A BOOST TECHNIQUE FOR IRRADIATION OF MALIGNANT CANINE NASAL TUMORS

Eighteen dogs with malignant nasal cavity tumors were treated with radiation therapy, including a boost technique. Three 3:0 Gy boost doses were added to a treatment protocol consisting of sixteen 3.0 Gy daily fractions, bringing the total dose to 57 Gy. This boost technique was implemented without an associated increase in overall treatment time by giving the boost doses on a twice-a-day basis. Boost doses were given during the first half of the radiation therapy period. The treatment was completed as planned in 16 of the 18 dogs; two dogs received lower doses (51 and 54 Gy). Median survival was 177 days, poorer than in some other reported studies of nasal tumor irradiation. Acute effects were unacceptable, with 11 of the 18 dogs developing severe mucositis, desquamation, edema, swelling, and pruritus. The extensive nature of the acute reactions compromised assessment of the effect of the increased radiation dose on the tumor. Although there is justification for assessing more aggressive radiation protocols in canine nasal tumor patients, total doses approximating 60 Gy can not be given as described because of the inability of acutely responding normal tissues to compensate.     

PROTON IRRADIATION OF FELINE NASAL PLANUM SQUAMOUS CELL CARCINOMAS USING AN ACCELERATED PROTOCOL

Fifteen cats were treated for squamous cell carcinoma of the nasal planum using proton beam radiation. The protocol used was accelerated with eight equal fractions given on four consecutive days, with a minimum of six hours between fractions. Total dose of radiation delivered was escalated with nine cats receiving 40.4 CGE (60Co Gy equivalent), and three cats each receiving 42.4 and 44.8 CGE. Complete response to the protocol was 60% (9/15), partial response was 33% (5 of 15), and no response was seen in 6.6% (1 of 15). Tumor control rate at one year was 64% and no cat had tumor recurrence after one year. Median survival was 946 days (+/- 516 days). Side effects were minimal with no severe reactions noted in the early or late period. This protocol offers an effective treatment for squamous cell carcinoma of the feline nasal planum with minimal side effects and may be adaptable to conventional radiation sources particularly when the field size is very small.     

PROGNOSTIC SIGNIFICANCE OF TUMOR HISTOLOGY AND COMPUTED TOMOGRAPHIC STAGING FOR RADIATION TREATMENT RESPONSE OF CANINE NASAL TUMORS

Prognostic significance of tumor histology and four computed tomography (CT) staging methods was tested retrospectively in dogs from three treatment centers that underwent intent-to-cure-radiotherapy for intranasal neoplasia. Disease-free and overall survival times were available for 94 dogs. A grouping of anaplastic, squamous cell, and undifferentiated carcinomas had a significantly shorter median disease-free survival (4.4 mo) than a grouping of all sarcomas (10.6 months). Disease-free survivals were not significantly different, when all carcinomas were compared with all sarcomas. The published original and modified WHO staging methods did not significantly relate to either survival endpoint. A modified human maxillary tumor staging system previously applied to canine nasal tumors was prognostically significant for both survival endpoints; a further modified version of that CT-based staging system resulted in improved significance for both survival endpoints. Dogs with unilateral intranasal involvement without bone destruction beyond the turbinates on CT, had longest median survival (23.4 months); CT evidence of cribriform plate involvement was associated with shortest median survival (6.7 months). Combining CT and histology statistically improved prognostic significance for both survival endpoints over the proposed CT staging method alone. Significance was lost when CT stages were collapsed to 相似文献   

USE OF RADIATION AND A SLOW-RELEASE CISPLATIN FORMULATION FOR TREATMENT OF CANINE NASAL TUMORS

The purpose of this study was to evaluate the combined use of radiation and a slow-release cisplatin chemotherapy formulation for treatment of malignant nasal tumors in dogs. In this retrospective analysis, 51 dogs were evaluated with respect to treatment toxicity, tumor type, stage of disease, cribriform plate involvement, and overall survival. In general, treatment was well tolerated. Mean and median survival as assessed by the Kaplan-Meier product limit method was 570 and 474 days, respectively. No other factors, including tumor type, stage of disease, or cribriform plate invasion had a significant impact on survival. In conclusion, a combination of slow release cisplatin chemotherapy and radiation for the treatment of canine nasal tumors is well tolerated. Results of this analysis warrant further study to elucidate possible other beneficial radiation potentiating drugs and dosing schedules.     

