Treatment of intracranial neoplasia in dogs using higher doses: A randomized controlled trial comparing a boosted to a conventional radiation protocol.

BACKGROUND: Local progression of intracranial tumors can be the consequence of insufficient radiation dose delivered. Dose increases in the brain must be made carefully so as not to risk debilitating adverse effects such as radiation necrosis. HYPOTHESIS: A new protocol with 10 × 4 Gy + 11% physical dose increase limited to the macroscopic tumor volume results in a clinically better outcome compared to a 10 × 4 Gy protocol. ANIMALS: Fifty-seven client-owned dogs with primary intracranial neoplasia. METHODS: Randomized controlled trial. Twenty-eight dogs were assigned to the control protocol (10 × 4 Gy) and 29 to the simultaneous integrated boost (SIB) protocol with 4.45 Gy dose increase. Treatment groups were compared for outcome and signs of toxicity. RESULTS: Mild, transient acute or early-delayed adverse radiation effects were observed in 5 dogs. Severe late adverse effects were not seen. Between the protocols, no significant differences were found for outcome (intention-to-treat analysis): overall time to progression (TTP) was 708 days (95% confidence interval (95% CI) [545,872]), in the control group it was 828 days (95% CI [401,1256]), and in the SIB group 627 days (95% CI [282,973]; P = .07). Median overall survival (OS) was 684 days (95% CI [516,853]), in the control group it was 724 days (95% CI [623,826]), and in the SIB group 557 days (95% CI [95,1020]; P = .47). None of the tested variables was prognostic in terms of outcome. CONCLUSION AND CLINICAL IMPORTANCE: The dose escalation used with an 11% physical dose increase did not result in better outcome.

Dose-escalated simultaneously integrated boost radiation protocol fails to result in a survival advantage for sinonasal tumors in dogs.

The prognosis for canine sinonasal tumors remains rather poor despite definitive-intent radiotherapy (RT). Theoretical calculations predicted improved outcomes with simultaneously integrated boost (SIB) protocols. With the hypothesis of clinically detectable differences in outcome between groups, our retrospective study evaluated prognostic variables and outcome in dogs treated with regular versus SIB RT. Dogs with sinonasal tumors treated with either a regular (10 × 4.2 Gy) or new SIB protocol (10 × 4.83 Gy to macroscopic tumor) were included. Information regarding signalment, tumor stage, type, clinical signs, radiation toxicity, response, and outcome was collected. Forty-nine dogs were included: 27 treated regularly and 22 treated with SIB RT. A total of 69.4% showed epistaxis, 6.1% showed epileptic seizures, 46.9% showed stage IV tumors, and 6.1% showed lymph node metastases. Early toxicity was mostly mild. Late grade 1 skin toxicity (alopecia/leucotrichia) was seen in 72.1% of dogs, and a possible grade 3 ocular toxicity (blindness) was seen in one dog. Complete/partial resolution of clinical signs was seen in 95.9% of patients as best clinical response and partial remission was seen as best imaging response in 34.7%. The median progression-free survival (PFS) was 274 days (95% CI: 117-383) for regular and 300 days (95% CI: 143-451) for SIB RT, which was not significantly different (P = 0.42). Similarly, the median overall survival (OS) was 348 days (95% CI: 121-500) for regular and 381 days (95% CI: 295-634) for the SIB RT (P = 0.18). Stratified by protocol, the hazard ratio of stage IV versus stage I-III tumors was 2.29 (95% CI: 1.156-4.551, P = 0.02) for OS but not PFS. All dogs showed acceptable toxicity. In contrast to theoretical predictions, however, we could not show a statistically significant better outcome with the new protocol.

Retrospective assessment of radiation toxicity from a definitive-intent, moderately hypofractionated image-guided intensity-modulated protocol for anal sac adenocarcinoma in dogs.

