Reirradiation of Canine Nasal Carcinomas Treated with Coarsely Fractionated Radiation Protocols: 37 Cases
Data from 37 dogs with nasal carcinomas treated with two or more coarsely fractionated courses of radiation therapy (RT) were retrospectively reviewed. The median radiation dose for the first course of RT was 24 Gray (Gy). All dogs clinically responded, and 11 had complete resolution of signs for a median of 114 days. Dogs were retreated at relapse, with a median dose of 20 Gy, and 26 of 37 dogs (70%) had clinical responses. The second course of RT was initiated at a median of 150 days following completion of the first course. Side effects were mild: four dogs had chronic ocular conditions necessitating medication, one of which required enucleation. Median survival time (ST) from the first dose of RT was 453 days and 180 days from the first dose of the second course of RT. The following factors were examined but were not significant for survival: total RT dose, dose of the first course of RT, complete resolution of clinical signs, use of either chemotherapy or nonsteroidal anti-inflammatory drugs (NSAIDs), and stage (T1/T2 versus T3/T4). Dogs responded well to reirradiation with a subset experiencing chronic ocular side effects.
Introduction
Malignant neoplasms of the nasal cavity and paranasal sinuses cause local soft tissue and bony destruction, resulting in clinical signs such as epistaxis, sneezing, facial deformity, and upper airway dyspnea.1–24 Without therapy, the reported median survival time (ST) of 16 dogs with various intranasal neoplasms was 10.5 wk from the initial onset of clinical signs and 3.5 wk from presentation to a veterinary facility.2 In a more recent study of 139 dogs with untreated nasal carcinomas, STs ranged from 7 to 1,114 days, with a median of 95 days.3 Historically, treatment options for dogs with nasal carcinomas include surgery, external beam radiation therapy (RT), brachytherapy, and chemotherapy.2–24 External beam RT has become the treatment of choice for nasal tumors because treatment with either surgery or chemotherapy alone rarely provides long-term tumor control.4–24 Median STs for dogs treated with external beam RT ranges from 6 mo to 18 mo, and fractionation schedules vary among institutions. Unfortunately, even with treatment, most dogs with nasal carcinomas are eventually euthanized because of local disease progression and worsening of clinical signs.6
Recurrence of clinical signs in dogs with nasal tumors previously treated with RT typically indicates either progressive growth or tumor recurrence. “Rescue” treatments including traditional or metronomic chemotherapy, growth factor receptor inhibitors, nonsteroidal anti-inflammatory drugs (NSAIDs), and procedures to attempt to ameliorate clinical signs (such as carotid artery ligation and hydropulsion) have been attempted; however, the response to those therapies is inconsistent and euthanasia may be requested due to clinical signs such as uncontrollable sneezing, facial pain, and epistaxis.3,18,25 Two veterinary studies have been published examining the efficacy and side effects of reirradiation for recurrent nasal and other tumors, which have shown promising results.20,26
In a previously published study by one of the authors (T.G.) involving 48 dogs with nasal carcinomas treated with coarse fraction RT, 11 dogs were reirradiated at the time of clinical relapse (i.e., tumor progression was documented by cross-sectional imaging) at a median of 171 days after the first course.4 In that group of dogs, 9 of the 11 dogs (82%) had a complete clinical response to the second course of radiation. For seven dogs, the clinical response duration was > 100 days. Based on that information, the authors believed that additional investigation into reirradiation for the treatment of relapsed nasal carcinomas was warranted. The authors’ hypothesis was that dogs with recurrent nasal carcinomas treated with a coarsely fractionated primary treatment protocol would respond clinically to reirradiation with a similar protocol and would have few life-threatening side effects.
Materials and Methods
Criteria for Selection of Cases
Fifty-five patient records from 10 contributing institutions were reviewed. Dogs with histologically confirmed nasal carcinomas treated with ≥ 2 courses of coarse fraction RT were included. Dogs treated with steroids or antibiotics prior to or concurrent with RT were included in the study. Dogs receiving NSAIDs or chemotherapy prior to, concurrent with, or after completion of RT were included in the study and were evaluated as separate groups. Dogs treated with < 4 Gray (Gy)/fraction in either course were excluded to decrease variability in dosing schemes used in the study.