REIRRADIATION OF RECURRENT CANINE NASAL TUMORS

Canine nasal tumors are typically treated with radiation therapy but most patients develop local recurrence. Our purpose was to evaluate tumor and normal tissue response to reirradiation in nine dogs. The median dose delivered with the first protocol was 50 Gy (range 44–55 Gy) and the median fraction number was 18 (range 15–20). For the second protocol, the median dose was lower intentionally, median of 36 Gy (range 23–44 Gy), without changing the median fraction number of 18 (range 14–20) to avoid late effects. The median time between protocols was 539 days (range 258–1652 days). Median survival was 927 days (95% confidence interval [CI] 423–1767 days). Median time to progression following the first and second courses was 513 days (95% CI 234–1180 days) and 282 days (95% CI 130–453 days), respectively. These were not significantly different (P=0.086). The qualitative response assessment was better for the first course compared with the second (P=0.018). Severity and timing of skin, mucous membrane, and ocular effects were similar for early side effects between the two courses (P>0.05 for all comparisons). All dogs experienced some late side effects, with two out of nine being classified as severe. These severe effects were blindness in each dog, possibly related to tumor recurrence. Reirradiation of canine nasal tumors resulted in a second clinical remission in eight of nine dogs, although the second response was less complete. Acute and late effects for seven of nine patients were not life threatening, indicating that reirradiation of canine nasal tumors may be a viable treatment option after recurrence.     

COMBINATION OF RADIATION THERAPY AND FIROCOXIB FOR THE TREATMENT OF CANINE NASAL CARCINOMA

Carcinomas represent two‐thirds of canine nasosinal neoplasms. Although radiation therapy (RT) is the standard of care, the incidence of local recurrence following treatment is high. Cyclooxygenase‐isoform‐2 (COX‐2) is expressed in 71–95% of canine nasal carcinomas and has been implicated in tumor growth and angiogenesis. Accordingly, COX‐2 inhibition seems rational to improve outcome. Dogs with histologically confirmed, previously untreated nasal carcinomas were randomized to receive the combination of a selective COX‐2 inhibitor (firocoxib) and palliative RT (Group 1) or RT and placebo (Group 2). Patients were regularly monitored with blood tests, urinalysis, and computed tomography. Pet owners were asked to complete monthly a quality‐of‐life questionnaire. Twenty‐four dogs were prospectively enrolled. According to Adams modified system, there were five stage 1, five stage 2, three stage 3, and 11 stage 4 tumors. Two dogs had metastases to regional lymph nodes. Median progression‐free interval and overall survival were 228 and 335 days in Group 1 (n = 12) and 234 and 244 days in Group 2 (n = 12). These differences were not statistically significant. The involvement of regional lymph nodes was significantly associated with progression‐free interval and overall survival (P = 0.004). Quality of life was significantly improved in Group 1 (P = 0.008). In particular, a significant difference was observed for activity and appetite. Although not providing a significant enhancement of progression‐free interval and overall survival, firocoxib in combination with RT is safe and improved life quality in dogs with nasal carcinomas.     

