those treatments, and the right opportunity to consider a medical trial instead of an approved treatment. The goal of the oncology team is to keep extending the time the patient has and managing the quality of life. Besides the obvious reason for extending life, a critical reason is that new treatments are getting approved regularly and a curative treatment may come along.
There are really two slices of time in your journey when you can go for a clinical trial.
- First is when you need a change of treatment but are otherwise generally doing well enough that you can afford a period of uncertainty related to the treatment working or not working. That window of time needs to be at least 6–9 months to go through sufficient treatment cycles and get some directional assessment of the effectiveness of the trial.
- Second is when you have run out of most of the standard of care treatment choices and now you are mostly in the land of experimental therapies.
In my case, it was the first one. By the summer of 2021, I was already through the first 3 opening plays in the treatment playbook. While I was far from remission and my PSA was rising over the past 20 months, these treatments kept me well enough to have a decent and active quality of life. So, while a change of treatment was necessary, given I that was physically and emotionally doing well, this was a good time to go for a clinical trial and see if I could catch a lucky break with a new emerging experimental treatment.
How do clinical trials work?
Clinical trials, by nature, have a lot of uncertainty. Things are being “tried” based on the initial research hypotheses and they are far from proven. The positive and negative impacts of these treatments are not well known, and even the right dosage may be unknown. Clinical trials are typically structured in 3-phases to work through these unknowns. Once the patients are selected and start treatment, they are monitored more closely than the standard of care treatments (industry parlance for FDA-approved treatments). The goal of the investigators running the trial is to have as controlled of an experiment as possible, so they put a very specific set of constraints on patient enrollment. Trials may be randomized (half the patients go through new treatment and the other half go through standard treatment) or non-randomized (all patients go through the same experimental treatment).
My goal above is not to create a “dummies guide to clinical trials” — but to indicate that the process from a patient’s perspective can be very tedious and unnerving. First, there are 100s of trial options out there. Your medical team/cancer institute you are working with will help narrow those down to maybe 2–4 viable options at a specific time. But the decision to finally opt for a specific trial is on the patient and the family. Then there are weeks of going through screening criteria, tests, and disclosures; ensuring you actually qualify for the chosen trial and the research team can get all the starting data that they need and how they need it — like specific biopsies and types of scans. This can take 3–6 weeks before you even know you are approved to enroll in the trial — a period of uncertainty and anxiety — as you are off other treatments (washout requirements) and you are waiting to see what’s next.
In my case, I went through this process once in late 2019 also only to be randomized to a placebo arm of the trial (i.e., staying on the standard of care treatment) that we were considering at that time. I dropped out of that trial as there was no benefit for me to be on that at the time. And here I was going through this again in 2021.
Even as a spouse of a physician, the whole process of getting into a clinical trial is daunting. Monika spent hours and nights scouring through trial databases and details to understand the options even after consultation with 3 independent expert oncologists in my regular panel. Because of her network, we could reach out to other cancer institutes and experts outside of the norm to hear other trial options before deciding on our final choice. For patients who don’t have that type of medical support system other than their main oncology team, this can be very hard.
But in the end, we must put faith in something, gather up our determination to work through an uncertain period of enrollment and then the treatment, and hope that the outcome will be positive.
There is also an aspect of giving back to the community. The standard of care treatments are there because a set of previous patients enrolled in trials and helped researchers conclude the effectiveness of those therapies. Medical research can only move forward with patients’ willingness to participate. Whatever the specific personal outcome may be related to treatment efficacy for oneself, the data helps researchers draw conclusions that will help the next set of patients. So, participating in a clinical trial has a good peripheral noble deed associated with it and one should not discount it.
Statistics show that only 2–3% of cancer patients ever take part in clinical trials. Also, 86% of U.S. clinical trials are delayed because of a lack of enrollment. Complexities and inefficiencies of the system pointed out above impact both the patients and the research community — slowing down the availability of new treatments and progress in the fight against cancer, as well as the possible life-changing impacts on patients through trial treatments. There are some not-for-profit organizations like Cancer Commons, as well as new startup companies like Power, that are working on tackling this problem from different angles… but we need a higher sense of urgency across the board.
Immunotherapy and the magic of Keytruda
Immunotherapy is the new kid on the block in cancer treatments that has very high promise. The trial I enrolled in at UCSF was an Immunotherapy trial, called 177Lu-PSMA-617 and Pembrolizumab in treating patients with mCRPC. I started my first treatment on Aug 19, 2021. Immunotherapy drug Pembrolizumab (sold as brand name Keytruda) has proven to be magical and very effective for certain types of cancers like melanoma, lung cancer, head and neck cancer, Hodgkin lymphoma, stomach cancer, cervical cancer, and certain types of breast cancer. First approved in the US in 2014, it has regularly been getting approval for additional types of treatments and has become even a first line of treatment for certain types of cancers ahead of chemotherapy.
However, Immunotherapy has not yet proven to be effective for prostate cancer. Prostate cancer cells are considered “cold” for Immunotherapy (immune checkpoint inhibitors unable to infiltrate tumor T-cells) and hence it has not worked as is. 177Lu-PSMA-617 is a radioactive therapy (experimental at that time but FDA approved in the US in March 2022 as a standalone therapy) that targets prostate cancer tumor cells and breaks them up. The concept of this trial was to use 177-Lu-PSMA-617 as the initial dose to break open prostate cancer tumor cells and hopefully turn them into “hot” cells for Immunotherapy to work on. The trial construct was a single dose of 177-Lu-PSMA-617, followed by Keytruda dosages every 3 weeks.