Case Data
Data collected from the medical records included age, weight, breed, presence and duration of clinical signs prior to initiation of the first course of RT, treatments prior to diagnosis of nasal neoplasia, imaging methods used for patient staging, histopathologic diagnosis, radiation source, dose/fraction, number of fractions, total RT dose administered, schedule for each course of RT, description of the radiation treatment plan (when available), the occurrence of adverse effects associated with RT, the use of medications during and following completion of RT, whether clinical signs resolved during or following completion of RT, follow-up information including response duration, ST, and cause of death. Follow-up information was obtained during examinations performed by either the attending medical/radiation oncologist or referring veterinarian and by telephone interviews with the referring veterinarian and/or owner. When available, information was also recorded on the results of staging procedures, including results of cytologic examination of regional lymph nodes, radiography of the thorax and abdomen, and ultrasonography of the abdomen. Systemic staging was performed according to clinician preference. Clinical tumor staging was evaluated on the basis of computed tomography (CT) or MRI findings reported in the medical record, and tumors were categorized according to a published classification system for sinonasal tumors.5 When either CT or MRI scans were not performed, clinical tumor staging was not assessed.
Statistical Analysis
Duration of clinical signs prior to RT was defined as the interval between the onset of clinical signs attributable to nasal neoplasia, as reported in the medical record, and the initiation of the first course of RT. For dogs experiencing complete resolution of clinical signs (complete response [CR]), response of duration was defined as the interval between the start of the response to the recurrence of clinical signs. Dogs that did not experience CR of clinical signs were not included in analysis of response duration. ST was defined as the time from the first dose of the first course of RT until death from any cause. Dogs alive at the last follow-up point were included in analyses until the last day of follow-up and then censored.
Potential risk factors analyzed to determine their effect on survival included stage (stages T1/T2 versus T3/T4), RT dose for the first course of RT (< or > than the median, which was 24 Gy), total overall RT dose (< or > than the median, which was 40 Gy), CR after the first course of RT (yes or no), use of NSAIDs (yes or no), and chemotherapy administration (yes or no). A statistical software package was used and the Kaplan-Meier product limit method was used to generate survival curves for each risk factor and obtain the median STa. For each risk factor, the log-rank test for censored data was used to compare curves. The effect of Adams’ stage (T1/T2 versus T3/T4) and dose of the first course of RT on clinical response to therapy (CR versus either partial response [PR] or no response) were also examined. The χ2 test and Fisher’s exact tests were used. For dogs that had a CR to the first course of RT, a log-rank test was used to determine if those factors influenced the duration of response. For all analyses, P < 0.05 was considered significant.
Results
Signalment and Staging
Medical records of 37 dogs from six institutions were included in the study. Eighteen cases were excluded because one or more courses of RT included dose/fraction < 4 Gy. Twenty dogs were castrated males and 17 were spayed females. Patient body weight ranged from 3 kg to 54.5 kg (median, 25 kg), and age ranged from 5 yr to 15 yr (median, 11 yr). Twenty dog breeds were represented. The most common breeds included Labrador (n = 4) and golden (n = 3) retrievers, and eight patients were mixed-breed dogs. Most tumors were diagnosed via rhinoscopic biopsy, but a surgical biopsy was required in one case. There were 19 adenocarcinomas, 15 solid or undifferentiated carcinomas, and 3 squamous cell carcinomas. Further histopathologic differentiation and slide review were not available due to the retrospective nature of this study.
