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. 2021 Oct;62(10):1117–1122.

Recurrence analysis of intraoperative acridine orange-photodynamic therapy for dogs with intranasal tumors

Takuya Maruo 1,✉, Yasuhiro Fukuyama 1, Yuta Nishiyama 1, Yuki Nemoto 1, Eiichi Kanai 1, Shinpei Kawarai 1, Hideki Kayanuma 1, Kensuke Orito 1
PMCID: PMC8439338  PMID: 34602642

Abstract

Intraoperative acridine orange-photodynamic therapy (AO-PDT) and cribriform plate irradiation are used to treat canine intranasal tumors. The purpose of this study was to evaluate the effects of AO-PDT on intranasal tumors and the recurrence rate of tumors after this treatment. Treatments with AO-PDT were performed on 38 dogs through a narrow window of the dorsal nasal cavity. The median progression-free interval was 12 mo and recurrence was detected in 21 dogs. Based on computed tomography, recurrence in 16 dogs was biased to the following areas: lateral (n = 10), medial (n = 2), ventral (n = 0), rostral (n = 0), and caudal (n = 8). Side effects were mild and included subcutaneous emphysema and rhinitis. The median survival time was 24 mo. Although AO-PDT with cribriform irradiation is an effective treatment for intranasal tumors, AO-PDT techniques should be improved to treat the nasal cavity more uniformly and thoroughly.

Introduction

Photodynamic therapy (PDT), which is administered to diseased tissue, involves 3 important components: light of an appropriate wavelength, tissue oxygen, and a photosensitizer (1–3). Light is used to activate the photosensitizer, which then interacts with oxygen molecules to produce reactive oxygen species that are responsible for causing vascular stasis and necrosis, membrane damage, and apoptosis (1–3). Acridine orange (AO) is a photosensitizer (4) used for intraoperative photodynamic therapy (AO-PDT) (5).

An adequate margin is essential for malignant tumor resection (6); however, wide resections of musculoskeletal sarcomas of the limb often result in poor limb function (5). Therefore, intralesional or marginal excision combined with AO-PDT is used to avoid damage to intact tissues and to maintain better limb function with a lower (or at least equal) risk of local recurrence (4,5). Intranasal tumor resection alone is not recommended because of the high rate of recurrence, without a significant extension of life expectancy, associated with the procedure (7). Acridine orange-photodynamic therapy has been used in Stage 1 canine intranasal tumors in combination with cribriform plate intraoperative radiotherapy (IORT) (8,9). The median survival time after therapy was 22 mo (8).

The reported recurrence rate of intralesional or marginal excision combined with AO-PDT for musculoskeletal sarcomas of the limb in humans is between 5 and 40%, depending on tumor stage (5). Recently, this procedure has been adopted for injection-site sarcomas in cats (10). Recurrence was reported in 2 of 30 cats. However, the recurrence rate of intranasal tumors is 57% for dogs with Stage 1 intranasal tumors (8), higher than that of human musculoskeletal sarcomas and feline injectionsite sarcomas. The purpose of this study was to evaluate effects of AO-PDT on intranasal tumors and tumor recurrence rate after this treatment.

Materials and methods

The AO-PDT was performed at the Azabu University Veterinary Teaching Hospital between 2010 and 2019. Data were collected retrospectively from medical records of dogs that underwent intranasal tumor resection, including breed, sex, age, body weight, histopathological diagnosis, tumor stage at the time of initial diagnosis, status of the turbinate around the cribriform plate (TAC) (i.e., intact versus destroyed), treatment (5 Gy of single-photon IORT, 25 Gy electron beam cribriform plate IORT), concomitant treatment (preoperative 7.5 Gy single or hypofractionated radiotherapy, chemotherapy), adverse events (surgery, radiotherapy), recurrence, progression-free interval (PFI), percentage of recurrence tumor size, recurrence area, recurrence treatment, and overall survival.

For the recurrence analysis, computed tomography (CT) cases were included. The percentage of tumor recurrence was calculated using the formula (recurrence tumor size/original tumor size) × 100 by CT. Recurrent tumors attached to all sides of the nasal cavity were excluded from the recurrence area analysis, as the origin of the recurrence could not be determined. The recurrence area was classified as either rostral, caudal (cribriform plate), ventral, lateral, or medial.

The turbinate around the cribriform plate (TAC) was identified as the area located 5 mm rostrally and caudally from the cribriform plate on axial CT images (9). It was noted if the turbinate was intact or destroyed. The modified Adams staging system for tumors was used (11). Radiation injuries were classified according to the Veterinary Radiation Therapy Oncology Group (VRTOG) criteria (12). Surgical complications were classified using the Japan Clinical Oncology Group (JCOG) postoperative complication criteria, based on the Clavien-Dindo classification (13).

