​I began my 7th cycle of enfortumab vedotin and pembrolizumab (Padcev+Keytruda) on May 31.  I continued with pembrolizumab only on June 21.  On September 13 I began my 6th cycle of pembrolizumab only.  This is my second follow-up using CT with contrast since changing to immunotherapy alone.  I would like to schedule a PET/CT and/or circulating tumor DNA to confirm - but I am happy to see a report of no evidence of recurrence or new disease by CT.   

My cancer journey is documented on this blog.  After over 30 years of leading software development of medical devices for the detection and treatment of cancer, I've had the opportunity to view the state of the industries I've contributed to as a member of the population they exist to serve.  I've also begun work as a patient advocate and have had a chance to meet many fine folks who have walked or are walking through a bladder cancer (or other cancer) journeys.  I now have a series of recommendations and new causes to pursue:

Educate and advocate for PET/CT staging of advanced  muscle invasive bladder cancer
After transurethral resection of my bladder tumor (TURBT), pathology confirmed it as invasive high grade papillary urothelial cell carcinoma with musclaris propria present.  Anatomic imaging - CT and MRI, with and without contrast, were ordered for staging.  No incidental findings were observed.
I then requested a PET/CT.  A whole-body PET/CT scan found locoregional spread to left presacral and left pelvic lymph nodes.   This significantly changed the standard of care guidance for my case.
Review of the current data demonstrates the promise of PET/CT relative to CT and MR for detection of lymph node or metastatic involvement in muscle invasive bladder cancer (MIBC).  Standardization of the process may lead to wider adoption and reimbursement and reduced understaging of MIBC. 

Educate and advocate for bladder sparing treatment with trimodality therapy (particularly with protons)
A majority of patients with muscle invasive bladder cancer undergo radical cystectomy (surgical removal of bladder, lymph nodes and often other nearby organs) and a urinary diversion: ileal conduit (incontinent diversion), neobladder(continent diversion) or continent cutaneous diversion. There remains a significant rate of recurrence with radical cystectomy (RC).  There may also be neoadjuvant or adjuvant chemotherapy to minimize microscopic disease.
Trimodality therapy is a bladder sparing option which employs radiation therapy and concurrent chemotherapy following TURBT.  Having lead software development for a new proton therapy system, I had intended to pursue trimodality therapy with radiation delivered by a proton therapy system.  I had access at a facility 20 minutes away in Knoxville or with the system I had lead software development for in Franklin Tennessee (where my sister now lives).  I was initially disappointed to see that bladder cancer was not listed as an indication on the web site of either facility.  After inquiring, I was happy to learn that a limited number of  bladder cancers and lymph nodes had been treated at both facilities.  
A recent publication concluded that their "multi-institutional study provides the best evidence to date showing similar oncological outcomes between radical cystectomy and trimodality therapy for select patients with muscle-invasive bladder cancer. These results support that trimodality therapy, in the setting of multidisciplinary shared decision-making, should be offered to all suitable candidates with muscle-invasive bladder cancer and not only to patients with significant comorbidities for whom surgery is not an option.”
I believe that proton therapy provides improved sparing of health tissue and quality of life and had initiated a consultation. A recent review comparing proton and x-ray therapy in MIBC showed improved overall survival with proton therapy - calling for more study and follow up. Access and reimbursement remains a challenge for the proton therapy industry and trimodality therapy for bladder sparing seems to me to be a significant opportunity to collaborate in demonstrating its benefits.

Educate and advocate for potential bladder sparing with EV/pembro 
I knew that in Tennesse, my best route for approval of proton therapy was through Medicare.  On learning of my diagnosis I resigned my job, left my employer insurance and applied for Medicare Part B (I was 66).  My application was delayed (although I had sent in all the required forms) and while I was waiting, I read of the practice changing results presented for enfortumab vedotin and pembrolizumab (EV/Pembro) in the EV-302 phase III trial.  My Medicare was approved on Dec 1, 2023 (retroactive to Nov 1, 2023).  I began treatment with EV/pembro on Dec 11, 2023.  On Dec 15, the FDA granted accelerated approval of EV/pembro as a first line option for locally advanced or metastatic urothelial cell cancer.  29% of the participants in the EV-302 trial had a complete pathological response.  The details are presented in this blog - I currently have no evidence of disease by imaging or circulating tumor DNA and at present have no plans to pursue chemoradiation or surgery.  More data needs to assembled following high responders to EV/pembro to quantify durability of the response to see if trimodality or RC can be avoided.  As part of this activity, guidance for dose de-escalation for high responders to EV/pembro needs to be generated.

​Advance biomarker development to predict response to EV/pembro
EV/pembro is an all comers treatment not requiring biomarker tests for inclusion.  Tests exist today to evaluate expression of PD-L1 to predict response to pembrolizumab.  I did have genetic testing done (after beginning treatment) which showed I have a PD-L1 CPS score of 10 - indicating likelihood of benefit to pembrolizumab.
Enfortumab vedotin is an antibody drug conjugate which binds to an immunoglobulin like protein Nectin-4.  Nectin-4 is overexpressed in 97% of bladder cancers.  The diagnostic and prognostic potential of Nectin-4 is currently being explored.  A PET radiotracer (68)Ga-N188 has been developed for imaging of Nectin-4 and may offer a tool for diagnosing bladder cancer and selecting patients for treatment with/predicting response to enfortumab vedotin.  It may also be possible someday to engineer theranostic pairs employing alpha and beta emitting radionuclides similar to those available today for prostate cancer.

