Rene and Eddy,
My father was diagnosed with Hepatocellular Carcinoma (HCC) in April 2016 and presented with a 3-4 cm lesion in his right lobe. He had long standing cirrhosis so surgery was not an option. We listed for transplant and underwent Y90 theraspheres to kill the tumor and keep him eligible for transplant.
Follow up MRI showed the Y90 effective on the original tumor, however tumor thrombus was now present in the portal and hepatic veins. This vascular invasion delisted him from the transplant list. We were told no one could treat these tumor thrombi in the veins.
He failed an 8 week course of Sorafenib (targeted chemo), the standard of care, and new live tumor developed above and below the original necrotic right lobe tumor. We then were given the option of IV Keytruda. He's received 2 doses and is scheduled for his third dose March 16.
I found a doctor in a high volume cancer center who can treat this with SBRT with 6 treatments. We were glad to find him as I knew we could benefit from radiation or cryoablation in combination with Keytruda.
Prior to finding this covered treatment in the US, I had consulted with a doctor who proposed cryoablation, intratumoral injections of Yervoy and Keytruda, 2 additional rounds of IV Keytruda and low dose cyclophosphamide. This would require travel to Mexico which poses other GI illness, etc. and insurance will not cover this. This plan seemed to be more comprehensive, but the radiation plan seemed to be worth considering as this doctor seemed to have more experience and success with treating liver cancer.
I'm wondering if choosing radiation and Keytruda is an advisable first step as it did work for Mary and Jimmy Carter.
I wonder if not having a CTLA4 in the radiation plan will be inferior to the out of country approach. My thought was to try radiation first as this doctor has achieved 60-85% long term disease free progression with SBRT alone, 50% of patients he's treated had disease free progression with the vein involvement (PVTT).
Thoughts on my options? Anything I can do or add to the radiation/Keytruda plan to enhance immunotherapy?
Although my dad remains Child Pugh A, I don't think his liver could handle Yervoy and Keytruda IVs together so I discounted clinical trials. The intratumoral dose uses smaller amounts of the immuno drugs allowing the benefit of both with less toxicity.
If the radiation plan fails, I reason I could pursue the intratumoral approach if we get a new tumor target.
I'd appreciate your thoughts on this scenario. Thank you...
1) Radiation-resistant tumors: Is there a possibility that the new tumors around the necrotic tumor are radiation-resisitant? We’re not familiar with Y90 theraspheres and don’t know if the radiation extended to the area where the new tumors are growing. If the new tumors are radiation-resistant, SBRT may not be as effective? The numbers you have for SBRT's disease free progression are for patients who had not been treated with radiation before?
2) Radiation life-time maximum - One thing to keep in mind is there is a limit to how much radiation can be used in an area due to the detrimental side effects (for eg - I've reached my lifetime maximum for radiation to the head+neck after my IMRT treatment). Radiation may be a good option for the tumors in the vein, as cryoablation is usually not effective for tumors near blood vessels (cannot get those areas cold enough to kill the tumor).
3) Cryoablation - Have you explored cryoablation of the liver tumors next to the necrotic tumor (if they are not near large blood vessels)? Radiation-resistant tumors can still be killed with cryoablation (re: concern in 1)). Cryoablation can be done in the US - PM us if you would like contacts.
4) CTLA4 - CTLA4 IV side effects are much worse compared to PD1 IV. It is reasonable to try IV PD1 before adding on CTLA4 (intratumorally or IV).
5) Low dose cyclophosphamide - can be prescribed off-label in the US. See Chapter 7, section "Coley's Toxins and the Fearsome Bodyguards of Tumors" pgs 115-116; Chapter 11, section "Devising a combination strategy", pgs 178-180; Chapter 16, Table 3, pg 272.
6) Other combination possibilities: Chapter 16, Table 3 pg 272.
Thank you so much for your reply...
1.) I'm not sure if the Y90 reached the areas of new tumor. Although it is a targeted treatment, I was told it is less precise than SBRT.
We are not sure if the Y90 caused the tumors in the veins, or if they materialized on their own. They are near the original tumor in the right lobe. My thoughts are the Y90 did not kill all of the tumor and it spread.