AO-PDT and cribriform plate IORT procedure

General anesthesia administration, intranasal tumor resection, and performance of AO-PDT through the bony window of the dorsal nasal cavity, were done as described (8,9). Cribriform plate electron beam IORT was performed in most cases owing to destruction of the TAC. Furthermore, in some cases, it was followed by 5 Gy of single-photon irradiation for the existing tumor area (8). Two dogs were given AO intravenously before anesthesia. This procedure was performed in accordance with the guidelines approved by the Azabu University Animal Experimentation Committee (approval No. 120921–2).

Radiotherapy procedure

Computed tomography (Asteion; Toshiba, Tokyo, Japan) was completed before radiotherapy and the CT images were used to plan the radiotherapy procedure using XiO software (Elekta, Tokyo, Japan). Radiotherapy was conducted using a linear accelerator (Primus; Toshiba, Tokyo, Japan). The head of each dog was positioned using a bite-block-type head immobilization device (14). The mass lesion was defined as gross tumor volume (GTV). When the mass lesion was surrounded by bone, the clinical tumor volume (CTV) was equal to the GTV (CTV = GTV). An irradiation margin was created with a 5-mm isotopic expansion from the CTV; therefore, the planning tumor volume (PTV) equaled the CTV with the addition of a 5-mm margin. Single 7.5 Gy photon irradiation or hypofractionated radiotherapy was completed before surgery. Intraoperative radiotherapy was set at 5 Gy. The 1-week protocol for radiotherapy was ≤ 20 Gy (15). A cuttable 1-cm gel sheet (Hitohada-gel Hardness 0; EXSEAL, Gifu, Japan) was used.

Statistics

The progression-free interval and overall survival were calculated using the Kaplan-Meier survival curve. For the PFI, dogs that survived without recurrence were excluded, and recurrence or death was classified as an event. For overall survival, dogs that survived or were lost to follow-up were excluded. Prognostic factors were determined using the log-rank test. Investigated factors included age (young, old), body weight (light, heavy), tumor stage, pathology (epithelial or sarcoma), with or without radiotherapy, and 5 Gy single-photon IORT or preoperative hypofractionated radiotherapy. All statistical analyses were performed using JMP statistical software (Version 8.02; SAS Institute, Cary, North Carolina, USA). Statistical significance was defined as P < 0.05.

Results

Thirty-eight dogs underwent AO-PDT (Table 1). The breeds were: Shiba Inu (n = 6), miniature dachshund (n = 5), border collie (n = 4), golden retriever (n = 4), Labrador retriever (n = 4), Pembroke Welsh corgi (n = 4), bearded collies (n = 1), Beagle (n = 1), bichon frise (n = 1), cocker spaniel (n = 1), Italian greyhound (n = 1), Old English sheepdog (n = 1), shetland sheepdog (n = 1), West Highland white terrier (n = 1), and mixed breed (n = 3). Seventeen dogs were male (9 neutered) and 21 were female (17 spayed). The mean age and body weight were 11.6 ± 2.0 y and 15.9 ± 9.7 kg, respectively. Tumors were classified as adenocarcinomas (n = 14), transitional cell carcinomas (n = 10), chondrosarcomas (n = 3), epithelial tumors (n = 3), squamous cell carcinomas (n = 2), adenosquamous carcinomas (n = 2), olfactory neuroblastomas (n = 1), osteosarcomas (n = 1), undifferentiated adenocarcinomas (n = 1), and undifferentiated carcinomas (n = 1). Twenty-seven tumors were classified as Stage 1, 1 as Stage 2, 2 as Stage 3, and 8 as Stage 4. Destruction of the TAC was detected in 34 dogs.

Table 1.

Summary of signalment.

