Rheumatic issues and arthralgias (joint pain) when utilizing anti-PD-1 (Opdivo and Keytruda) melanoma treatments

Unfortunately, joint pain while on immunotherapy is fairly common.  The degree to which the patient suffers is almost the only variable.  Some of us are managed fairly well with things like ibuprofen and stubbornness.  Others are debilitated to the point that treatments must be delayed and other medications like steroids and immune modulators like Remicaid are required.  If you search this blog under 'immunotherapy side effects', you will find zillions of articles on joint pain and immunotherapy. 

 Now, there's this:

Rheumatic immune-related adverse events secondary to anti-programmed death-1 antibodies and preliminary analysis on the impact of corticosteroids on anti-tumour response: A case series. Mitchell, Lau, Khoo, et al. Eur J Cancer. 2018 Nov 12

Rheumatic immune-related adverse events (irAEs) occur in approximately 10-20% of anti-programmed death 1 (anti-PD1)-treated cancer patients. There are limited data on the natural history, optimal treatment and long-term oncological outcomes of patients with rheumatic irAEs.

The objective of the study was to describe the spectrum and natural history of rheumatic irAEs and the potential impact of rheumatic irAEs and immunomodulators on anti-PD1 tumour efficacy.

Cancer patients with pre-existing rheumatic disease before anti-PD1 therapy or de novo rheumatic irAEs on anti-PD1 therapy were retrospectively reviewed across three sites. Patient demographics, treatment history, anti-PD1 irAEs, and anti-PD1 responses were evaluated. Relationships between the development or pre-existence of rheumatic irAE, use of immunomodulatory agents and outcomes were evaluated.

This multicenter case series describes 36 cancer patients who had rheumatic disease before anti-PD1 therapy (n = 12) or developed de novo rheumatic irAEs (n = 24). Thirty-four of the 36 patients sustained rheumatic irAEs (median time to rheumatic irAE: 14.5 weeks), including 24 de novo (18 inflammatory arthritis, three myositis, two polymyalgia rheumatica, one fasciitis) and 10 flares in 12 patients with pre-existing rheumatic disease. Corticosteroids were used in 30 of 36 patients (median duration: 10 months), and disease-modifying antirheumatic drugs were used in 14 of 36 patients (median duration: 5.5 months). The objective response rate to anti-PD1 therapy was 69% (n = 25/36) overall and 81% (n = 21/26) in the melanoma subgroup.

Rheumatic irAEs are often chronic and require prolonged immunomodulatory therapy. Prospective studies are required to define optimal management of rheumatic irAEs that maintain long-term anticancer outcomes.

So yes, there may be the need to continue treatment for joint pain and arthralgias after completing immunotherapy.  However, these response rates look pretty good!!!  Pros and cons - the life of a melanoma rattie.  Hang tough out there! - c

Chaotic Cookery! ~ French Daub, my version!!

 I've been cooking for years and years!  Literally:

Yep!  That's me at the age of 3, rolling out pie dough!!  I still love cooking.  I once wrote:  It is an artistic outlet with love and utilitarianism combined.  For me, cooking is fun, relaxing, and provides a delicious result!!  But, better than all those things, it allows me to share time and love with dear ones.  Brent and I worked hard to make sure that we sat down to dinner with the kids EVERY DAY!  It was a precious opportunity to share our day, laugh, and EAT!!!  We are all hardy and adventurous eaters which added to our cooking fun.  For us, our travels often began in the kitchen with a cookbook and culminated in bringing the tastes and smells discovered on our adventures back home, as we worked to recreate dishes we had enjoyed.  Which brings me to this....

As I clipped recipes and documented my own, I kept them in this black spiral notebook.  Eventually, the kids dubbed it the "Black Magic Cookbook" and made this cover!

If you want the best "Beef Stew" in the world, there's just no competition.  Simply turn to Julia Child's Boeuf Bourguignon!  You can't beat it.  For an easier, cheaper, yet still really delicious version there are lots of French Daubs.  Here's mine...

Do NOT get hung up on specific quantities or ingredients!  It's stew after all!  Add what you like.  Don't want to use wine, use extra broth or water.  Don't like carrots?  Leave them out.  Got some mushrooms wasting away in your fridge?  Toss them in!!!

Stew is not the most photogenic dish!

But on a cold day in January, it is a beautiful the thing. And if you aren't careful, your bowl will empty before you remember to take a pic!
Now, if only some birds would come to my feeder!!

Guess they heard me!!  HA!