PRIMARY IRRADIATION OF CANINE INTRACRANIAL MASSES

Twenty-nine dogs received primary radiation therapy for intracranial lesions and clinical signs suggestive of neoplasia. Presumptive diagnosis and tumor categorization was based on computed tomographic or magnetic resonance images. Meningioma was the most likely tumor type in 22 dogs and glioma or choroid plexus tumors were tentatively identified in 4 and 3 dogs, respectively. Cobalt-60 radiation was delivered in 3 Gy fractions on a daily, Monday-through-Friday basis for a total dose of 48 Gy (16 fractions) in 28 dogs; one dog received 54 Gy. Two of 29 dogs died during treatment of signs suggestive of progressive tumor growth but were included in the overall evaluation of response to treatment. Median overall survival was 250 days (range 21-804). Mild acute radiation effects on normal tissue developed and did not influence outcome in any dog. Late radiation effects could not be evaluated in this study. No significant predictive indicators were identified from the clinical or imaging data. Radiation therapy is superior to medical treatment of brain tumors in dogs with steroids, is useful for tumors that are not currently operable and may be preferable to surgical resection in dogs if the mass appears infiltrative. However, 22/29 (76%) dogs died of recurrent progressive neuropathy suggestive of tumor regrowth or progression. Thus, alternative methods for delivery of radiation to dogs with brain tumors or novel combinations of therapy should continue to undergo evaluation.     

FACTORS INFLUENCING SURVIVAL AFTER RADIOTHERAPY OF NASAL TUMORS IN 130 DOGS

Improvements in survival of dogs with nasal tumors have been slow to develop throughout the past three decades. Despite multiple studies examining various radiation time-dose schema, the advancement of CT-based computerized treatment planning, and the evaluation of detailed staging systems, the optimal treatment regimen, and most important prognostic factors regarding survival remain unclear. In this study, data from four previous studies were combined with data from 44 additional dogs, and this population of 130 dogs was evaluated for factors which influenced survival. Twenty-one dogs were treated with orthovoltage at the University of Pennsylvania. One hundred nine dogs were treated with cobalt photons at North Carolina State University. Sixty-five of these 109 dogs had been previously described. Of the 44 dogs not previously described, 35 were treated with a shrinking field technique. Survival was determined from the medical record, or from information derived by telephone or mail survey. The univariate Cox regression model was used to examine for relationship between various patient, tumor, and treatment variables and survival. Significant relationships identified in the univariate analysis were further analyzed using the multivariate Cox regression model. Median survival of the 130 dogs was 8.9 months (95% C.I., 8-11 months). In the univariate analysis, the following variables were associated with decreased survival: 1) age >10 years old, 2) regional lymph node metastasis, 3) advanced tumor stage, 4) use of megavoltage radiation, 5) overall total dose >55 Gray, and 6) boost technique performed. In a multivariate analysis of 125 dogs with complete data for age, radiation type, and radiation dose, age (p < .001) and radiation type (p = .02) were identified as joint predictors of survival. After adjusting for age, the staging system lost prognostic significance (p = .06). In a subset of dogs that received cobalt radiation, after adjusting for age, dogs treated with a boost technique had decreased survival (p = .001). In general, local control of canine nasal tumors following aggressive radiation therapy is poor. Early diagnosis and selection of appropriate patients is warranted and palliative types of treatment should be considered in dogs with a poor chance of long term survival.     

RADIATION THERAPY COMMUNICATION: NASAL PASSAGE AND PARANASAL SINUS LYMPHOMA IN A PONY

An aged pony with extensive paranasal sinus and nasal passage B-cell lymphoma was treated with palliative radiation therapy. Sixteen gray were administered in two fractions, 7 days apart. A lateral field was used for the first fraction and a dorsal field for the second. Because of tumor being present in the left frontal sinus, gross tumor was knowingly excluded from the treated volume in the lateral field. The tumor regressed within 2 months and the pony remained free of clinical disease for 2.5 years. Acute, temporary blindness developed shortly after the second radiation fraction, but a direct causal relationship with the radiation therapy was not confirmed. The only radiation side effect was leukotrichia. Palliative treatment was successful in improving and prolonging the quality of life. These results suggest that localized equine B-cell lymphoma is radiosensitive, and that palliative radiation therapy is a reasonable consideration for large tumors, even when tumor volume prevents all gross tumor from being irradiated.     