The duration of clinical signs prior to evaluation for and diagnosis of nasal cancer was known for 27 dogs and ranged from 1 day to 365 days (median, 90 days). Clinical signs included epistaxis (n = 21), sneezing (n = 17), nasal discharge (n = 13), facial deformity (n = 8), decreased ocular retropulsion (n = 4), and seizures (n = 3). Most dogs had more than one clinical sign at presentation. Twenty-three dogs were treated empirically for their nasal signs prior to diagnosis of sinonasal neoplasia, and either a PR or CR of signs following treatment was documented in eight dogs (those responses were typically < 1 mo in duration, and clinical signs recurred in all dogs prior to the start of RT). Dogs were treated with antibiotics (n = 14), NSAIDs (n = 5), steroids (n = 5), antihistamines (n = 4), or combinations of those medications prior to RT. In addition to the above treatments, three dogs had dental cleaning and/or extractions in an attempt to resolve their nasal discharge. That approach was not documented to be successful in any case.
Staging tests were performed in most dogs and were generally unremarkable. Complete blood counts were performed in the majority of dogs (n = 30) and revealed mild to moderate anemia in two dogs that had epistaxis. Serum biochemical analyses (n = 31) and urinalyses (n = 15) were unremarkable. Thoracic radiographs (n = 23) revealed a mediastinal mass in one dog and a presumed primary lung tumor in one dog. Abdominal imaging was performed as part of systemic staging in two dogs (without evidence of metastasis elsewhere), which was normal. Seven dogs had a single mandibular lymph node aspirated, and two dogs had enlarged lymph nodes. Two dogs had cytologic evidence of lymph node metastasis (one with an enlarged ipsilateral lymph node), and one dog with bilaterally enlarged mandibular lymph nodes had concurrent lymphoma (confirmed by polymerase chain reaction).
Tumor stages based on retrospective evaluation of radiologists’ reports of CT (n = 25) and MRI (n = 1) were T1 (n = 6), T2 (n = 3), T3 (n = 2), and T4 (n = 15).5 Due to the small numbers of dogs in the T1 and T2 stages, dogs were grouped into T1/T2 and T3/T4 for statistical purposes.
RT
Patients were treated with a course of RT using a protocol determined by the standards of each institution. The selection of a coarsely fractionated protocol was a decision made by the attending radiation oncologist and pet owner. Following induction of general anesthesia, dogs were treated with megavoltage radiation with a linear accelerator. Treatment planning was computer-based or nongraphically planned from cross-sectional imaging, skull radiographs, and anatomic landmarks. Treatment plans included conformal field shaping with a multileaf collimator, hand blocks, and wedges in some cases, but this varied among institutions. Ipsilateral mandibular lymph nodes were irradiated in two dogs. One of those dogs had cytologic evidence of metastasis, and the reason for lymph node irradiation was unknown in the other dog.
For the first course of RT, the total dose ranged from 16 Gy to 24 Gy (median, 24 Gy). The dose/fraction ranged from 4 Gy to 8 Gy (median, 7 Gy). All dogs clinically responded to the first course of RT. In 11 dogs, there was a CR of clinical signs by either the end of or soon after completion of RT. For the remaining dogs, only a PR to therapy was reported or it was difficult to discern from the record if all of the clinical signs resolved. For 24 dogs in which the time to the start of a clinical response (either a CR or PR) was known, the median time to response was 7 days after the start of RT (range, 4–49 days). For the 11 that had a CR, the median response duration was 114 days (range, 60–305 days). Clinical signs of relapse were typically the same as the original clinical signs. In two dogs, clinical signs of disease progression did not occur, but progression was documented on elective CT scans at 114 days and 136 days after completion of RT, respectively.
At the time of relapse, staging tests were performed in the majority of dogs to document tumor progression and overall health status. Two dogs developed lymph node metastases, and one dog developed presumed pulmonary metastases from the nasal tumor. The dog that had lymphoma concurrent with the nasal tumor developed lymph node metastases of the nasal carcinoma, but the lymphoma cytologically was in remission (that dog was treated with chlorambucil concurrently with the first course of radiation and beyond). The dog with the presumed primary lung tumor developed a second pulmonary nodule, for which he was asymptomatic. No dogs had either repeat biopsies or rhinoscopy when tumors recurred. Fourteen dogs had repeat CT scans that documented unchanged tumor stage in all but one dog (which progressed from stage T1 to T4). The remaining dogs were retreated with the same RT plan as the first course of RT without additional cross-sectional nasal imaging (this decision was made between the attending radiation oncologist and the owner and was typically based on lack of finances for repeat imaging). The second course of RT was initiated 35–465 days following completion of the first course of RT (median, 150 days).
