Comparative evaluation of a novel, moderately hypofractionated radiation protocol in 56 dogs with symptomatic intracranial neoplasia

BACKGROUND: Use of strongly hypofractionated radiation treatments in dogs with intracranial neoplasia did not improve outcomes and yielded increased rates of toxicosis. OBJECTIVES: To evaluate safety and efficacy of a new, moderately hypofractionated radiation protocol of 10 × 4 Gy compared to a standard protocol. ANIMALS: Convenience sample of 56 client-owned dogs with primary symptomatic brain tumors. METHODS: Retrospective observational study. Twenty-six dogs were assigned to the control standard protocol of 20 × 2.5 Gy (group A) and 30 dogs to the new protocol of 10 × 4 Gy (group B), assigned on owners' informed consent. Statistical analysis was conducted under the "as treated" regime, using Kaplan-Meier and Cox-regression analysis. Treatment was delivered with technically advanced image-guided radiation therapy. The 2 treatment groups were compared in terms of outcome and signs of toxicosis. RESULTS: Overall progression-free interval (PFI) and overall survival (OS) time were favorable, with 663 (95%CI: 497;828) and 637 (95%CI: 403;870) days, respectively. We found no significant difference between the two groups: PFI for dogs in group A vs B was 608 (95%CI: 437;779) days and mean (median not reached) 863 (95%CI: 644;1083) days, respectively (P = .89), and OS for dogs in group A vs B 610 (95%CI: 404;816) and mean (median not reached) 796 (95%CI: 586;1007) days (P = .83). CONCLUSION AND CLINICAL IMPORTANCE: In conclusion, 10 × 4 Gy is a safe and efficient protocol for treatment of primary intracranial neoplasia and future dose escalation can be considered

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

Cell line-specific efficacy of thermoradiotherapy in human and canine cancer cells in vitro

Objective Aims were to investigate sensitivity of various human and canine cancer cell lines to hyperthermia and the influence of particular treatment conditions, and to analyze the DNA-damage response and mode of cell death in cell line radiosensitized by hyperthermia. Additionally, we were interested in the involvement of HSP70 in radiosensitization. Methods Radiosensitization by hyperthermia was determined in a panel of human and canine cancer cell lines using clonogenic cell survival assay, as well as levels of heat shock proteins (HSPs) using immunoblotting. The influence of the hyperthermia-radiotherapy time gap, different temperatures and the order of treatments on clonogenicity of hyperthermia-sensitive A549 cells was investigated. Additionally, DNA damage and cell death were assessed by Comet assay and an apoptosis/necrosis assay. Further we induced transient knockdown in A549 cells to test HSP70’s involvement in radiosensitization. Results Out of eight cell lines tested, only two (A549 and Abrams) showed significant decrease in clonogenic cell survival when pre-treated with hyperthermia at 42˚C. Strong induction of HSP70 upon thermoradiotherapy (HT-RT) treatment was found in all cell lines. Transient knockdown of HSP70 in A549 cells did not result in decrease of clonogenic cell survival in response to HT-RT. Conclusion Tumor cell-type, temperature and order of treatment play an important role in radiosensitization by hyperthermia. However, hyperthermia has limited potency to radiosensitize canine cancer cells grown in a 2D cell culture setting presented here. DNA damage and apoptosis/necrosis did not increase upon combined treatment and cytosolic levels of HSP70 appear not to play critical role in the radiosensitization of A549 cells

Near‐infrared fluorescent image‐guided lymph node dissection compared with locoregional lymphadenectomies in dogs with mast cell tumours

