Hemangiosarcoma… and a general plea to show me the data

This is not a typical post. It’s some combination of an ode to my dog who is in the late stages of hemangiosarcoma, combined with some commentary on information I found related to the diagnosis. This is not an update on the state of research on hemangiosarcoma — it’s just a post following the path of about an hour’s worth of my thoughts as I processed information. I’ll put a review of the state of research on hemangiosarcoma on my to-do list.

A little over a month ago, my beloved dog Ginny started bleeding internally from a tumor on her spleen. She went through a few bouts of lethargy over a few weeks before the diagnosis was made. I made the quick decision to have her spleen + tumor removed and she made a rapid recovery to her usual self. For a lovely month, we joked that her spleen was just weighing her down. She didn’t miss it at all and we didn’t have to miss her.

The surgery was on a Tuesday and we got biopsy results back early the following week — visceral hemangiosarcomy (HSA). I don’t know why I didn’t look up more information at the time or ask more questions of the vet. In retrospect, it’s rather unlike me, but I didn’t want to dwell on what I couldn’t control. I wanted to spend quality time with best friend. The vet who gave me the news simply said that the cancer was “in her blood” and she would have symptoms again at some point — it could be in months or years and there was no way to know. It might have just been what I wanted to hear, but I feel she emphasized the years option more than the months option. She said we would do check-ups every 6 months, instead of every year. She said to look out for signs of liver disease, but she didn’t say (that I remember) to stay on the look out for more internal bleeding. And she didn’t tell me that dogs with this type of cancer that’s not treated with chemo are more likely to survive a few months — it’s pretty rare to go a whole year or more. I’m not saying this to criticize or blame — it’s just what happened. I trusted and interpreted implicit messages how I wanted to and chose not to ask more questions. It seems I have a habit of trusting too much in personal matters. And, there’s the interesting aspect of clinicians simplifying things for people with little science background — she isn’t someone I had enough of a relationship with for her to know I’m a statistician and fully capable of digesting and evaluating information about uncertainty in outcomes — but that’s a bigger topic for another day.

Ginny was just shy of her 10th birthday at the time — and we celebrated her 10 years in this world on June 24th. We adopted her from a local animal shelter when she was 4. The six years went by so fast. She made our lives richer and brought daily joy to the family. She’s an incredibly perceptive dog, always in tune with our emotions and determined to always be with us. She looks deep into my eyes with her wise, beautiful brown ones. She’s smart and very stubborn. She’s my first dog with extreme facial hair — and I have grown to love it so much. I love her bed-head when she wakes up in the morning and I love smoothing it out for her. She’s not soft to the touch, but she doesn’t need to be.

It turns out we had weeks, not months… and certainly not years. Early last week she got lethargic and weak again, and I knew … even though I didn’t want to know. I tried to blame it on a raw hide we had given her, but my gut took us back to the vet — where they confirmed she was bleeding internally again. I knew there wouldn’t be options, beyond keeping her comfortable with medication and trying some medicine to help clotting and reabsorption. After a night of thinking we might lose her, she slowly got better over a few days — some really good hours turned into a few really good days. She even took a couple steps toward chasing a bunny, she chased a magpie out of the yard, she played with a little stuffed horse she found that makes neigh sounds, and she had a couple of nice walks with wading in creeks and rivers.

I wrote most of this post last week, but never found the time to finish it up and post it — probably for a reason. This morning she’s lethargic again and her gums are pale again. The looks she gives me are hard. I’m sitting on the floor next to her while she rests. Maybe the bleeding will stop again and maybe it will not. It is a lesson in accepting and living with uncertainty.

This post really is more about her than hemangiosarcoma. But, I’ll still share thoughts that came up as I looked through some information. It helps things sink in a little more, as I start to learn and wonder more about this type of cancer.

