How Many Chemotherapy Sessions are Best for Osteosarcoma in Dogs?

If you are researching osteosarcoma chemotherapy choices for cats and dogs, you may find conflicting information about the most effective number of chemotherapy treatments for this cancer. Veterinary oncologists recommend anywhere from four to six rounds of chemotherapy, depending on their own remission success rates and which veterinary oncology studies they follow.

CSU Studies Carboplatin, Doxorubicin Protocols for Dogs with Osteosarcoma

In an attempt to reach a consensus about the best number of chemo sessions for canine osteosarcoma patients, researchers at Colorado State University’s College of Veterinary Medicine and Biomedical Sciences conducted a study called

“Comparison of Carboplatin and Doxorubicin-Based Chemotherapy Protocols in 470 Dogs after Amputation for Treatment of Appendicular Osteosarcoma.”

We don’t have the scientific background to interpret the study but thankfully Tripawds member Katy Richards-Hrdlicka, aka Jackson’s Mom, does! She kindly wrote the following guest blog post to help us makes sense of the study and its accompanying conclusions. Here it is (along with fun photos and video of Tripawd Hero Jackson, 18 months post -diagnosis and doing great!).

“Many pawrents here grapple with the decision to proceed with IV chemotherapy for very good reasons. There are side effects to consider, types of drug(s), route of administration (oral, known as metronomic chemotherapy vs intravenous, the more common and traditional), duration (3, 4, 5, or 6 rounds, 1 year, 1.5 years, etc), and cost. If you have a great relationship with your oncologist and that oncologist is up on the literature, having a discussion about these factors can be a relief, grant sanity, ease restless nights, form bonds, and give life.

But then there’s the assessment that no one can answer: will it work? Is it worth it?

When a new Tripawd joins the club due to osteosarcoma, we see different treatment plans. For the most part, carboplatin is the recommended drug and it’s administered 4-6 times, each 3 weeks apart. Understandably, when one dog gets 6 rounds and another 4, folks may think (especially the owners!) “more is better.”

To address this concern, we turn to a recent study out of Colorado State University’s College of Veterinary Medicine. We respond with: “there’s no difference between 4 and 6, so save the time and money and go with 4 rounds of carboplatin.”

Here’s the rub, for me anyway: I’m a trained scientist, so when I hear there’s no difference between 4 or 6 rounds of IV carboplatin for osteosarcoma, I want to know the details. I got in touch with the study’s lead author and when the final paper came out, Dr Selmic emailed me its PDF.

Here’s the title, author info, and abstract:

Comparison of Carboplatin and Doxorubicin-Based Chemotherapy Protocols in 470 Dogs after Amputation for Treatment of Appendicular Osteosarcoma: L.E. Selmic, J.H. Burton, D.H. Thamm, S.J. Withrow, and S.E. Lana

Many chemotherapy protocols have been reported for treatment of canine appendicular osteosarcoma (OSA), but outcome comparisons in a single population are lacking.

Objective: To evaluate the effects of protocol and dose intensity (DI) on treatment outcomes for carboplatin and doxorubicin-based chemotherapy protocols.

Animals: Four hundred and seventy dogs with appendicular OSA.

Methods: A retrospective cohort study was performed comprising consecutive dogs treated (1997 – 2012) with amputation followed by 1 of 5 chemotherapy protocols: carboplatin 300 mg/m2 IV q21d for 4 or 6 cycles (CARBO6), doxorubicin 30 mg/m2 IV q14d or q21d for 5 cycles, and alternating carboplatin 300 mg/m2 IV and doxorubicin 30 mg/m2 IV q21d for 3 cycles.

Adverse events (AE) and DI were evaluated. Kaplan–Meier survival curves and Cox proportional hazards regression were used to compare disease-free interval (DFI) and survival time (ST) among protocols.

Results: The overall median DFI and ST were 291 days and 284 days, respectively. A lower proportion of dogs prescribed CARBO6 experienced AEs compared to other protocols (48.4% versus 60.8–75.8%; P = .001). DI was not associated with development of metastases or death. After adjustment for baseline characteristics and prognostic factors, none of the protocols provided a significant reduction in risk of development of metastases or death.