Breed Sex Age (y) Body weight (kg) Diagnosis Tumor stage TAC status
1. Shiba Inu MI 13 10.9 AC 1 Destroyed
2. Beagle FS 12 9.5 TCC 4 Destroyed
3. Labrador retriever MI 12 31 TCC 1 Intact
4. Labrador retriever FI 13 25 AC 1 Intact
5. Labrador retriever MI 14 31 TCC 4 Destroyed
6. Golden retriever MI 10 31.5 UACA 4 Destroyed
7. Miniature dachshund FS 11 6.8 CSA 2 Intact
8. Old English sheepdog MC 8 36.1 CA 1 Destroyed
9. Pembroke Welsh corgi MC 11 15.1 AC 4 Destroyed
10. Golden retriever MI 13 40.2 OSA 4 Destroyed
11. Cocker spaniel FI 11 11.4 CSA 3 Destroyed
12. Miniature dachshund MC 8 4 CA 1 Intact
13. Mixed breed FS 12 8.5 AC 1 Destroyed
14. Shiba Inu MC 13 16.5 TCC 3 Destroyed
15. Border collie FS 12 12 AC 4 Destroyed
16. Miniature dachshund FS 11 6 AC 1 Destroyed
17. Shetland sheepdog FS 13 12.1 ASCC 1 Destroyed
18. West Highland white terrier MC 7 8.5 AC 1 Destroyed
19. Miniature dachshund MI 9 5.2 AC 4 Destroyed
20. Pembroke Welsh corgi FS 14 9.8 TCC 1 Destroyed
21. Mixed breed MC 14 14.9 CA 1 Destroyed
22. Border collie MC 11 14.3 ASCC 1 Destroyed
23. Bichon frise FI 13 9.6 TCC 1 Destroyed
24. Pembroke Welsh corgi FS 11 9.3 UCA 1 Destroyed
25. Golden retriever FS 7 35.6 SCC 1 Destroyed
26. Shiba Inu MC 13 12.2 AC 1 Destroyed
27. Labrador retriever FS 12 25.3 SCC 1 Destroyed
28. Shiba Inu FS 12 7.5 TCC 1 Destroyed
29. Border collie MC 10 16.2 AC 1 Destroyed
30. Italian greyhound MI 14 6.9 AC 1 Destroyed
31. Bearded collie FS 12 16.7 TCC 1 Destroyed
32. Golden retriever FS 9 26.8 TCC 4 Destroyed
33. Shiba Inu FI 12 13.3 CSA 1 Destroyed
34. Shiba Inu FS 14 14.5 AC 1 Destroyed
35. Border collie FS 12 12.3 ONB 1 Destroyed
36. Pembroke Welsh corgi FS 12 10.9 TCC 1 Destroyed
37. Mixed breed FS 10 18.5 AC 1 Destroyed
38. Miniature dachshund MI 14 6.6 AC 1 Destroyed
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AC — adenocarcinoma; ASCC — adenosquamous cell carcinoma; CA — carcinoma; CSA — chondrosarcoma; FI — female intact; FS — female spayed; MC — male castrated; MI — male intact; ONB — olfactory neuroblastoma; OSA—osteosarcoma; SCC — squamous cell carcinoma; TAC — turbinate around the cribriform plate; TCC — transitional cell carcinoma; UACA — undifferentiated adenocarcinoma; UCA—undifferentiated carcinoma.

Treatments and results are summarized in Table 2. Eight dogs received 5 Gy of single-photon IORT, 3 dogs received preoperative photon irradiation (7.5 Gy), and 33 dogs received a median 25 Gy (range: 10 to 25 Gy) of cribriform plate IORT. Concomitant treatments included preoperative hypofractionated radiotherapy (median: 20 Gy; range: 18 to 35.5; n = 7), toceranib administration (Palladia; Zoetis Japan, Tokyo, Japan) (n = 2), chemotherapy with carboplatin (carboplatin 450 mg; Sawai Pharmaceutical, Osaka, Japan) (n = 3), and tegafur/gimeracil/oteracil therapy (TS-1; Thaiho Pharmaceutical, Tokyo, Japan) (n = 2).

Table 2.

Summary of treatments and results.

Photon irradiation (Gy)/fractions Cribriform plate IORT (Gy) Concomitant treatment Side effects: Surgery and radiotherapy PFI (mo) Recurrent treatment Overall survival (mo)
1. 5 Gy/1 fraction — — 7 — < 13
2. 5 Gy/1 fraction 20 — chronic rhinitis, subcutaneous emphysema 4 — 8
3. 5 Gy/1 fraction Carboplatin TS-1 chronic rhinitis 36
4. 5 Gy/1 fraction — chronic rhinitis 9
5. 5 Gy/1 fraction 15 — chronic rhinitis 14
6. 5 Gy/1 fraction 20 — chronic rhinitis 12
7. — — 19 RT < 19
8. 25 — 5 RT 10
9. 25 — — < 3.5
10. 35.5 Gy/7 fractions 0 — white hair, alopecia, conjunctivitis 25
11. 25 — chronic rhinitis 36 — < 36
12. 5 Gy/1 fraction 25 — 42
13. 5 Gy/1 fraction 20 — — < 33
14. 25 — subcutaneous emphysema 6 RT 8
15. 22.5 Gy/3 fractions 10 white hair, chronic rhinitis 11 RT < 11
16. 7.5 Gy/1 fraction 15 — chronic rhinitis 6 Re-AO-PDT 24
17. 25 — chronic rhinitis < 17
18. 25 carboplatin TS-1 12 Re-AO-PDT 30
19. 25 — subcutaneous emphysema, chronic rhinitis 26 RT 40
20. 25 — subcutaneous emphysema, pneumocephalus 13 Re-AO-PDT 22
21. 25 — < 21
22. 10 — 4 RT 7
23. 25 — subcutaneous emphysema 15
24. 7.5 Gy/1 fraction 20 carboplatin 3 — 3
25. 25 — 16 Re-AO-PDT 29
26. 25 palladia chronic rhinitis 18
27. 25 — subcutaneous emphysema 11 Re-AO-PDT < 36
28. 20 Gy/5 fractions 15 — pneumocephalus < 31
29. 25 — subcutaneous emphysema, chronic rhinitis < 20
30. 25 — subcutaneous emphysema 1 RT, palladia 28
31. 18 Gy/4 fractions 15 palladia 12 RT 14
32. 20 Gy/5 fractions 25 — 8 8
33. 7.5 Gy/1 fraction 25 — chronic rhinitis < 12
34. 25 — subcutaneous emphysema 3
35. 25 subcutaneous emphysema 6 palladia 10
36. 18 Gy/4 fractions 20 — chronic rhinitis 3 — < 8
37. 25 3 — < 2
38. 24 Gy/4 fractions 13 subcutaneous emphysema, conjunctivitis, alopecia < 1
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IORT — intraoperative radiotherapy; PFI — progression-free interval; Re-AO-PDT — re-resection and acridine orange-photodynamic therapy; RT — radiotherapy; TS-1 — tegafur/gimeracil/oteracil.