May you enjoy a lovely winter day!!  And, if you're up to it - a little Chaotic Cookery!!! - love, les

Baseline levels of IL-9 predicted response to Adoptive cell therapy (ACT) using TIL in melanoma and a complete response in TIL paired with nivo (a case study)

A little old, and I don't tend to post much on TIL - but still....  Here are two reports:

Prospective analysis of adoptive TIL therapy in patients with metastatic melanoma: response, impact of anti-CTLA4, and biomarkers to predict clinical outcome. Forget, Haymaker, Hess, et al. Clin Cancer Res. 2018 May 30.

Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TIL) has consistently demonstrated clinical efficacy in metastatic melanoma. Recent widespread use of checkpoint blockade has shifted the treatment landscape, raising questions regarding impact of these therapies on response to TIL and appropriate immunotherapy sequence.

Seventy-four metastatic melanoma patients were treated with autologous TIL and evaluated for clinical response according to irRC, overall survival and progression free survival. Immunologic factors associated with response were also evaluated.

Best overall response for the entire cohort was 42%; 47% in 43 checkpoint naïve patients, 38% when patients were exposed to anti-CTLA4 alone (21 patients) and 33% if also exposed to anti-PD1 (9 patients) prior to TIL ACT. Median overall survival was 17.3 months; 24.6 months in CTLA4 naïve patients and 8.6 months in patients with prior CTLA4 blockade. The latter patients were infused with fewer TIL and experienced a shorter duration of response. Infusion of higher numbers of TIL with CD8 predominance and expression of BTLA correlated with improved response in anti-CTLA-4 naive patients, but not in anti-CTLA-4 refractory patients. Baseline serum levels of IL-9 predicted response to TIL ACT, while TIL persistence, tumor recognition and mutation burden did not correlate with outcome.

This study demonstrates the deleterious effects of prior exposure to anti-CTLA-4 (though perhaps that result is only due to those patients being "infused with fewer TIL"??????!!!) on TIL ACT durability and perhaps more importantly shows that baseline IL-9 levels can potentially serve as a predictive tool for response and help guide treatment sequence and selection.

On the other hand:

Rapid complete remission of metastatic melanoma after first-line treatment with nivolumab plus tumor-infiltrating lymphocytes. Zhao, Yang, Li, et al. Immunotherapy. 2018 Sep 10.

Melanoma is the most common type of skin cancer in both men and women in the USA. The standard treatment modality for advanced melanoma is immunotherapy, either alone or in combination. As single-agent immunotherapy is usually inadequate, combined immunotherapy might be a good choice and combined treatment modalities appropriate for melanoma need to be explored. Herein, we report a case of metastatic melanoma successfully treated with combined therapy of tumor-infiltrating lymphocytes and nivolumab. Complete remission was achieved approximately 4 months after the initiation of treatment. The treatment was well tolerated and only grade 1 fatigue occurred. The patient was still on complete remission 1 year after stopping the treatment. Our result showed that this treatment modality might be an ideal option for patients with metastatic melanoma.

Wonder if that patient would have had that complete and durable response to nivo alone, as I know from personal experience (and that of others) that nivo alone CAN provide complete responses in contradiction to the statements made in this report.  Additionally, how did this patient attain this therapy?  Hmmm....

For what it's worth. - c

Sew Chaotically! ~ Three MEN's shirts! Three happy boys! M6044

Since October I have had a blast sewing for others.  This challenge was no exception.  Three men's shirts for three of my fave boys!  The challenge was that I had none of their actual measurements nor bods available for fittings.  But, there was a lot of love and a resident "Mannie" (aka B!!!) to use as a block for adjusting the garment smaller or larger in areas I felt appropriate for each recipient.  I chose this McCall's pattern as it had good reviews and the simple lines I wanted.  Poor Jamester's shirt was the guinea pig, in that I made his first.  For him, I made a straight medium with no adjustments.  It went together very well! Fabric choice by his girl, Miss Roo!!!

Rather lame pic, as MY "mannie" is way too small for this shirt....but still!

Much cuter on the Jamester himself!!!

Now - nice flannel versions for my Dear Double D's.  Pic from a celebration with Dan and Don a couple of years ago!

I had fun playing with the pockets!

The placket for the cuff was super easy because the sleeve was made in two pieces.  Leaving a portion open and hemmed formed the placket. I flat felled the seams using one of my favorite tricks - sliding a plastic clip board underneath the fabric so pinning is easy while the piece remains on my ironing board.

Ta dah!!!!!

And they're done!

I think they liked them!!  At any rate - I had fun!  Sew chaotically!!! - les

First follow-up appointment after CAPOX for ex-goblet cell adenocarcinoma of the appendix (GCC) and a RUN!!!

Yesterday was my first follow-up appointment with my oncologist after completing (in my own special way, full deets in prior posts) the 4 rounds of oxaliplatin and capecitibine in the past 3 months prescribed as adjuvant for my Stage II GCC.  Whew!  In so many ways!