Conclusions and Clinical Importance: Although choice of protocol did not result in significant differences in DFI or ST, the CARBO6 protocol resulted in a lower proportion of dogs experiencing AEs, which could be advantageous in maintaining high quality of life during treatment. DI was not a prognostic indicator in this study.

I’m now going to summarize the study, give you my thoughts as a scientist (I have a PhD in genetics from Yale University) and doggie-mom (Jackson is 18 months post-amp for OSA in his right hind limb), and some context:

Which Osteosarcoma Dogs Were Studied?

• 470 dogs were enrolled in this study. It was retrospective. They basically called clinics and got records of dogs that fit the criteria: OSA, amputation, followed by 1 of 5 different chemo options. The 5 chemo options:

1. carbo x 4 doses,
2. carbo x 6,
3. doxy every 14 days x 5,
4. doxy every 21 days x 5, or
5. alternating carbo and doxy for a total of 3 doses each (grand total, 6 doses of chemo).

• This is perhaps the largest sample size ever! Kudos! But, retrospective is tough. They had no control over what else came with the criteria, such as equal sample sizes per chemo option or exact dosage levels per body weight. They also had no control over how or how often the dogs were monitored, which impacts a major, common statistic: disease free interval (DFI) – more on this later.
• I learned that nearly 40% of dogs will not complete their prescribed treatment! I didn’t realize it was this high. The protocols that have the highest dropout rate are mostly explained by the time commitment (3 vs 6 rounds) and side effects. Owners and sometimes our wallets take a beating and we cannot proceed with as many treatments as prescribed. Or there are vacations, family events, etc., that postpone (called, “treatment delay”) or cancel chemo plans altogether. Dogs getting carbo6 had the most treatment delays; this was one of the two significant findings from the study.
• The other significant finding was that all pets, no matter the treatment, experienced fewer side effects as treatments continued, especially in the carbo6 group. This could be that physiologically, chemo was less harmful as the patient proceeded through treatment. However, what is probably happening (and we read it here all the time) is that owners learn how to manage side effects better so there simply is less data on side effects. I also have a pet theory: carbo is expensive and if given 6 doses, the owner had the time and resources for it. I wonder if with carbo, anti-nausea are more commonly administered? It’s an economic issue, then, and maybe not a “side effect” issue. I wonder if dogs that got carbo ALSO got meds and advice to help mitigate side effects altogether?
• Perhaps another similar economic sidenote: dogs that developed mets and got subsequent metronomic therapy and/or Palladia were more likely to have had carbo, especially 6 rounds of it, than anything else. Carbo is more pricey. If an owner has committed the resources to carbo AND 6 rounds of it, I suspect (another pet theory of mine!) that owner is also more likely to keep fighting with metronomic therapy and/or Palladia.

Here”s the revelatory part. I was stunned. Speechless.

The common, industry-approved metric for processing these stats is to lump all the patients together based on their PRESCRIBED treatment, not by what they actually got. That means that if you agreed to 6 rounds of carbo, but mets were discovered before the 3^rd round and you stopped treatment, your dog and all her stats would be included in the “6 rounds of carbo” group.

This is a major problem. I understand that this stat needs to continue as so many foundational studies have used this and that means folks can compare outcomes. Or does it? Thankfully, Dr Selmic did other analyses with the ACTUAL doses in the Supplemental Info, but not in the manuscript’s main text. If you also have access to her work, you”ll now notice I’m going to largely ignore the rest of the tables and data from the main text and focus on the Supplemental Info.

[youtube]http://youtu.be/fj2jeg_GaKI[/youtube]

Which Osteosarcoma Dogs Lived Longest?