The new spots above and below the original treated tumor surfaced later... November and December while he took
Sorafenib. I am not sure if they were exposed to Y90 or are radiation resistant.
2.) Lifetime max for radiation: I believe it is still safe to do the SBRT after the Y90 theraspheres as the treating doctor was aware of the prior Y90. We have 6 SBRT sessions scheduled. I will see how the tumors respond. If they are radiation resistant, I would definately consider cryoablation.
3.) The doctor who suggested cryoablation would also do intratumoral injections of Yervoy and Keytruda. I will keep in mind your words of Yervoys toxicity, even in the lower intratumoral dose.
If the SBRT does not kill these tumors in the right lobe, I'm hoping the antigenic release it causes from hitting the venous tumors combined with Keytruda will elicit an immuno response.
If not I hope to pursue cryoablation, possible intratumoral Yervoy/Keytruda plus low dose chemo if needed/able. I would have to pursue the immunotherapy doctor for this with possible travel to Mexico.
Alternately, I considered consulting at Sloan Kettering to see what they would do in terms of immunotherapy treatment. We got the name of a specialist there but appointments were 6 weeks out. Our local oncologist did a doctor to doctor consult and told us they would not treat this any differently than the IV Keytruda as monotherapy we are receiving now. I will pursue Sloan Kettering in the future if needed.
Your table in the book is excellent. I have shown that to our local oncologist as I don't think IV Keytruda is enough to address the heterogeneity of hepatocellular carcinoma. I will consult the other sections when I get the book back from my sister!
I will PM you for a list of doctors who would cryoablate in the US in case this is needed.
Thank you from the bottom of my heart. Your insight is invaluable.
We hope the radiation and PD1 will help keep your father's tumors under control. It's good that you are planning ahead for the next treatments in case radiation and PD1 are not sufficient.
Thank you. I appreciate your help with planning next steps if needed. I always try to plan other options to keep his spirits hopeful.
He did get his first radiation treatment today and now has the chills. This reminds me of your Coley's toxin treatments. It is a common side effect after radiation. Maybe he is having an immune response. I can only hope! My goal is long term management as new treatments are being studied. Thank you again.
Wow, that's a strong reaction from the radiation! Keep him warm and let him rest as much as possible to maximize the immune response.
He took naproxen sodium (Alleve) as he feared his temp would rise too high. It was 101. Should he take that or let the fever run? Does the antifever medication hurt the immune response? I forget the logic with that... yet we don't want the temp getting above 103/104 as it could start harming cardiac function etc... ?
If your father doesn't have any medical condition that would make a fever dangerous to him, I personally would let my fevers run. The natural increase in body temperature during a fever helps many aspects of the immune response. I recommend re-reading Chapter 8, Sections "The benefits of fever" (pgs 126-127), "The dangers of suppressing fever" (pgs 127-129).
Thank you ... I'll do that ... I remember you addressing fevers and tolerating them. I need to get that book back from my sister! She is trying to read it too.
SBRT radiation #2 yesterday ... my dad got chills 3 hours after which happened with first dose, but no fever. Dose #3 is tomorrow.
I will see if Cleveland Clinic has a strong immunotherapy department and try to consult with an immunologist for continued care after the radiation is completed next week.
If not, who do you recommend (preferably close to Buffalo, NY) as an immunotherapy specialist?
We got the name of a doctor at Sloan Kettering and may pursue this. I know Beth Isreal/Harvard and Dana Farber also are doing good work with immunotherapy. Feel free to PM me with names or recommendations.
Thank you...
That is very encouraging that he had chills after radiation. We hope he has a very good response with the Keytruda and radiation.
We hope you'll find an doctor experienced with checkpoint blockades to monitor your father. The doctor's experience is key when monitoring for immunotherapy treatment effect. The story of Jake illustrates this.
Update on my father with HCC:
He had a large right lobe liver mass 10x12 cm with tumor thrombus in hepatic and portal veins.
He received 2 weeks of SBRT (radiation therapy) every other day and gets IV Keytruda every 3 weeks.