For the second course of RT, the median total dose was 20 Gy (range, 8–32 Gy), and the median dose/fraction was 8 Gy. Twenty-six dogs (70%) were known to have either a PR or CR. The median time to response was 7 days for 16 dogs whose time to response was known (range, 1–30 days). Response duration (CR or PR) was documented after the second course of RT for 12 dogs and ranged from 18 to 332 days (median, 80 days).
In 21 dogs, oral medications including steroids, NSAIDs, and/or antibiotics were administered during and/or following completion of the first course of RT. Those medications were used to aid in controlling clinical signs related to the nasal tumor, for other conditions (such as osteoarthritis), and/or to ameliorate side effects of RT. NSAIDs may have antitumor effects on carcinomas due to inhibition of cyclooxygenase-2, which is overexpressed in some nasal carcinomas.27 Medications including eye lubricants, topical cyclosporine, and topical ophthalmic antibiotic ointments were prescribed during and/or following completion of RT in 4 dogs with at least one eye in the radiation field.
Side Effects
Due to the retrospective nature of this study, the grading of adverse effects from RT by the use of standardized schemes was not possible.28 For 10 patients, adverse effects were reported during or after the first course of RT. Acute toxicities were generally mild and included the following: oral mucositis (n = 6), dermatitis (n = 3), pitting edema in the irradiated field (n = 1), and keratitis (n = 1). Some patients had multiple concurrent adverse effects. The incidence of acute ocular toxicity was difficult to discern because some dogs were treated prophylactically with eye lubricants and topical anti-inflammatories or antibiotic ointments or drops during RT and for 2–4 wk postRT. Chronic ocular toxicities (i.e., conditions necessitating medications beyond 4 wk postRT when acute toxicities are typically resolved) were reported in four dogs that had at least one eye in the irradiated field. Those toxicities included corneal ulceration (n = 2), keratoconjunctivitis sicca (n = 4) and cataract formation (n = 1). Most dogs that experienced chronic ocular toxicity had multiple concurrent ocular side effects. Unilateral enucleation was required in one dog that had medically unmanageable corneal ulcers with a subsequent desmetocele. Nonlife-threatening late effects of radiation, including alopecia, leukotrichia, and hyperpigmentation of the skin in the irradiated field, were common in dogs that survived > 3 mo postRT. Neither severe nor life-threatening late side effects were documented. Some dogs had ongoing nasal discharge that was difficult to discern between ongoing radiation side effects (nasal cavity mucositis) and tumor recurrence. Acute side effects were reported in 14 dogs after the second course of RT. In seven dogs, side effects were clinically worse than after the first course of RT. Due to variations in treatment schemes, it was not possible to discern whether side effects were worse in dogs that had higher total doses of RT or higher doses/fraction.
Four dogs were treated with chemotherapy either concurrently with or following completion of RT. Chemotherapy was not intentionally used as a radiation sensitizer and was most commonly used when either RT failed to completely control clinical signs or when disease progression was apparent. Chemotherapy treatments included carboplatin (n = 2), metronomically dosed chlorambucil (n = 1), and chlorambucil to treat concurrent lymphocytic lymphoma (n = 1).
Dogs were followed after the second course of RT until death. Three dogs were treated with a third course of RT when their clinical signs progressed. The total radiation dose/patient ranged from 32 Gy to 64 Gy (median, 40 Gy). Thirty-four dogs died during the follow-up period. No necropsies were performed. The majority of dogs were suspected to have died (or humanely euthanized) as a result of tumor progression; however, due to lack of necropsies in the dogs of this study, the cause of death (tumor versus radiation side effects versus other causes) could not be definitively determined. The median ST from the first dose of RT was 453 days (range, 119–1,099) and from the first dose of the second course of RT was 180 days (range, 21–601 days). None of the variables studied were prognostic for either survival or achieving a CR to therapy.
