34th Annual Scientific Meeting proceedings

Introduction
Canine thyroid carcinoma is a malignant tumour of the thyroid gland in dogs, which is commonly encountered by different practitioners at specialist or referral level.

Treatment is usually straightforward when the tumour is mobile and surgical excision alone can result in long-term survival. Local recurrence and metastases can occur, which may necessitate radiation therapy or systemic therapies, for both local and distant tumour control, respectively.

These tumours can be locally invasive and surgical excision can be impossible, beyond what the owner or surgeon feels is appropriate for the patient or carry a risk of high morbidity. Thyroid carcinoma can have a high metastatic potential overall, and whilst metastases often progress slowly (i.e. not necessarily negating a rationale for local disease control), the presence of metastases may result in a vet/owner choosing a less invasive (non-surgical) option due to a more uncertain outcome.

Radiotherapy has emerged as a valuable tool in managing this cancer and there is published data reporting efficacy. In addition, with more sophisticated (and more readily available in the UK) radiation techniques, there are a variety of radiation options to treat thyroid cancer in pets.

Fractionated Radiation Therapy
This is where the total radiation dose is split into smaller doses (called “fractions”) and delivered daily Monday-to-Friday over ~3-4 weeks. The unit of radiation dose is the Gray (Gy). A typical prescription for curative-intent (probably better called “definitive-intent”) treatment is ~45-54 Gy in 2.5-3.0 Gy fractions (usually around 15-20 treatments in animals). This is to allow a high total radiation dose to be delivered, as splitting the dose makes it more tolerable long-term for certain normal tissues near to the tumour (i.e. prevention of serious, late-onset side effects of radiation). When the goal is cure or long-term tumour control, acute (short-term, temporary) side effects can be tolerated, and can be more severe/frequent with these types of protocols.

When treatment has a palliative-intent, it is important that acute side effects are minimal/tolerable and the protocol should be relatively short with few treatments, less anaesthesia and easy for both pets and their owners. For this reason, hypofractionated protocols are often utilised (a small number of large doses), most commonly with one dose being given per week for 4-6 treatments (e.g. 8 Gy once per week for 4 sessions, 6 Gy once per week for 6 sessions). The total dose given is less and there is longer gap between sessions; again to minimise short-term toxicity. But this also leads to a lower probability of durable tumour control.

There are variations to these protocols, but these are “typical” examples.

The most commonly published definitive-intent protocol is ~48 Gy given over ~4 weeks. Studies are small. In two small studies (n=8, n=25), this protocol was associated with median survival times of 2 years and median not reached with 1-year and 3-year survivals of >80% and >70%, respectively. Importantly, thyroid tumours may shrink slowly, which may have implications for severely clinically affected cases (8-22 months for shrinkage nadir in one study). This is mixed in reports however, as in one of these studies all patients had a complete response by 6 months post-RT. I have seen many cases that have achieved long-term stable disease, but there has only ever been very modest (or no) appreciable shrinkage. Therefore, no/modest shrinkage or very slow gradual shrinkage over months is often the norm, in my experience.

Importantly, toxicity can be marked with most dogs experiencing some degree of dermatitis, pharyngitis, dysphonia or dysphagia. Whilst this is temporary, and will typically resolve within a month of RT completion, it can result in morbidity and additional medication requirements. I have noticed in particular that patients with cranially positioned ectopic tumours can develop more obvious dysphagia/drooling which could also increase the risk of regurgitation or anaesthesia complications. Owners need to be prepared for this. Using IMRT protocols may help to reduce this toxicity by limiting the dose to normal structures, particularly for smaller well-defined tumours which are unilateral – but given the typical extent of these tumours, a large volume of the neck is still often treated.

There are two published studies looking at hypofractionated/“palliative” radiation therapy, which report very different outcomes:

• One study from 1999 where dogs (n=13) were treated with a uniform protocol of 9 Gy x 4, on a once-per-week basis. The median survival time was ~2 years (Survival at 1-year and 2-years was 80% and 45%) and presence of metastasis made no difference to outcome
• One study where pets received various (mostly hypofractionated) palliative-intent protocols and the median survival time was ~5 months (but the majority were deemed by owners to have improved symptom control and QOL, and would have done it again). Those that had a complete response did well for many months

I think it is important to consider that:

• Thyroid carcinoma is heterogeneous, which could result in these disparate outcomes, particularly given the small numbers
• The protocol in the former study was homogenous and 9 Gy fractions are highly damaging (note: to both tumour and normal tissue…), whereas the latter study utilised a variety of protocols
• In the latter study, dogs were largely highly advanced cases with voluminous tumours (20% didn’t complete the protocol) – possibly a different (worse) patient population
• In the latter study, patients were selected for these protocols as they were being treated with “palliative intent”. In the former study, whilst the protocol was hypofractionated, this was simply the protocol that the investigators treated with (machine availability in the UK at the time in the 90’s) – i.e. patient were treated with this protocol regardless of the “intent” or expectations. This highlights that protocol “intent” is important – we know for some tumours hypofractionated may work at least as well (if not better) – but they might be less preferred because they are more damaging to normal tissue. However, with the advent of new technologies that allow for greater focus and precision (shielding of more normal tissue), hypofractionation is making a comeback in both veterinary and human medicine

Overall, based on the published data, it does appear that definitive-intent RT is associated with longer survivals overall – though there are no high-powered comparative studies.