• If you’re wondering whether my non-oncologist instinct was correct: when all dogs, no matter if they completed their prescribed treatment, are examined for survival time (regardless of chemo option), the average survival time is 284 days (actually, statistically between 248-316 days). When the dogs that dropped out of chemo are removed from the same calculation, it jumps to 367 days (actually, between 325-401 days)! THAT, my friends, shows there’s a SIGNIFICANT difference between chemo drop-outs and sticking to the plan…most certainly when it comes to stats. I’m assuming the dogs that dropped out had 1 or 2 or 3 doses of chemo.
• The results show the same trend with DFI (291 days vs 398 days for dogs that completed chemo). A little more about DFI: for this type of cancer, it’s known to progress to the lungs next. It can go elsewhere, too, but primarily to the lungs. There are some owners out there who have chest xrays done every 3 months and there are others who never do (I am one of those pawrents). An owner who prefers regular xrays is bound to find mets earlier than an owner like me. Because this was a retrospective study, there’s no good way for the authors to tell the “true” time of mets – before clinical signs (i.e., mets appeared in chest xrays) or with clinical signs (with or without xrays to confirm). Thus, I think the stat of DFI is skewed and hard to interpret. I prefer to look at survival time, as death is an obvious endpoint. Of course using death as the endpoint is also problematic: what about the dogs that live for 2 weeks with mets vs a year with mets? In this case, the endpoint is still obvious (death), but the quality of life is different!
• Dogs that had 6 rounds of carbo lived longer and developed mets less often! Hold on, though, it gets complicated. Let me introduce some other important factors about fighting this battle:

• For years now, oncologists have known there are certain predictors that increase the likelihood your dog will succumb earlier or later to OSA. These include if the tumor was in the proximal humerus (nearest the body, not the paws, which is radial), high grade tumor or high mitotic rate, and elevated serum ALP. Also, pure bred dogs and heavier dogs (note, this isn’t saying overweight, as in obese) fare less well. The age of the dog only predicted a shorter survival time, but that’s not saying much: senior dogs die more often than young dogs just like elderly humans die more often than younger humans.
• The above info is really important just on its own. If your pup has any of these predictors, studies suggest your battle will be shorter. Some may read that and decide that it’s not worth investing loads of vet visits and money into a cancer that’s really aggressive. Some will read that and decide that it’s even more important to fight like the dickens and throw every resource at it.
• I suggest is you bring this knowledge to your oncologist and discuss, as there are particulars: is the mitotic index crazy wicked high (grade 3 vs. 20, for example)? Maybe the tumor was in the proximal humerus, but you guys caught it early so that spread was probably more contained than if the tumor were huge. PLEASE discuss these predictors with your oncologist!

Back to the paper. OK, so 6 rounds of carbo show the longest DFI and ST. But, not really. That’s because once the authors controlled for the above predictors in only the dogs that actually completed the prescribed protocol, there was no statistical difference among ANY chemo option in terms of DFI or ST. What does this mean? Dogs that made it through their prescribed protocol and did NOT have any of the known predictors above were used in the statistical calculations.

• This shows that the predictors are real, as the statistical test had different results between the two pools of dogs (those with predictors and regardless of predictors). Dogs that have all the above predictors had shorter DFIs and STs.
• It also means that if your dog doesn’t have one of these predictors and completes its prescribed chemo, your pup’s DFI and ST aren’t influenced by the chemo protocol!
• Or, they didn’t have a large enough sample size to detect a difference.
• Here are the data for dogs that actually completed their prescribed protocol (in the supplemental info section, table 3). We see that there is a longer DFI (605 days) and longer ST (390 days) when given 6 rounds of carbo vs 4. But what isn’t shown here are the stats (confidence intervals) that go with these, but the authors tell us there’s no statistical significant difference. The results are equal because the power to assess the true ST and DFI is either too low (thus, too few dogs enrolled in each of these treatment groups), or there really is no difference:

Do Your Best to Complete Chemotherapy

In conclusion, the type of chemo given didn’t make a statistical difference about the dog’s DFI or ST, assuming the dog finished its prescribed protocol. What DID make the difference was whether the treatment was finished at all. And by “finished,” at the least, that’s 4 doses of anything. This aspect was not emphasized in the paper. It wasn’t really the paper’s aim, but as a Tripawd-Warrior mom, that IS my aim!

I want to know how many doses should we go for? If there are side effects and we’ve done 3, should we push it and do 1 more or 3 more? From these data, it appears doing anything for 4 rounds is as good as 6 rounds of anything.

Then again, there may not have been enough pups enrolled to differentiate between 4, 5 or 6 rounds, or of what protocol.

Bottom line: do your best to complete the chemo protocol, on time, with the proper dosage.

Many thanks to Katy for contributing this important information to the Tripawds nation. If you have experience in an applicable topic that you’d like to share with the community, contact us today, we especially love guest blog volunteers!