Discussion
In this study, 37 dogs with nasal carcinomas were treated with two courses of coarsely fractionated external beam RT. Dogs that clinically responded to the first course were treated with a similar course at a median of 150 days following completion of the first course. The majority of dogs (70%) responded to the second course, and side effects were mild to moderate and not life threatening in any dog. The median ST from the first dose of RT was 453 days, and from the first dose of the second course of RT, ST was 180 days. This study is unique in that to the authors’ knowledge, it is the first documentation of a series of dogs treated with two courses of coarsely fractionated RT.
Unfortunately, the long-term (> 2 yr) tumor control rates postRT for canine nasal tumors were low, with reported 1 yr and 2 yr postRT STs ranging from 37% to 60% and 15% to 43%, respectively.6,7,9,13 There are three reasons for either tumor recurrence or progression of local cancer that initially responded to radiation. The first is radiation-resistant subpopulations of tumor cells, and the second is geographical misses (i.e., missing the defined target that includes viable tumor cells due to either interfraction or intrafraction set up error). The third reason is the development of second primary malignancies within the radiation field.29,30 In dogs with nasal tumors, the most likely explanation for tumor recurrence is radiation resistance. Few veterinary studies have documented ongoing, objective (cross-sectional imaging-based) tumor responses in canine nasal tumors, and it is unlikely that tumors have CRs after RT. In human medicine, terms to describe ongoing or recurrent tumors include “local persistence” (local failure in < 6 mo postRT) and “local failure” (> 6 mo postRT). Perhaps those terms should also be used to describe veterinary patients with tumors that relapse. The cells that continue to grow both during and postRT may either inherently have or develop mechanisms of resistance, including decreased apoptosis and increased ability to repair DNA damage. Cells in hypoxic tumor areas (that are likely to occur when bulky disease such as nasal cavity tumors are present) have decreased amounts of critical DNA damage (i.e., double-stranded DNA breaks) compared with oxygenated cells due to decreased oxygen “fixation” of free radicals created by ionizing radiation. Additionally, geographical misses could be due to understaging of the initial disease, either the primary or metastatic components. In the current study, not all dogs had CT scans prior to RT; therefore, gross tumor could have been missed during treatment. Regional lymph nodes were not routinely either aspirated or irradiated, and two dogs were documented to have lymph node metastases. Clinicians should always include regional lymph node aspiration in their staging plan to ensure that all known disease is treated. Finally, secondary primary malignancies in the radiation field have been reported in dogs (but are rare), typically > 2 yr after completion of an initial RT protocol, so it seems unlikely to be the cause of recurrent nasal cancers in the majority of patients.
Reirradiation of recurrent tumors is controversial in human and veterinary patients.20,26,29–33 The primary argument against reirradiation is the notion that normal tissues cannot tolerate additional radiation without significant risk of morbidity. In general, acutely responding tissues such as skin and mucosa heal almost completely after radiation, and late responding tissues (including vasculature, muscles, nerves, and bones) do not heal completely and, therefore, are the most susceptible to injury with reirradiation. The probability of injury to late responding tissues with reirradiation depends on the specific tissue type, time between courses of RT, total dose, dose/fraction of the initial and subsequent treatments, species, patient age, use of concurrent chemotherapy, and the presence of other comorbidities.29–33 Most of the information on tissue tolerance comes from normal animal studies, which seldom mimic clinical conditions. Although several studies in human medicine have documented that reirradiation is generally well tolerated and effective, standards of care do not exist in this realm of radiation oncology. In this study, the authors documented that reirradiation of dogs with nasal carcinomas treated with ≥ 2 courses of coarsely fractionated RT is generally safe and effective in the majority of patients.