[Some thoughts on information I found]

This fact sheet by the American College of Veterinary Internal Medicine (ACVIM) seemed like a good place to start to me:

• Cancer of the epithelial cells that make blood vessels
• More common in dogs than in any other species [interesting…]
• Primary sites it shows up are spleen, liver, heart, and skin [Ginny got spleen first]
• Internal tumor symptoms: unexplained weight loss, bulging belly [Ginny had], decreased exercise/stamina [Ginny had], lethargy/sleeping more [Ginny had], decreased appetite [Ginny had only when feeling really bad], increased panting, pale gums [yep], weakness [yep], cough [nope], and collapse [nope].
• “There is not currently a perfect blood screening test for HSA, though one has been developed and investigators are working on refinement of our understanding of how to use such a test.” [Interesting — we did not get that option and went with the biopsy after removing the tumor on her spleen.]
• “it is rare when patients with spleen HSA are cured following surgery to remove the spleen as tumors that arise in that site are usually associated with metastasis (spread of tumor cells from primary site via the blood stream to new locations such as lung). This metastasis occurs even if there is no evidence of secondary tumor sites at the time of surgery. The average survival prognosis for patients with spleen HSA following surgery alone is approximately two months, with only 10% survival at one year. The average survival for dogs with spleen HSA treated with surgery and chemotherapy is improved at six to eight months and patients typically experience an excellent QoL during with treatment.” [This one is interesting, and clearly relevant. I actually really appreciate that the vet did not just hand me the average survival prognosis! She made it very clear that the prognosis was uncertain and could be a couple months to a few years. She focused on variability rather than average. I do find it somewhat ironic though that despite my often loathing averages, it looks like my dog is pretty close to average (only on this outcome of course). We weren’t offered and didn’t consider chemotherapy.]

In my hour of looking and reading, here’s the second source I took the time to read and a couple of quotes:

• “The reported median survival times for dogs with splenic hemangiosarcoma treated only with surgery are 19-86 days. Nevertheless, patients who do undergo surgery tend to feel better in the short term.” [I can attest to the feeling better and Ginny was in the 28 day range]
• “Chemotherapy after surgery is often recommended because hemangiosarcoma is highly malignant and readily metastasizes. Indeed, this cancer has typically already spread at the time of diagnosis. Many different chemotherapeutic agents have been investigated to treat hemangiosarcoma. Use of the drug doxorubicin is associated with longer survival times. The reported median survival times for splenic hemangiosarcoma treated with surgery and doxorubicin-based chemotherapy is 141-179 days.”

I then found this trial at University of Minnesota, but…

For a few minutes, it made me wish I would have done immediate research, but really I am really at peace with where we ended up. I don’t know what chemotherapy effects might look like and there is a financial reality, even if that’s hard to admit.

And finally, here’s a 2018 paper describing a Brazilian study comparing outcomes from surgery vs surgery + doxorubicin (the same treatment being looked at in the University of Minnesota study). The analysis uses survival data from 37 dogs who were treated between 2005 and 2014. It’s retrospective and they do a good job of making that clear. Of course, there’s “significance” all over the place and it’s not clear if they mean statistical significance or practical or both — but I think they make the common mistake of assuming statistical significance implies practical importance. And, it’s hard for me to stay engaged with papers when I get to paragraphs like this:

But to be fair, there’s a lot of good stuff in the paper and I don’t blame the authors specifically — they’re doing what they’re expected to do within the system they work in. But, when will expectations shift to require real justification of the reasonableness of p-value cutoffs? What will it take? Why does it not make scientists uncomfortable that most people using p-value cutoffs probably could not provide a reasonable justification for their choice if forced to? But, for today, I can forgive the cut-offs… I just really want to see the raw data displayed clearly and with relevant information. I mean, there’s only 37 dogs at the beginning… should not be a huge task. Just show me the data. But no such luck.

They do show Kaplan-Meier curves and give estimates of median survival time for the two groups, trying to take into account censoring for dogs that were still alive at the end of study. But no raw data plots, or even tables, just some descriptions in the text. It is my experience that we don’t teach creative data visualization in data analysis courses and many researchers do not have the computing skills to make non-automatically generated plots from raw data. Again, a fault of the system and norms — but I can’t help but wonder how they cannot really want to see their data. But, just because I love looking a raw data and thinking about creative ways to display relevant information with it (like treatment (obviously), age, severity, etc.).

In this case, of the 37 total dogs included, the paper states that 11 were alive at time of data analysis and 2 were were lost to follow-up. Twenty three of the 37 dogs were treated with surgery only and 14 with surgery + the chemotherapy. It’s not explicitly stated (that I saw), but looking at the stats, it appears that all 11 of the dogs still alive at time of data analysis were in the chemo group. That would be some important information!? What survival times are actually going into the 274 day summary statistic? What about the two lost for follow up that were censored? Were they treated in the same way as dogs who were still alive? Instead of offering an intuitive discussion of the raw data, as the information going into the model, it’s all about default and automatic results from the survival analysis. I just want raw data… is that too much to ask?