It was pretty non-eventful as expected.  Here's my self report:  My feet still burn quite a lot.  Although I no longer feel like I am walking in over-sized clown shoes!  My fingers are still pretty numb at the tips but I can type, pick up pins and deal with other fine motor skills much better than previously.  The area of the IV infiltration to my right forearm is still red, weird and tender - but improving since B had the genius idea of putting a moderate strength steroid cream on it twice daily.  It is no longer waking me with pain when I accidentally smush it in my sleep!  I have been dealing with pretty significant joint pain, particularly to ankles, knees and hips since the very start of treatment and they are still hanging around with a vengeance!  The brown splotchy lesions I developed are gradually resolving.  Oddly, patches of vitiligo that I began to develop in my Opdivo trial are increasing.  So, weird.  BUT!  My abdominal pain is gone!!  I can eat pretty much what I want though I am taking that adventure slowly and still taking my pepcid.  Currently, salads, citrus fruit, and apples with peels are back on the menu! FYI (with a TMI warning!!) ~ After surviving 2 months of liquid poopage every 2 hours round the clock following surgery to remove my appendix and right 1/3 of my colon, succeeded by obstruction and a second surgery, and all sorts of crazy poopage problems while on CAPOX with at least 4-6 loose stools on the good days, things are much better!  Stooling is not "normal" with 2-3 loose stools per day combined with some urgency ~ when you gotta go - you gotta go!!!  Still, if you are facing this sort of colon removal, it is a manageable process!

Anyhow, the main point of my recheck was to determine a plan for long term follow-up.  B rechecked with the docs I consulted at Vanderbilt, not to mention all the papers and peeps knowledgeable about GCC.   We went over their points and her own perspective with my local oncologist.  In the end, we determined that I will have my first follow-up scan (a low dose CT without contrast of the chest and regular CT with and without contrast of the abdomen and pelvis) at the end of March.  Future scans are planned to be a CT without contrast of the chest combined with a CT of abd/pelvis WITH contrast only, in order to keep continued radiation exposure to a minimum.  The consensus is to have your first scans 6 months after diagnosis and then annually.  Additionally, I will be seeing the oncologist and having lab work, to include a "CEA" level, every 3 months.  What is "CEA"?  Carcinoembryonic antigen is a protein in your blood that is normally very high in a fetus, but is usually low in healthy adults. It can be elevated in those adults should there be a growing thyroid, lung, breast, ovarian, pancreatic, stomach, bladder, colon, or rectal cancer.  As you see from the list, GCC is NOT included.  We are rolling with this test due to its usefulness in colon cancer which may, or may not, match up with my cancer. In fact, when it was drawn in the hospital just after having said cancer, my levels were normal.  But, we'll try it.  B is also researching other tests we may add to the mix.  How long will this go on?  The end point was not conclusively determined, but will likely be somewhere between 3-5 years.  All peeps interviewed agreed that we are at the point in my melanoma ta-dah (16 years overall, 9 years Stage IV and over 8 NED) that I am no longer in need of scans in that department.  Obviously, additional studies would be ordered should I develop untoward symptoms or demonstrate adverse numbers in my lab values.

In the spirit of upward and onward, combined with a break in the cold rainy weather that has been a bit perpetual lately,  B and I have done some "structural" work on our garden (taking out some saplings and overhanging tree branches, pruning overgrown roses, crepe myrtles, fruit trees, and rhodies) as well as taking down some netting/fencing that prevented the intrusion of rabbits and deer not at all!  I have continued to increase my indoor work-outs moving from 10 minutes to 15 on the elliptical as well as upping the 'level' from 3 to 4!  I am doing more sit-ups, push-ups, planks and reps with my weights.  But, the coup de grace to call an end to my incarceration is this:  I completed my first run since August!  It was more of a slog.  Only a mile.  But, I did it!!! 

Pre run!

On my return!!!  None the worse for wear.  With photos from my ever watchful Medical Meerkat Photog!

It is not always easy, but in the words of wise dear Jeanne, "Life is good!" - love, les

More evidence that Vitamin D matters for melanoma and cancer patients generally!

Not news, really.  Here are a zillion related posts!!!
2014:  Vitamin D and Melanoma 
2016:  Vit D and melanoma - Part 2 
Jan 2017:  Vitamin D - low levels associated with a worse prognosis in melanoma...again... 
June 2017:  Vitamin D and melanoma - folks with higher levesl do better - again!!! 
September 2017:  Vitamin D and melanoma

Now this:

Circulating 25-hydroxyvitamin D up to 3 decades prior to diagnosis in relation to overall and organ-specific cancer survival.  Weinstein, Mondul, Yu, et al.  Eur J Epidemiol. 2018 Aug 2.