Enough medical jargon above, the end result was that the trial did not yield any effective positive outcome for me. I had my last treatment on Dec 3, 2021. As a quick indicator, you can see how my normalized PSA went from 52 to 186 during this phase.
While PSA is a good first-level indicator and a rising PSA is never a mentally comfortable thing, symptoms and scans are additional data points necessary to establish true disease status. In Aug at the beginning of this trial, I was symptom-free and physically doing well (other than loss of muscle and hence strength due to prior range of treatments). In Oct, we traveled to Arches, Canyonland, Bryce, and Zion National Parks in Utah, and I could do a good number of moderate hikes every day.
But by November of 2021, I was starting to experience physical activity triggered bone pains — a sign of tumor growth and flare-up, causing pains. This started to get progressively worse by December, making us regroup with the UCSF and Kaiser oncology teams on the lack of effectiveness of the trial treatment and the need to switch treatments again. On Dec 20th, a few days before my 7th Keytruda treatment, we concluded that there was no expected additional benefit to stay in the trial and stopped it. I needed to start back on chemotherapy to get the disease under control. I wanted to have a break from new treatment during the holidays and spend some quality family time. We scheduled my chemotherapy to begin on Jan 4th, 2022.
We spent Xmas at home with extended family, and then post Xmas we spent time in San Francisco with the kids enjoying the city. Overall, it was a quiet and good period, but Dec 31st happened to be a very active day… my step count that day was >18k, while that week's average was 9k steps. At about 4 a.m. on Jan 1st, a few hours after we went to sleep after celebrating the New Year, I woke up with debilitating pain in my pelvic area. I had clearly crossed the threshold of my body’s comfort and my tumors were screaming back at me — reminding me of living with the beast and the need to keep it in hibernation. The festivities of the previous day soon turned into a not-so-happy start of 2022, with a strong pain management regimen (steroids, opioids, and acetaminophen) pressed into action to keep the pain manageable.
My learning has been that once you disturb the beast and get to this level of pain, it does not recede quickly. It took me months to completely wean off the pain medication in parallel with the chemotherapy treatment to get my disease below the threshold of severe pain. More on that phase in the next blog.
Takeaways from my clinical trial
I truly hope the research team got some good takeaways from my case. There were about 30 patients enrolled in this trial at UCSF. The trial is still ongoing (but not enrolling new patients). It takes significant treatment times and follow-ups to quantify the benefits of any such treatment. Till the data is eventually published from this trial, I will not know the actual overall benefit of this Immunotherapy approach to the broader population; all I can say is it did not work for me.
Cancer of any kind is not homogenous and has many variables based on specific genetic mutations and other factors. Researchers' challenge is to isolate variables that have a correlation to the effectiveness or ineffectiveness of these new therapies and see if that data is statistically significant to drive meaningful conclusions.
From my point of view, I feel I have done something to contribute to medical research that needs acceleration. I survived the trial period without significant harm to myself. I tolerated the treatments well with minimal side effects, I bought myself 6 months of additional time before restarting a standard of care treatment. While in the end, I had a few months of the beast causing terrible pain at times, I did survive that also.
While I wish my trial outcome was different and the proclaimed magic of immunotherapy had worked for me in controlling my disease, enrolling in this clinical trial in the summer of 2021 was still the right decision for me.
I am hopeful that the research community will find the right modification to Immunotherapy to make it effective for prostate cancer as well — let’s keep the hope alive.
Reassessing life and my cancer journey
I was 3 years into my cancer journey by the Winter of 2021. I had gone through 3 lines of treatments and a clinical trial and adopted a whole slew of better diet and lifestyle practices, yet nothing was giving me a true edge over cancer. There were a few much-needed small victories and mostly good quality of life, and I was thankful for them. But it felt like we had not yet made a real dent in the battle against the disease. There was a limited choice of the standard of care treatments to look forward to, and they will get more aggressive and possibly challenging on my body as well.
So, it was a good time to rethink how I wanted to spend my time moving forward. Professionally I had excellent support from Micron to work as many hours as I wished and pretty much drive my own agenda and path within the organization… but at this time, even small hours working and away from my family felt like the wrong tradeoff. I owed it to myself and my family to dedicate my complete time to my own physical and mental health, and prioritize everything around my wife Monika, our kids, extended family, and giving back to society.
So, I decided to completely step back from my professional life at this time.
In the past 6 months at Micron, I had established and was leading Micron’s first internal new business incubator with a solid funding corridor and a good pipeline of ongoing startups and new ideas. I was, and still am very passionate about this — but I decided to walk away from it all. I don’t regret that decision to date… and when I beat this cancer, I can revisit getting back in the industry.
Some decisions may appear hard, but when faced with life-threatening situations, choices become relatively clear.
My journey through blogs so far (in chronological order)
My Ongoing Journey with Stage 4 Prostate Cancer: Mission Beat the Beast (MissionBTB)
Why am I finding my cancer diagnosis so late?
Creating a Personal & Professional Support System
First treatment and first win… but too short-lived and humbling!
Can I eat my way out of cancer?