We went for a 10 week check up last Wednesday to evaluate effectiveness. We reviewed the MRI with our doctor. The treated areas appeared necrotic but we do not have the final radiology report yet.
Unfortunately there is a new 1.3 cm mass in his healthy, left lobe. Fortunately it is in a treatable area and the tumor board recommended cryoablation.
The left lobe did hypertrophy 10% we think and is functioning to keep his liver labs and blood counts relatively stable.
We will meet with the doctors early July to discuss their treatment plan. We did speak to a melanoma doctor last visit to discuss checkpoint inhibitors like you recommended. She recommended we continue Keytruda for at least 6 months and then assess effectiveness and need to continue.
Alternately, we have a doctor that can treat us in Mexico with cryoablation and intratumoral injections of Keytruda and Yervoy. His protocol also as more facets to it, like low dose chemo and some other elements needed for success with immunotherapy.
This is private pay so we're hesitant, but if the treatment has better results than we can get in the US it may be time to consider this approach. Liver cancer keeps resurfacing and soon we will be out of healthy liver so I think we need the strongest immunotherapy approach possible. We will consult with this doctor soon. I welcome any thoughts on our situation and treatment options.
Thank you ...
It’s very encouraging that necrosis was detected in the treated tumor.
We are not familiar with the liver, but could the hypertrophy and new 1.3cm mass detected reflect immune activity? Sometimes with immunotherapy, “new” tumors pop up (as it did for me) because the immune system is now able to recognize and attack tumors. Perhaps his main oncologist and the melanoma oncologist can comment on that.
We feel cryoablation of the 1.3cm mass is a good option, in terms of killing any tumor and the immune effect in combo with PD1. With your concern about remaining healthy functional liver: Will cryoablated liver still be functional after some time? (From our understanding, cryoablated bone regenerates, cryoablated nerves heal and my cryoablated lung tumor areas have resolved over the years, but we don’t know how liver responds to cryoablation.) Even if the cryoablated liver area will not be functional, it will have eliminated the risk of that 1.3cm mass growing larger and not having treatment options.
It is hard to distinguish immune activity vs. tumor growth. One method that is still under research, but may help distinguish the two is DWI-MRI (diffusion weighted imaging MRI). It depends if the radiologists at your hospital are familiar with interpreting DWI-MRI for liver masses (we’re not sure if research has been done for this part of the body… DWI-MRIs are usually done for the brain).
We feel that your access to cryoablation and PD1 in the US is a good solid set of immunotherapy treatments, and does not necessitate going out of country for more treatments. Also, one thing to note is that more immunotherapy treatments is not necessarily better (Chapter 15).
At the time being, it doesn’t seem like your father’s tumors are going out of control, and it will take time to evaluate whether the treatments are working (Chapter 10).
Thanks for all of that great information.
I'm not sure how the liver tissue will respond to cryoablation. I'll be sure to ask when we consult with Cleveland Clinic in July. The liver tends to regenerate in general so we wondered if it hypertrophied to compensate for the right side since that has been almost completely consumed by tumor. The radiation doctor thought the body would eventually break down and absorb the dead right lobe. Maybe new liver tissue will regenerate there. Space is tight now. I wish we could debulk the dead tumor to make room more quickly.
Maybe we try cryoablation and PD1 in the states and give it more time to evaluate. It just seems like every 6-7 months he gets new tumor, which is characteristic of liver cancer. This started with a small right lobe tumor. After treating that we saw the vascular invasion. After radiating both of those areas, the left lobe tumor surfaced.
His AFP tumor marker was 7100 before radiation, dropped to 1200 in May, and just rose to 2900 with the surfacing of the new left lobe tumor. This makes us think this is tumor vs tumor flare from immunotherapy. We hope that immunotherapy is working and are trying to wait, but we can't damage the remaining healthy tissue or allow this tumor to engulf it like the right lobe tumor did.
He did take the chemo Sorafenib for 2 months and it seemed to accelerate the right side tumor growth. I read research that talked about Sorafenib suppressing immunotherapy creating a microenvironment conducive to cancer growth! This seemed to happen. Rate of progression prior to Sorafenib was slow with his tumor staying relatively stable for 4 months. After 2 months of Sorafenib, tumor tripled.