While vitamin D has been associated with improved overall cancer survival in some investigations, few have prospectively evaluated organ-specific survival. We examined the accepted biomarker of vitamin D status, serum 25-hydroxyvitamin D [25(OH)D], and cancer survival in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. Of 4616 cancer cases with measured serum 25(OH)D, 2884 died of their cancer during 28 years of follow-up and 1732 survived or died of other causes. Proportional hazards regression estimated hazard ratios (HR) and 95% confidence intervals (CI) for the association between pre-diagnostic 25(OH)D and overall and site-specific survival. Serum 25(OH)D was significantly lower among cases who subsequently died from their malignancy compared with those who did not (medians 34.7 vs. 36.5 nmol/L, respectively). Higher 25(OH)D was associated with lower overall cancer mortality. Higher 25(OH)D was related to lower mortality from the following site-specific malignancies: prostate, kidney, and melanoma, but increased mortality from lung cancer. Improved survival was also suggested for head and neck, gastric, pancreatic, and liver cancers, though not statistically significantly, and case numbers for the latter two organ sites were small. Higher 25(OH)D status years prior to diagnosis was related to improved survival for overall and some site-specific cancers, associations that should be examined in other prospective populations that include women and other racial-ethnic groups.

For what it's worth.  - c

HAPPY NEW YEAR!!!!!!!!!!!! (And ~ CAPOX as adjuvant for ex-goblet cell adenocarcinoma of the appendix = DONE!)

Happy 2019, my dear peeps!!!

The past 4 months have been a crazy, horrible nightmare, in so many ways.  As I noted here, on day 5 (12/21) of round 4, this one with capecitibine alone, my oxaliplatin having been held due to my neuropathies, abdominal pain and misery were in full force.  For five days I did nothing but move excruciatingly slowly and carefully - as anything jarring or touching my abdomen (like my own arm!!!) produced even more pain - from bed, to chair, to couch; managing that only by virtue of B's assistance and lots and lots of marinol!!  By Wednesday (12/26) my abdomen was still swollen and tender, but less so and I was able to putter about the house a little.  We held the capecitibine all that time as my colitis was too severe to handle more.  Once I was better we discussed attempting more doses, finally deciding I was done.  That was all I could stand.  The whole CAPOX tadah was pretty hellish!!!  BUT!  The most important word in that sentence is ~ WAS!!!!!!!!!!!  I AM DONE!!!!  It has been one heck of an experience!  Hopefully, it did me some good.  Lord knows, if side effects are a positive indication, I should be good to go!!!  I will see my oncologist on the 7th and develop a follow-up plan of some sort.  There is my Stage IV melanoma status to be considered.  B is concerned about all the radiation I have been exposed to with CT scans of my neck, chest, abdomen and pelvis every 3 months for the years of my trial followed by years of them every 6 months and then annually for a couple more.  And that's not even counting various PET scans, chest x-rays, and CT scans I had from 2003 to 2010 or the ones I had while hospitalized in August!  We'll see what we figure out.

I was finally able to get back on the elliptical 4 days ago for my big 15 minutes.  And today ~ I worked in my yard!!!  Though I will certainly be sore tomorrow, it was glorious!  I was able to breathe the fresh air and imagine all the beauty that spring will bring.  I still have some numbness in my fingers and hands.  My feet are burning as I type.  The nasty red painful area remains on my right forearm where the last oxaliplatin infusion infiltrated on 12/3, though it is slowly getting better.  The residual neuropathies should gradually resolve as well.

My dear peeps from near and far, pulled me through - again!!  ALL of YOU, are the reason I am here!  I have been blessed with physical and emotional support that I will NEVER be able to repay or even fully express my gratitude for.  I have been lifted up when I could not - literally (Ruthie and Bentie!!!) and emotionally by ever so many.  Kind words via cards, texts, phone calls, emails and on message boards.  Sweetness that spoiled me in all sorts of ways ~ supportive visits, inspiring books, helpful salves, anti-nausea ginger chews, beautiful talismans, playful gadgets, bright red buttons, funny distractions, meals on wheels, warm slippers, beauty in ever so many forms!  I am blessed.  I appreciate each and every one of you  more than you will ever know.

Together we've made it to 2019!  As for me, I will march forward WITH my past.  All of it.  The difficult and the beautiful.  Working to regain my strength.  Doing my best to appreciate what each day brings.  Striving to make my time on this spinning ball worth something.  Enjoying the wonder of it all.  Appreciating all of you.

For all my dear sweet peeps, may this year bring much joy, love, peace and adventure.  Much love, les