The largest study of reirradiation of tumors in dogs and cats documented 51 patients with various tumors in different locations, including four nasal cavity tumors.26 All of the tumors had biopsy-confirmed recurrence within the original radiation field after a definitive course of external beam RT or iridium Ir 192 interstitial brachytherapy. The median time between RT courses was 10 mo. Similar to the current study where 70% of patients responded clinically to reirradiation, the majority of animals had either a PR or CR to reirradiation (44 of 51 [86%]), and the 1 yr tumor control rate postreirradiation was 38%. Acute side effects were mild in all cases. Severe late side effects occurred in 6 patients (12%), including normal tissue necrosis (which was not well described). Patients with squamous cell carcinoma and those with reirradiation field sizes > 30 cm2 had a higher risk of severe postRT complications. When the interval between courses of radiation was > 5 mo, the risk of complications was significantly lower. In the current study, the only severe late side effects were ocular side effects; however, it is probable that the incidence of acute and late side effects were underreported due to lapses in follow-up times between radiation courses and following the second course of RT. Ideally, veterinary patients treated with RT should receive regular physical examinations and be evaluated objectively with cross-sectional imaging both during and postRT to document changes in the radiation field, including side effects and tumor response or progression.
A study of a more uniform population of nine dogs with nasal tumors of various histologic types that were treated with reirradiation at the time of tumor relapse over a 10 yr period at a single institution was recently published.20 Cross-sectional imaging-based, three-dimensional RT planning was used in all cases, presumptively lowering the dose to normal tissues compared with previous studies in which manual setups were commonplace and theoretically decreasing the incidence of severe late side effects in susceptible normal tissues. The median dose of radiation delivered in the first course of radiation was 50 Gy delivered in 18 fractions. Reirradiation was initiated at a median of 539 days (range, 239–1,652) after the first course of radiation, and the median total dose was 36 Gy delivered in 18 fractions. The fraction size and total dose were lowered to try to decrease the likelihood of severe acute and late side effects following reirradiation. The median tumor reduction volume on CT after the first and second courses of RT was 86% and 63%, respectively. Clinically, all dogs improved after the first course of RT and all but one improved after the second course of RT. The median ST from the first dose of RT was 927 days (95% confidence interval [CI], 423–1,767 days). The median time to progression after the first course of RT was 513 days (95% CI, 234–1,180 days) and 282 days after the second course (95% CI, 130–453 days). Those times were not statistically different. Acute side effects were minimal to mild in all cases after both courses of RT. Late RT effects were seen in all patients (including skin changes, keratoconjunctivitis sicca, and cataracts) but were only deemed severe in two cases (blindness that was not related to cataract development and resulted in euthanasia). Although that study included only a small number of dogs, the STs following the first and second courses of RT were much longer than those in the dogs of this study, which may be related to a higher total dose of radiation and/or the use of computer-based treatment planning to decrease geographical misses.
In summary, the results of this study demonstrate that the majority of canine patients with nasal carcinomas tolerate reirradiation, and STs can be as long as in patients treated with single course protocols. Limitations of the current study include variability in radiation protocols and total radiation dose, lack of biopsy review of tumors to examine for outcome differences between tumor types, lack of complete clinical staging (including CT scans) in all cases, potential for underreporting of the incidence and severity of acute and late side effects of radiation, lack of necropsies to examine for late side effects and persistent or metastatic tumor, and lack of repeated cross-sectional imaging. STs for dogs in this study may be artificially elevated because only dogs that responded well to the first treatment were offered a second course of RT. Also, necropsies were not performed to determine the extent of remaining tumor and/or tissue side effects of radiation.
Conclusion
The majority of dogs with nasal carcinomas in this study responded to reirradiation and had few life-threatening side effects. Studies to further document the efficacy and safety of reirradiation for various tumor types and locations should be pursued by veterinary radiation oncologists. The increasing availability of advanced cross-sectional imaging and conformal treatment modalities in veterinary radiation oncology may result in fewer geographical misses and an opportunity for dose escalation for tumors with minimal dose to surrounding normal tissues, ultimately resulting in improved tumor control and longer STs.
Contributor Notes