I consider Mexico (doctor is based in Atlanta) because it may be a better approach at training the body's immune system due to CTLA4 and low dose chemo for longer term control. It does have more risk like you said. I will consult with him again to see what he thinks about the current picture and if his approach would be effective.
Right now my dad is functional. He just had some pain over his right liver area at times, especially with a deep breath. It does dissipate and recur.
It's a lot to think about. We will continue to monitor and consult and try to make the right choices. Thank you for you're reply. It is so helpful.
1.3cm is a pretty ideal size for cryoablation (big enough for cryo, and if done by an experienced cryo doctor, can kill it all. Larger tumors will have more post-cryo side effects.) The success of cryo does depend on the experience/ technique of the doctor. Since there is little room for error with the limited amount of healthy liver tissue, a possibility could be consult with the 2 doctors have the most experience with cryo that we know of: Dr. Littrup (http://www.cureasps.org/forum/viewtopic.php?f=55&t=1296) and Dr. Aoun (http://www.cureasps.org/forum/viewtopic.php?f=55&t=835)
One concept that has helped us in our battle is that when tumors are appearing, it's like weeding a garden. We try to find treatments that will complement the immune response against the tumor, while weighing the side effects and giving priority to more "dangerous" tumors that can jeopardize the situation.
Excellent, thank you. The left lobe tumor has grown from May to June scans, although rate of progression seems to have slowed since our post Sorafenib washout period.
We have a consult July 6 at Cleveland clinic. I am also consulting with an immunotherapy doctor in Atlanta, the one who recommended your book, who is reviewing scans and making recommendations also. He is an expert in cryoablation and has even developed better needles I believe. I can message you his name and website. He had some concerns about VEGF release which could accelerate tumor growth. We need to make sure the right lobe large mass is necrotic. This doctor injects anti VEGF if he cryoablates one tumor with other cancer present. I was unaware of this factor and will ask Cleveland.
You had mentioned Dr. Littrup before and I have his name logged. If time permits, I will try to consult with him. I'm hoping Cleveland has an experienced person as we are treated there.
Thank you for your advice and recommendations.
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Rene and Edward
I am sad to report that my father passed in September after his 16 month battle with liver cancer.
We did go to Mexico City for cryoablation and intratumoral injection of Optivo and Yervoy. These procedures were tolerated well and I believed were working.
Unfortunately my fathers right lobe tumor had tripled on the “standard of care” Sorafenib, a targeted chemo, we took in the US. In hindsight, we would have refused this treatment. He did not have enough liver reserve to sustain the immune response which we pursued in Mexico.
My dad was very healthy on the Tuesday before our trip to Mexico (blood work was excellent/normal), but went into liver failure on the plane ride down causing us to stop in Atlanta for a paracentesis.
I wish we would have gone to Mexico City first. The woman who referred us to these doctors is still alive, cancer free. His success rates are 69-80% I believe. This doctor’s procedures work best with a small tumor to target for the cryoablation in an attempt to ellicit the immune response. We knew this was difficult in our case due to our advanced disease, but my dad wanted to try anything to get well. He was amazingly brave.
Our doctor did not know Cleveland Clinic used SBRT on vascular tumors. Instead of Sorafenib, we could have gone here to radiate his vascular tumor that presented after the initial small right lobe tumor as treated with Y90. If the disease progressed to form a solid tumor in the liver after that, I would have then gone to Mexico City for immunotherapy.
The Sorafenib was the only option offered here. It has a low success rate and did more damage as I believe it is immunosuppressive. My dad also tried IV Keytruda after the Sorafenib failure, but that did not appear to help, or we didn’t have enough time to see if it would. There was inflammation of the liver when we presented to Mexico which may have been an autoimmune attack on the liver.
It was an amazing learning journey and my father continued to teach me things until his final days. I am grateful for your help through this process.
Our deepest condolences to you and your family. Thank you for sharing the difficult decisions that you wrestled through and the things learned on the journey.
Your father fought a very courageous battle, and was very blessed to have you fighting for him.