Objectives: Near-infrared fluorescent imaging has been described for intraoperative mapping of the draining lymph nodes in human cancer and canine oral tumours. The aim of this study was to retrospectively describe the results of lymphadenectomies in dogs with mast cell tumours treated either by standard unguided locoregional lymph node dissection or near-infrared fluorescent image-guided lymph node dissection. Methods: Medical records between 2012 and 2020 were reviewed for dogs that were presented for surgical resection of mast cell tumours with concurrent lymphadenectomy either with (near-infrared fluorescent image-guided lymph node dissection) or without near-infrared fluorescence image guidance (lymph node dissection). The number and location of lymph nodes planned for surgical dissection and actually dissected nodes, presence of metastases and perioperative complications were recorded. Results: Thirty-five patients underwent near-infrared fluorescent image-guided lymph node dissection, and 43 lymph node dissections. The number of nodes preoperatively planned for resection were 70 and 68, respectively. Fifty-eight of those (83%) were identified during near-infrared fluorescent image-guided lymph node dissection procedures, compared with 50 (74%) during lymph node dissection. near-infrared fluorescent image-guided lymph node dissection resulted in resection of additional fluorescent nodes not corresponding to locoregional nodes in 15 of 35 dogs. Using near-infrared fluorescent image-guided lymph node dissection, we identified at least one metastatic node in 68% of dogs (24 of 35) compared with 33% (14 of 43) when lymph node dissection was used without imaging. No complications related to near-infrared fluorescent imaging were reported. Clinical significance: The present study suggests that near-infrared imaging is a promising technique for intraoperative detection of the draining lymph nodes in dogs with mast cell tumours. Further validation of the technique is required to assess if near-infrared fluorescent imaging can detect the true sentinel lymph node

Radiation toxicity grading after chemoradiotherapy of canine urinary tract carcinomas: Comparing VRTOG to VRTOG_v2.0

Radiation toxicities may be underestimated after treatment of transitional cell carcinoma in dogs' lower urinary tract. Assessing acute and late toxicities and differentiating them from progressive disease (PD) impacts further therapeutic approach. We retrospectively assessed dogs treated with definitive‐intent chemoradiotherapy (12 × 3.8 Gy, various first‐line chemotherapeutics). Local tumour control, radiation toxicities and survival were evaluated. We classified radiation toxicities according to the previously published radiation toxicity scheme “VRTOG” as well as the updated version, “VRTOG_v2.0”. Fourteen dogs with transitional cell carcinoma of bladder ± urethra (n = 8), +prostate (n = 3) or solely urethra (n = 3), were included. Median follow‐up was 298 days (range 185–1798 days), median overall survival 305 days (95%CI = 209;402) and 28.6% deaths were tumour‐progression‐related. Acute radiation toxicity was mild and self‐limiting with both classification systems: In VRTOG, 5 dogs showed grade 1, and 1 dog grade 2 toxicity. In VRTOG_v2.0, 2 dogs showed grade 1, 3 dogs grade 2, and 3 dogs grade 3 toxicity. Late toxicity was noted in 14.2% of dogs (2/14) with the VRTOG, both with grade 3 toxicity. With VRTOG_v2.0, a larger proportion of 42.9% of dogs (6/14) showed late toxicities: Four dogs grade 3 (persistent incontinence), 2 dogs grade 5 (urethral obstructions without PD resulting in euthanasia). At time of death, 5 dogs underwent further workup and only 3 were confirmed to have PD. With the updated VRTOG_v2.0 classification system, more dogs with probable late toxicity are registered, but it is ultimately difficult to distinguish these from disease progression as restaging remains to be the most robust determinant

A shortened whole brain radiation therapy protocol for meningoencephalitis of unknown origin in dogs

IntroductionA variety of treatment options have been described for canine meningoencephalitis of unknown origin (MUO). Few studies focused on radiation therapy as a second line immunomodulating treatment, implicating its effective use. However, a standard radiation therapy protocol is lacking, and further research will help to evaluate the effect of different dose regimens.MethodsTen dogs diagnosed with MUO based on MRI and CSF findings were prospectively enrolled. The dogs were treated with a shortened whole brain radiation therapy protocol (5 × 4 Gy) in combination with prednisolone. Neurologic changes were quantified using an established scoring scheme. Follow-up MRI and CSF examination was scheduled three months after radiation therapy. Overall survival and time to progression were calculated. Histopathology of the brain was performed in case of death.ResultsSeven dogs were diagnosed de novo and three had a history of relapsing MUO. Neurological status improved in all 10 dogs during radiation therapy, with 4/10 returning to normal shortly after radiation therapy. Three dogs died within the first three months after radiation therapy. At follow-up MRI lesions completely resolved in two dogs, partially resolved in five dogs, and progressed in one dog. After follow-up MRI, dogs were further treated with prednisolone monotherapy (two dogs) and additional immunosuppressant drugs (five dogs). Overall, four dogs showed disease progression, with a mean time to progression of 691 days (95%CI: 396–987) and mean overall survival for all dogs was 723 days (95%CI: 436–1011) (both medians not reached). Histopathology confirmed MUO in three dogs but was suggestive for oligodendroglioma in one dog. Radiation induced side effects were not seen.ConclusionShortened whole-brain radiation therapy could be an additional treatment option for MUO in conjunction to prednisolone, specifically for cases that require rapid relief of symptoms and with relapsing history