A recent calculation study predicted acceptable toxicity in pelvic organs at risk for a new definitive-intent, moderately hypofractionated radiation therapy (RT) protocol (12 x 3.8 Gy), when used with image-guided intensity-modulated radiation therapy (IG-IMRT). We hypothesized this protocol to result in clinically acceptable radiation toxicities. Dogs diagnosed with and irradiated for anal sac adenocarcinoma (ASAC) were retrospectively assessed. Eleven dogs were included, six had prior surgery. Before any therapy, staging according to Polton et al. resulted in the following distribution: stage 1 (n = 1), stage 2 (n = 1), stage 3a (n = 6), stage 3b (n = 3). We scored radiation toxicities at the end of therapy, at weeks 1, 3 and every 3 months after RT according to Veterinary Radiation Therapy Oncology Group radiation toxicity criteria. Clinical follow-up was maintained on regular intervals combined with computed tomography (n = 3). Median follow-up time for dogs still alive was 594 days (range: 224-972 days). Within 1 week post treatment, eight dogs (73%) developed grade 2 and four dogs (36%) grade 1 acute toxicity in the perianal region. All acute toxicities resolved or improved to grade 1 within 3 weeks after treatment. Late toxicity, for example, chronic colitis/diarrhoea, ulcerations, strictures or myelopathies was not observed in any patient. Five dogs were euthanized 105, 196, 401, 508 and 908 days after RT and six dogs were still alive, one in spite of progressive disease. The median progression-free survival was 908 days (95%CI: 215; 1602). The previous theoretically described definitive-intent, moderately hypofractionated protocol using IG-IMRT for the treatment of advanced ASAC showed clinically acceptable acute and late toxicities.

Canine presumed glial brain tumours treated with radiotherapy: Is there an inferior outcome in tumours contacting the subventricular zone?

Post-treatment outcome in canine glial tumours is described with a broad range of survival times between 2 and 28 months. After surgery or radiation therapy, the tumours may progress locally or spread within the central nervous system. It is unknown if tumour- or patient-specific factors influence prognosis. In humans, glioblastoma involving the subventricular zone has been found to recur distantly, with shortened time to progression and overall survival. We included 32 dogs irradiated for a presumptive primary glial brain tumour in this retrospective cohort study. Tumours were grouped relative to subventricular zone contact and overt ventricular invasion assessing pre-treatment magnetic resonance images. Median time to progression (TTP) for all cases was 534 days (95%CI, 310-758), with a significantly shorter TTP in dogs with lesions at the subventricular zone (median TTP, 260 vs. 687 days; p = .049). Tumours at the subventricular zone progressed more often (p = .001), and more likely as CNS-metastasis (52.9% vs. 13.3%, p = .028). Median overall survival (OS) was 489 days (95%CI, 147-831) and median tumour-specific survival 609 days (95%CI, 382-835). Involvement of the subventricular zone was significantly associated with a shorter tumour-specific survival (median, 306 vs. 719 days; p = .044). Glial tumours contacting the subventricular zone in dogs have a shorter tumour-specific survival and a higher rate of progression and CNS-metastasis. Despite local tumour control, metastasis must be considered and should prompt further treatment approaches.

Reducing margins for abdominopelvic tumours in dogs: Impact on dose-coverage and normal tissue complication probability.

Image-guided, intensity modulated radiation therapy (IG-IMRT) reduces dose to pelvic organs at risk without losing dose coverage to the planning target volume (PTV) and might permit margin reductions potentially resulting in lower toxicity. Appropriate PTV margins have not been established for IG-IMRT in abdominopelvic tumours in dogs, and herein we explore if our usual PTV 5 mm margin can be reduced further. Datasets from dogs that underwent IG-IMRT for non-genitourinary abdominopelvic neoplasia with 5 mm-PTV expansion were included in this retrospective virtual study. The clinical target volumes and organs at risk (OAR) colon, rectum, spinal cord were adapted to each co-registered cone-beam computed tomography (CBCT) used for positioning. New treatment plans were generated and smaller PTV margins of 3 mm and 4 mm evaluated with respect to adequate dose coverage and normal tissue complication probability (NTCP) of OAR. Ten dogs with a total of 70 CBCTs were included. Doses to the OAR of each CBCT deviated mildly from the originally planned doses. In some plans, insufficient build-up of the high dose-area at the body surface was found due to inadequate or missing bolus placement. Overall, the margin reduction to 4 mm or 3 mm did not impair dose coverage and led to significantly lower NTCP in all OAR except for spinal cord delayed myelopathy. However, overall NTCP for spinal cord was very low (<4%). PTV-margins depend on patient immobilization and treatment technique and accuracy. IG-IMRT allows treatment with very small margins in the abdominopelvic region, ensuring appropriate target dose coverage, while minimizing NTCP.