Here are a couple of relevant results paragraphs:

They talk about clinical stage, type of tumors, and give the numbers of dogs in each of these groups. They even get their p-value comparing estimated survival time for different stages, but they don’t take into account treatment in that analysis. That is, the analysis looks at potential questions separately (e.g., differences in stages are completely separate from differences in treatments) — making the very strong implicit assumption that there is no interaction between the stage of disease and effect of treatment (or choice of treatment). There may not be enough data to estimate the interaction, but that doesn’t mean it should unquestionably be ignored in the analysis or discussion.

I appreciate that they gave the fractions of dogs in different categories and not just the percentages. At least that some adherence to the raw data.

They acknowledge the “absence of a significant difference” among primary organ … may represent a false-negative due to a type II error related to the small sample size of the study.” It would be interesting to look into how often the possibility of type II errors are brought up in papers when large p-values occur vs. the possibility of type I errors when small p-values occur. Just a thought. They even say “it is not possible to establish definitive conclusions on the importance of primary tumor locations of HSA based on our study.” It is just 37 dogs that are likely pretty heterogeneous in many respects.

If I can get beyond the usual issues I have reading scientific papers that overly rely on automatic, default-like use of statistics, I do get useful information from this one. It does appear — and I could get this without any statistical modeling — that survival times were generally longer for the dogs whose owners chose the chemotherapy option after surgery. The raw data would be helpful! Eleven of the dogs were still alive at the time of data analysis, so really they would just have to give me 26 numbers and some text about characteristics of the still alive dogs. Even without the skills to made a cool plot, it could easily all go into an ugly (but useful) table. I can look at the Kaplan Meier curves and pull out a lot of information, but should I have to?

Finally, I do appreciate the last paragraph. I think it is humble and honest and doesn’t try to oversell anything. Overall, my take is the authors did a good job within their understanding and skills relative to data analysis and the system they are operating in.

As I said in the beginning, this post is not meant to be a thorough or rigorous review of hemangiosarcoma research. I just provided a running view of my thoughts as I spent an hour looking up information. Am I being overly picky and critical of the paper I found? Maybe. But, most of the time I don’t think so. To me, the point is to consider what the people making care recommendations and decisions are getting out of such an article. That is — what is the veterinarian getting out of it? What’s the take home message? Likely the take home message would be that chemotherapy is helpful and should be recommended if the dog’s humans are open to it and can afford it. And maybe that’s the right choice, but this paper doesn’t provide as much support for that as I think a vet would conclude. Vets are busy treating our beloved dogs and shouldn’t be expected to have the time or specific expertise to dig into how trustworthy a data analysis is – to think about the information in the data vs. the information inserted through modeling assumptions. They may not understand the issues with p-values and the assumptions underlying estimates from a Kaplan-Meier survival analysis — so they are put in a situation to trust. I guarantee they could easily understand a plot (or even table!) of the raw data though — particularly one that codes by stage of cancer, breed, etc. In my opinion, no fancy statistical modeling was needed here. We just needed to see the raw data in ways that are easy to digest and include as much relevant information as possible. But, statistical software packages automatically spit out Kaplan-Meier plots, but they don’t automatically spit out creative and useful plots of the raw data. So, here we are. We need statisticians whose job is creating plots of raw data for people — I would take that job, as long as I don’t have to do needless modeling for the sake of modeling.

Thank you

And finally… I have to do it. Thank you Ginny. Thank you for all the support, the laughs, and the general joy you brought me over the last six years. You have been my constant. I hope we gave you as much. Regardless of estimated survival times and raw data, I just can’t imagine life without your wise, caring, deep brown eyes keeping an eye on me.

Like many of you — I’ve had enough of 2020.

References

Batschinski, K., Nobre, A., Vargas-Mendez, E., Tedardi, M. V., Cirillo, J., Cestari, G., Ubukata, R., & Dagli, M. (2018). Canine visceral hemangiosarcoma treated with surgery alone or surgery and doxorubicin: 37 cases (2005-2014). The Canadian veterinary journal = La revue veterinaire canadienne, 59(9), 967–972.

https://vetmed.umn.edu/centers-programs/clinical-investigation-center/current-clinical-trials/pro-dox-propranolol-and-doxorubicin-dogs-splenic-hemangiosarcoma

http://www.acvim.org/Portals/0/PDF/Animal%20Owner%20Fact%20Sheets/Oncology/Onco%20Hemangiosarcoma.pdf