Recognize importance of insurance navigation resources
As noted above, I orignally pursued enrolling in Medicare to increase likelihood of reimbursement for proton therapy.  I was extremely fortunate to be recommended to an excellent Medicare guide shortly after I was diagnosed with cancer.  He recommended a Medigap G plan for my Medicare Part C. The Medigap coverage adds a monthly premium (in total less than my previous private insurance) - however, along with Part A, B and a Part D drug plan - my medical costs for my EV/pembro treatment have been very manageable.

As described in my first blog posts, in 2017, I began a (first) health journey, losing 100 lbs. and reversing type 2 diabetes, and after 30 years, began e-biking (I ride the beautiful hills of East Tennessee).  I joined the Great Cycle Challenge, where tens of thousands of bikers spend a month riding to raise research funds for children’s cancers. I am riding this month for the seventh year.  Although it is devastating to children and their families, due to relatively smaller numbers receives only 4% of federal research funds.  Bladder cancer receives roughly 1% of federal funds. So, like the Bladder Cancer Advocacy Network (BCAN), this activity provides young investigators with the funds they need to advance their ideas that may lead to practice-changing breakthroughs such as that I am benefiting from. Data shows the benefits of exercise for cancer patients, and I continue to bike year-round during my journey.

BCAN discusses exercise and cancer here.
You can find my Great Cycle Challenge challenge story here

 I had a genetic test done after I began my treatment (enfortumab vedotin + pembrolizumab / Padcev+Keytruda).  This treatment performed so well in its phase 3 trial that no pre-testing (e.g. for PD-1 ) is required for patients presenting with locally advanced or metastatic muscle invasive bladder cancer.
I did request genetic testing where I found I had a  PD-L1 CPS score of 10, which indicated that Keytruda should be effective (there is currently no approved biomarker to predict effectiveness of Padcev).
I also had germline testing. This is a genetic test that looks for inherited mutations in your DNA that may increase your risk of developing certain types of cancer. These mutations are present in virtually all cells of your body and can be passed down from one generation to the next. I wanted my daughter to be aware of any mutation that might increase her cancer risk.
The test found one variation in the CHEK2 gene.  When the results came in I met with a genetic counselor who told me that the most recent data suggest a possible increase in breask cancer risk - but that the probability does not warrant any more than the screening which is currently recommended for all women.
Germline testing for cancer patients is currently underutilized - I am glad, for my daughter's sake that my oncologist suggested it.

On Monday, July 29, I had an outpatient procedure at my primary provider - the University of Tennessee Medical Center - to implant a chemo port.  It was my first opportunity to see, up close, interventional radiology equipment from my old employer Siemens.  I didn't see it long - I remember being wheeled into the room and then waking up in the recovery room.  It was not intubated and happy to be under moderate sedation.  A Tylenol the first night after surgery was the only medication I needed.  The picture above was from the following morning.  I need to keep the incisions dry for a week. The surgical glue will flake off and the sutures will dissolve in time - I need to be the incisions dry for a week.
I was curious and a bit anxious about my next infusion just 4 days after the the implantation surgery.  On check-in I said that i had a port installed on Monday.  I recognized the nurse who would be performing my first insertion.  She carefully organized a set of packets of items which would be required - including masks for both of us.  She prepared the area with sanitizer, brought over the access needle, asked me to take a deep breath and then applied the needle.  The prick was quick and certainly no worse than the arm poke typically done for lab work.  After flushes to ensure that the line was clear, blood for this today's lab work was drawn.  The access needle and catheter were left in place and secured with an adhesive patch - the connection would also be used to deliver the infusion.
We met with my doctor and then headed upstairs to the infusion suite.  My nurse was happy to hear that I had a port, and when my Keytruda was ready, the previously prepared line was connected.  No search for a patent IV vein!  When the infusion was complete, the line was again flushed and I was on my way.
I expect that at my next infusion in 3 weeks, the implantation incisions will be healed.  I may look into a getting a lidocain cream that some folks apply about an hour before the access needle is pushed in - but I am not sure that it's really necessary for me. 
As I am looking at continuing Keytruda for another year and a half - I believe that getting  the chemo port was a very good decision.

Despite the positive results I have seen with my treatment, I still hesitated before pressing the button to download the notes from today's CT scan with contrast and hesitated again to read through it.  Seeing the conclusion brought great relief and a prayer of thanks for God's continuing grace.

Since suspending my enfortumab vedotin (Padcev) - my peripheral neuropathy (numbness in fingers and toes) is subsiding, my sense of taste in normalizing and hair is returning. I am continuing to receive immunotherapy - pembrolizumab (Keytruda) once every 3 weeks.