RADIOBIOLOGICAL AND TREATMENT PLANNING STUDY OF A SIMULTANEOUSLY INTEGRATED BOOST FOR CANINE NASAL TUMORS USING HELICAL TOMOTHERAPY

Feasibility of delivering a simultaneously integrated boost to canine nasal tumors using helical tomotherapy to improve tumor control probability (TCP) via an increase in total biological equivalent uniform dose (EUD) was evaluated. Eight dogs with varying size nasal tumors (5.8-110.9 cc) were replanned to 42 Gy to the nasal cavity and integrated dose boosts to gross disease of 45.2, 48.3, and 51.3 Gy in 10 fractions. EUD values were calculated for tumors and mean normalized total doses (NTD(mean)) for organs at risk (OAR). Normal Tissue Complication Probability (NTCP) values were obtained for OARs, and estimated TCP values were computed using a logistic dose-response model and based on deliverable EUD boost doses. Significant increases in estimated TCP to 54%, 74%, and 86% can be achieved with 10%, 23%, and 37% mean relative EUD boosts to the gross disease, respectively. NTCP values for blindness of either eye and for brain necrosis were < 0.01% for all boosts. Values for cataract development were 31%, 42%, and 46% for studied boost schemas, respectively. Average NTD(mean) to eyes and brain for mean EUD boosts were 10.2, 11.3, and 12.1 Gy3, and 7.5, 7.2, and 7.9 Gy2, respectively. Using helical tomotherapy, simultaneously integrated dose boosts can be delivered to increase the estimated TCP at 1-year without significantly increasing the NTD(mean) to eyes and brain. Delivery of these treatments in a prospective trial may allow quantification of a dose-response relationship in canine nasal tumors.     

DYNAMIC CT MEASUREMENT OF CONTRAST MEDIUM WASHIN KINETICS IN CANINE NASAL TUMORS

Tumor oxygenation affects the biologic behavior of a tumor and also its radiation response. Decreased tumor oxygenation has been associated with an aggressive phenotype and with decreased local tumor control following irradiation. Thus, measurement of oxygenation may be useful for pretreatment evaluation of a tumor. Many methods for assessing tumor oxygenation are available but most are invasive. There is a need for a non-invasive measure of oxygenation, or a surrogate for oxygenation. Measurement of perfusion has been suggested as a substitute for measurement of oxygenation. The use of washin kinetics of iodinated contrast medium to estimate perfusion has been shown to be related to radiation response of human carcinomas. We quantified the washin kinetics of iodinated contrast medium using dynamic CT in 9 dogs. All dogs had a malignant nasal tumor and perfusion was quantified at two sites in each tumor to evaluate intratumoral variation in perfusion. Dogs were given an intravenous bolus injection of contrast medium and arterial and tumor washin kinetics quantified using a helical CT scanner. Perfusion was estimated from these data using previously validated methods. Eight of the 9 dogs received definitive radiation therapy and perfusion was quantified a second time in these 8 dogs midway through irradiation. Pretreatment perfusion varied between dogs by a factor of 16.9. Between dog variation in perfusion was subjectively greater than within tumor variation based on comparison of two intratumoral regions. Changes in perfusion in individual dogs during irradiation were observed, but no identifiable pattern of perfusion alteration was detected. Measurement of perfusion in canine nasal tumors using dynamic CT is possible and further study of this parameter as it relates to radiation response is reasonable.     

SLOW RELEASE CISPLATIN COMBINED WITH RADIATION FOR THE TREATMENT OF CANINE NASAL TUMORS

Thirteen dogs with malignant tumors of the nasal cavity were treated with a combination of slow release cisplatin and megavoltage radiation. Radiation was delivered on a Monday through Friday schedule using a 6 MV linear accelerator. The median total dose was 49.5 Gy (range 49.5-56 Gy). Cisplatin was given using an open-cell polylactic acid polymer, impregnated with the drug and implanted intramus-cularly at a distant site, as a slow release delivery system (OPLAn-Pt [THM Biomedical, Inc]). The median dose used was 60 mg/m2 (range 60–100 mg/m2). When combined with radiation, this delivery system caused no systemic drug toxicity, and a local tissue reaction was seen in only two dogs. Acute side effects to normal tissue from radiation were not enhanced, as measured by subjective assessment. When compared to a group of historical controls that received radiation without OPLA-Pt, the dogs that received combined radiation and cisplatin had longer overall survival times, with a median of 580 days. The control group had a median survival of 325 days. Previously reported median survival times for comparable megavoltage radiation treatment range from 6 to 13 months. Some dogs in both groups also received adjubant chemotherapy but this did not influence survival time. By multivariate analysis, only the use of OPLA-Pt was found to significantly influence survival, with a p value of p = 0.023. Mega-voltage radiation and slow release cisplatin appears to be a well tolerated combination that may favorably affect survival of dogs with nasal tumors.     