Correlation of Pretreatment Polarographically Measured Oxygen Pressures with Quantified Contrast-Enhanced Power Doppler Ultrasonography in Spontaneous Canine Tumors and their Impact on Outcome After Radiation Therapy

Purpose: : To evaluate the use of noninvasive quantified contrast-enhanced power Doppler ultrasonography as a surrogate in the estimation of tumor hypoxia measured by invasive pO2 histography in canine tumors. Material and Methods: : Data of pretreatment tumor oxygenation status, tumor vascularity and blood volume, and tumor response after radiation therapy was collected in 48 spontaneous malignant oral tumors (Table 1). Tumor oxygenation status was correlated to vascularity and blood volume, and influences on outcome after treatment were analyzed. Results: : Although vascularity and blood volume correlated moderately with median pO2 (r = 0.51 and 0.61; p = 0.001 and < 0.0001) and percentage of pO2 readings ≤ 2.5, 5, and 10 mmHg (r = -0.37 to -0.42; p < 0.01-0.03) for all tumors, they did not correlate within the different histology groups (p = 0.06-0.9). For all tumors, pretreatment oxygenation status, vascularity and blood volume were not found to be of prognostic value (Tables 2 and 3). Conclusion: : These analyses show that quantified contrast-enhanced power Doppler ultrasonography does not represent a noninvasive indirect method to assess tumor hypoxia measured by invasive pO2 histography. Both technologies were nonprognostic indicators in spontaneous malignant canine oral tumor

Risk adaptive planning with biology-based constraints may lead to higher tumor control probability in tumors of the canine brain: A planning study

Background: Classical radiation protocols are guided by physical dose delivered homogeneously over the target. Protocols are chosen to keep normal tissue complication probability (NTCP) at an acceptable level. Organs at risk (OAR) adjacent to the target volume could lead to underdosage of the tumor and a decrease of tumor control probability (TCP). The intent of our study was to explore a biology-based dose escalation: by keeping NTCP for OAR constant, radiation dose was to be maximized, allowing to result in heterogeneous dose distributions. Methods: We used computed tomography datasets of 25 dogs with brain tumors, previously treated with 10x4 Gy (40 Gy to PTV D50). We generated 3 plans for each patient: A) original treatment plan with homogeneous dose distribution, B) heterogeneous dose distribution with strict adherence to the same NTCPs as in A), and C) heterogeneous dose distribution with adherence to NTCP <5%. For plan comparison, TCPs and TCP equivalent doses (homogenous target dose which results in the same TCP) were calculated. To enable the use of the generalized equivalent uniform dose (gEUD) metric of the tumor target in plan optimization, the calculated TCP values were used to obtain the volume effect parameter a. Results: As intended, NTCPs for all OARs did not differ from plan A) to B). In plan C), however, NTCPs were significantly higher for brain (mean 2.5% (SD±1.9, 95%CI: 1.7,3.3), p<0.001), optic chiasm (mean 2.0% (SD±2.2, 95%CI: 1.0,2.8), p=0.010) compared to plan A), but no significant increase was found for the brainstem. For 24 of 25 of the evaluated patients, the heterogenous plans B) and C) led to an increase in target dose and projected increase in TCP compared to the homogenous plan A). Furthermore, the distribution of the projected individual TCP values as a function of the dose was found to be in good agreement with the population TCP model. Conclusion: Our study is a first step towards risk-adaptive radiation dose optimization. This strategy utilizes a biologic objective function based on TCP and NTCP instead of an objective function based on physical dose constraints. Keywords: Biologic objective function; Biology-based; Brain tumor; Dog; IMRT; Intensity-modulated radiation therapy; NTCP; Radiation therapy; Risk-adaptive optimization; TCP