I began infusions (Padcev+Keytruda on day 1,  Padcev on day 7 and repeat on day 21) in December.  I have three tubes of blood drawn before every treatment to get lab results which are reviewed before treatment.  On the last three visits, what used to be one stick to start the treatment IV has been turning into two misses - different locations on the left or right arm or hand.  The nurses then go in search of the most experienced person on the floor to put in the IV. I don't suffer from an abject fear of needles (tyrpanophobia), but I will say that I don't look when they are being put in.  However, I do feel like I am wearing out my veins and have scheduled an outpatient surgery procedure on  July 29 (before my next infusion on August 2) to put in a chemo port.  Folks I've asked ovewhelmingly agree with the choice.
 

On the day I departed to Chicago to attend my first annual ASCO meeting as a patient advocate (see previous post), I drew blood for a second circulating tumor DNA test.  Once again, no evidence of molecular, residual disease was detected.

After 6 cycles with both pharmaceuticals I began to experience low grade  peripheral neuropathy (numbness in fingers and toes) and dysgeusia (taste change).  We took a brief "holiday" with two cycles of Keytruda alone.  My adverse effects began to subside and my hair began to return.  I then had one cycle both at a reduced dose of Padcev. 
​
With a second negative ctDNA test and previous positve results reported in earlier posts - we agreed in consultation with my care team to suspend Padcev and maintain Keytruda.  We also agreed to continue to keep my bladder (no radical cystectomy or chemo-radiation) and monitor status with periodic ctDNA and imaging.

I am interested in collecting data from patients who have experienced a complete pathological response to Padcev+Keytruda treatment after TURBT (prior to radical cystectomy or chemo/radiation) to inform a safe dose de-escalation strategy.

I am also interested in gathering from any patients who have used fasting to avoid adverse effects with Padcev+Keytruda treatment.

I arranged to attend my first annual meeting of the American Society of Clinical Oncology as a new patient advocate.  With over 40,000 domestic and international specialists in each and all of the world's many cancers  in attendance (and over 800 advocates) - McCormick Place in Chicago is one of the few venues which could accomodate this event. [When leading software development for PET/CT I would attend the annual Radiological Society of North America meeting here after Thanksgiving every year.]
  
​I invested in this trip to meet and learn more of the role of patient advocates in supporting clinical research and cancer survivors and learn of the latest advances in the patient care and treatment of bladder cancer. I was encouraged the skill, knowledge, passion and compassion exhibited by the presentations and posters and plenary talks.

In the exhibitor hall I met with representatives of the manufacturers of my treatment - Astellas (Enfortumab Vedotin/Padcev) and Merck (Pembrolizumab/Keytruda) and maker of my circulating tumor DNA test (Signatera from Natera) for detection of molecular residual disease.  One my interests is dose de-escalation for patients with locally advanced/metastatic muscle invasive bladder cancer who exhibit a complete pathological response to this new treatment (~29% of patients in the EV 302 trial which led to FDA approval).  This is clearly a next question of great interest which may be addressed as EV 302 trial participatns continue to be followed and experience from folks like myself can be acquired.

Towards the end of the meeting, I attended a session "The Art and Science of Hope" and commented on the content and quality of this gathering.

I set out on one of my beautiful rural road bike routes on the early evening of Monday April 22.  The next memory I have is waking up in the Emergency Department of the University of Tennessee Medical Center- from which I pieced together how I arrived there.
I ride with my cell phone and use the Beacon feature of the Strava app which allows my wife to follow my progress on her phone - which stopped about half way through.  She called my phone and reached a very  kind Good Samaritan (actually one of at least two) who found me unconscious by the side of the road and called the police who in turn called an ambulance.

The police report indicates that I stated that I fell off my bike on West Bull Run Valley but could not describe why.  I'm told I was repeating myself a bit.  I was happy to see that the UTMC documents at least referred to a " very pleasant 67-year-old male" and "a good historian". 
I had a series of physical and mental examinations which yieled no remarkable suprises to attend to.  At 10 PM a CT's of neck, chest adbomen and pelvis were unremarkable - however CT of the head revealed:
      Subarchnoid hemorrage
      Subdural hematoma
in addition to face lacerations and scraping of the hands and side.  I was scheduled for a follow up at 4 AM to see if my situation would stabilize and allow me to be discharged.
On return to my room - my wife and I settled down to a long series of "Murder She Wrote" episodes on my TV.  I was then wheeled in for a second CT without contrast:

I was then discharged and Kathy drove us home.  I had a bit a room-spinning when rising from sleep which is subsiding.  My wounds are scabbing over.  Soon I'll bring my bike in for a once over and see if I'm ready to get back in the saddle.

In January I drew blood for a new molecular residual disease test - Signatera . The test detects circulating tumor DNA.   The first results take about 8 weeks because genetic analysis of your tumor is needed to inform the analysis.  The predictive power for treatment response appears quite impressive.
I was informed today that my test results are negative - which combined with the news from the previous post would indicate that my first line treatment is working very well.
I am scheduled to begin a 6th cycle of treatment (Keytruda/Padcevv) next Friday and will discuss next steps with my medical oncologist.
In addition to hair loss, I've started to have a runny nose and a bit of taste change.  Claritin did a fine job of clearing up the runny nose.