A COMPARISON OF RADIOGRAPHIC AND COMPUTED TOMOGRAPHIC FINDINGS IN 31 DOGS WITH MALIGNANT NASAL CAVITY TUMORS

Nasal cavity radiographs and CT images from 31 dogs with nasal cavity cancer were compared. All dogs had abnormal clinical signs relating to -nasal cancer and histologic confirmation of malignant nasal cavity neoplasia. No dog had cyto reductive surgery prior to imaging. All radiographic and CT examinations were abnormal. CT was more accurate than radiographs in identifying unilateral versus bilateral nasal cavity disease and tumor extension into adjacent structures such as the cranial cavity, hard palate, and pterygopala-tine fossa. The improved accuracy of CT in these respects was not of benefit in the confirmation of nasal cavity disease because radiographs were abnormal in every instance. However, CT may be useful for more accurate tumor staging, predicting possible treatment-related complications, and planning of surgery and radiation therapy. It was also determined that one dorsally located radiation therapy portal bounded laterally by the medial ocular canthi, as described in previous reports, would not have been adequate for encompassing all abnormal tissue in 28 of the 31 dogs evaluated.     

DOSIMETRIC IMPACT OF DAILY SETUP VARIATIONS DURING TREATMENT OF CANINE NASAL TUMORS USING INTENSITY-MODULATED RADIATION THERAPY

Intensity-modulated radiation therapy (IMRT) can be employed to yield precise dose distributions that tightly conform to targets and reduce high doses to normal structures by generating steep dose gradients. Because of these sharp gradients, daily setup variations may have an adverse effect on clinical outcome such that an adjacent normal structure may be overdosed and/or the target may be underdosed. This study provides a detailed analysis of the impact of daily setup variations on optimized IMRT canine nasal tumor treatment plans when variations are not accounted for due to the lack of image guidance. Setup histories of ten patients with nasal tumors previously treated using helical tomotherapy were replanned retrospectively to study the impact of daily setup variations on IMRT dose distributions. Daily setup shifts were applied to IMRT plans on a fraction-by-fraction basis. Using mattress immobilization and laser alignment, mean setup error magnitude in any single dimension was at least 2.5 mm (0–10.0 mm). With inclusions of all three translational coordinates, mean composite offset vector was 5.9±3.3 mm. Due to variations, a loss of equivalent uniform dose for target volumes of up to 5.6% was noted which corresponded to a potential loss in tumor control probability of 39.5%. Overdosing of eyes and brain was noted by increases in mean normalized total dose and highest normalized dose given to 2% of the volume. Findings suggest that successful implementation of canine nasal IMRT requires daily image guidance to ensure accurate delivery of precise IMRT distributions when non-rigid immobilization techniques are utilized. Unrecognized geographical misses may result in tumor recurrence and/or radiation toxicities to the eyes and brain.     