Stereotactic Radiation Therapy (SRT)
Also called stereotactic body radiation therapy (SBRT), stereotactic ablative body radiotherapy (SABR) or stereotactic radiosurgery (SRS). This is a very hypofractionated form of radiotherapy, given over only a few doses, but a very large dose is given per fraction and over a short time period. This is made possible by using specialised linear accelerators with particular hardware, software, image-guidance and physics support that allow for extremely focussed radiation fields that are delivered with high precision. This allows normal tissue to be spared by avoiding it being in the high-dose region, rather than relying on the principle of fractionation of the dose. THEREFORE WE ARE TREATING GROSS TUMOURS – THIS IS NOT SUITABLE FOR POST-OP CASES WHERE WE ARE TREATING LARGE VOLUMES OF NORMAL TISSUE. A typical prescription might be 10 Gy x 3, daily or 8 Gy x 5, daily. In some instances a single dose could be given (20-30 Gy single fraction). The extremely accurate dose delivery often means a much higher total dose can be delivered to the tumour than could ever be delivered with conventional techniques, as these prescriptions would be very damaging to normal tissues. Individual protocols may be needed, as the tolerable dose (per fraction and total dose) will depend on the anatomy, tissues nearby and volume of those tissues that can be spared. The goal of SRT can be definitive or palliative – depending on the tumour type, disease stage and typical responsiveness.

There is one case series (n=23) assessing SRT in canine thyroid carcinoma. A variety or protocols were used but in 70% it was 10 Gy x 3 (30 Gy over 3 consecutive days: note the total dose is often lower than that given in definitive fractionated protocols, which is because high dose fractions are much more damaging to tumour or normal tissue). ~40% of pets had a grade 1 acute toxicity in skin or oesophagus (the lowest level of adverse effects) and the remainder had no reported toxicity at all. The median survival time was 1 year. Whilst this is lower than reported for definitive-intent fractionated cases, it is likely that this is partly due to case selection:

• 70% of these cases were “unresectable” – at a practice which specialises in surgical oncology
• Most tumours were very large
• Small tumours may be able to receive a much higher dose

Importantly, >80% of symptomatic patients had a clinical improvement within ~2 weeks of treatment (maybe more useful than conventional RT for very symptomatic pets?) and no pets had significant late effects (note: still have to consider this in cases anticipated to have a chance of long-term survival). Additionally, most pets had completed treatment in 1-3 days.

Ultimately, given there are no comparative studies, it is difficult to know whether SBRT is “as good” for thyroid carcinomas as conventional, definitive-intent RT. I will offer SRT if it is safe based on nearby anatomy and I can get a dose in there that is equivalent biologically to a standard definitive-protocol.

What about post-operative RT?
I generally don’t recommend this as local recurrence tends to be less of a problem (in my experience) – though it has been previously reported in up to 25% of cases in one study of mobile thyroid tumours. Because of my perceived low rate (?referral bias) of true local recurrence, and the fact that thyroid tumours tend to respond well in the gross disease setting, I tend not to offer adjunctive RT as standard – particularly for mobile cases, even if they reportedly breach the capsule histologically. That said, I will recommend CT the neck for post-op cases and monitor them this way. I will also discuss individual cases with surgeons – as if there is high concern for residual (albeit small volumes) of gross disease, then we can certainly discuss “proactive” adjunctive RT. Of course, if a tumour has already recurred locally and then been removed again, then of course I will offer adjunctive RT.

Haemoclips
I have found these to be very useful in individual cases. If a surgeon finds a case challenging and are worried about a particular area where the tumour was very adhering/concern for gross residual disease, then clips can be seen on the planning CT, which allows us to target a particular area of concern more specifically. This might then reduce the likelihood of missing tumour, reduce required field size and thus reduce toxicity.

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Canine thyroid carcinoma cannot be treated in this manner in the UK due to the doses involved. However, it does appear to be useful with doses ranging from 15-50 mCi in one study (Australian) and 100 mCi in another (USA). Median survival times of ~30 months were seen in both studies and in one surgery made no difference compared those that had radiation alone. In another study, metastasis reduced median survivals from 28 months to 12 months. Pancytopenia due to bone marrow suppression can be seen sporadically.

In cats, some hyperthyroid patients can have thyroid carcinoma. Various doses have been used, but ~30 mCi has been used successful with resolution in most.

Conclusion
Radiotherapy represents a valuable therapeutic option in the management of canine thyroid carcinoma. It is essential for surgeons and radiation oncologists to collaborate closely to ensure precise treatment planning and delivery.

It is clear that thyroid carcinoma can respond to many different RT fractionation schemes, and the ultimate choice will be based on patient age tumour size, location, costs, institutional availability of equipment, patient co-morbidities etc.

Although complications and side effects may occur, they are generally predictable and manageable. New techniques and more palatable protocols may offer hope for improved outcomes and extended survival in cases of canine thyroid carcinoma.

Continued research and advancements in veterinary radiotherapy techniques hold promise for further enhancing the efficacy of this treatment approach.