A COMPARISON OF NORMAL TISSUE COMPLICATION PROBABILITY OF BRAIN FOR PROTON AND PHOTON THERAPY OF CANINE NASAL TUMORS

This study compared the calculated normal tissue complication probability of brain in dogs with a nasal tumor, which had both photon and proton treatment planning. Nine dogs diagnosed with a variety of histologies, but all with large, caudally located nasal tumors were studied. Three-dimensional (3-D) photon dose distribution, and a proton dose distribution was calculated for each dog. To calculate the normal tissue complication probability (NTCP) for brain, the partial brain volume irradiated with the prescribed dose was determined, then a mathematic model relating complications to partial volume and radiation dose was used. The NTCP was always smaller for proton plans as compared to photon plans, indicating conformation of the dose to the target allows a higher dose to be given. If a 5% NTCP were accepted, the mean applicable dose for this group of dogs was 50.2 Gy for photons, but 58.3 Gy for protons. Not all dogs would benefit the same from proton irradiation. If a large partial brain volume has to be irradiated, the advantage becomes minimal. There is also a minimal advantage if the planning target volume (PTV) includes a small, superficial brain volume. However, for a complex PTV shape the degree of conformation is clearly superior for protons and results in smaller calculated NTCPs.     

POTENTIAL FOR INTENSITY-MODULATED RADIATION THERAPY TO PERMIT DOSE ESCALATION FOR CANINE NASAL CANCER

We evaluated the impact of inverse planned intensity-modulated radiation therapy (IMRT) on the dose-volume histograms (DVHs) and on the normal tissue complication probabilities (NTCPs) of brain and eyes in dogs with nasal tumors. Nine dogs with large, caudally located nasal tumors were planned using conventional techniques and inverse planned IMRT for a total prescribed dose of 52.5 Gy in 3.5 Gy fractions. The equivalent uniform dose for brain and eyes was calculated to estimate the normal tissue complication probability (NTCP) of these organs. The NTCP values as well as the DVHs were used to compare the treatment plans. The dose distribution in IMRT plans was more conformal than in conventional plans. The average dose delivered to one-third of the brain was 10 Gy lower with the IMRT plan compared with conventional planning. The mean partial brain volume receiving 43.6 Gy or more was reduced by 25.6% with IMRT. As a consequence, the NTCPs were also significantly lower in the IMRT plans. The mean NTCP of brain was two times lower and at least one eye could be saved in all patients planed with IMRT. Another possibility with IMRT is dose escalation in the target to improve tumor control while keeping the NTCPs at the same level as for conventional planning. Veterinary     

ORTHOVOLTAGE RADIOTHERAPY OF CANINE TRANSMISSIBLE VENEREAL TUMORS

Eighteen dogs with transmissible venereal tumors were treated with orthovoltage radiotherapy. Total radiation doses ranged from 10 to 30 Gy, given during periods of one to 34 days. Tumor cure, defined as lack of recurrence within one year after completion of radiotherapy, was observed in all 18 dogs. In seven of eight dogs, tumors were cured with a single dose of 10 Gy. The tumor that recurred after the single 10 Gy dose had been treated with chemotherapy prior to radiotherapy and was subsequently cured with additional radiotherapy. Data presented indicate that transmissible venereal tumors are radiocurable and that a single dose of 10 Gy is sufficient for cure in most dogs.     

FAILURE PATTERNS FOLLOWING COBALT IRRADIATION IN DOGS WITH NASAL CARCINOMA

The pattern of tumor recurrence was assessed in 24 dogs receiving cobalt radiation therapy for nasal carcinoma. Dogs were evaluated using nasal cavity computed tomography prior to treatment, and at 1, 3, 6 and 12 months after treatment, and at 6-month intervals thereafter if still alive. Dogs were treated with various combinations of total dose, and fraction size. Total doses were normalized to equivalent doses given in 3.0 Gy fractions. The extent of tumor regression or duration of tumor control were not dependent on absolute total dose, normalized total dose, or tumor type. The median duration of local control in all dogs was 312 days. Marked tumor regression was observed in 11 of the 24 dogs. Median duration of local control was significantly longer in dogs with marked tumor regression in comparison to dogs without tumor regression; 389 vs. 161 days respectively. When tumor recurrence was documented in dogs having tumor regression, the location of the recurrence was in the nasal cavity. No tumor recurred in a sinus or periorbital region, and only one geographic miss was detected. Tumor recurrence in the irradiated volume, including dogs with and without marked regression, was documented in 13 of the 24 dogs. The high local failure rate, coupled with the recurrence pattern in these dogs, suggests there may be an opportunity for improvement in local control through use of shrinking field techniques.