Subcutaneous emphysema (Grade 1 according to the Clavien-Dindo classification) was noted as an adverse surgical event in 11 dogs. It spontaneously resolved in all but 1 of these dogs, wherein surgical management was needed within 1 mo. Acute radiation injuries included alopecia (n = 2) and conjunctivitis (n = 2). Changes in hair color were observed in the 2 dogs. All changes were classified as Grade 1. Chronic rhinitis was observed in 14 dogs.

Recurrence was detected in 21 dogs (54%), and CT was performed in 18 cases. Other detection methods included X-ray or clinical symptoms (bleeding and neurologic deterioration). The median PFI was 12 mo (Figure 1). Among the 18 dogs that underwent CT, the median percentage of tumor recurrence was 21% (range: 9 to 114). Two lesions with recurrent tumors attached to all sides were excluded from the recurrence area analysis. Therefore, 16 lesions met the inclusion criteria for recurrence area analysis. Four lesions were attached to both sides. The recurrence of the tumor was located as follows: rostral (n = 0), lateral (n = 10), medial (n = 2), ventral (n = 0), and caudal (cribriform plate, n = 8). Zero (0) recurrence occurred in the ventral and rostral regions. Most recurrences were detected on the lateral and caudal (cribriform plate) sides of the intranasal cavity (Figure 2). The treatments for recurrence were re-resection and AO-PDT (re-AO-PDT) without cribriform plate IORT (n = 5), preoperative hypofractionated radiotherapy (n = 8), and toceranib administration (n = 2). Four dogs did not receive any treatment. The median overall survival time was 24 mo (Figure 3).

Figure 1.

Figure 1

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Progression-free interval (PFI) curve after marginal tumor resection followed by intraoperative acridine orange-photodynamic therapy (AO-PDT) in dogs with intranasal tumors. The median PFI was 12 mo.

Figure 2.

Figure 2

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A typical computed tomography image showing recurrence (A–D). Recurrence was detected on the lateral side of the nasal cavity.

Figure 3.

Figure 3

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Kaplan-Meier survival curve of the overall survival after marginal tumor resection followed by intraoperative AO-PDT in dogs with intranasal tumors. The median overall survival was 24 mo.

There were no significant differences in the progression-free interval and overall survival, nor were there any differences based on whether the dog received a single 5 Gy photon IORT and preoperative hypofractionated radiotherapy. The median overall of patients with recurrence was 27 mo after re-AO-PDT and 14 mo after hypofractionated radiotherapy, with no significant differences between the 2 groups.

Discussion

The recurrence rate was 54%, with recurrence sites biased to the lateral and caudal (cribriform plate) sides of the nasal cavity. No recurrence was observed on the ventral side. Recurrence rate of intranasal tumors was higher than that of musculoskeletal sarcomas in humans (5 to 40%) (4,5) and injection-site sarcomas in cats (2 in 30 cats) (10). A narrow bony window was used for tumor removal, xenon irradiation, and electron beam IORT. It may have been imperfect due to blind spots, resulting in persistence of residual tumor cells, imperfect tumor removal causing incomplete resection, imperfect xenon light irradiation causing a weak light side, and imperfect electron beam irradiation causing tumor recurrence. These might have been the reasons for the high recurrence rates in the lateral and caudal (cribriform plate) sides of the nasal cavity.

In combination with a single 5-Gy photon IORT as well as light beams, AO has a tumor synergistic cytocidal effect (16). Furthermore, AO also has a radiation-sensitizing effect (17). This radiodynamic therapy was named after Kusuzaki (16). Irradiation with 5-Gy photon was reported as being more effective than AO-PDT without radiodynamic therapy (18); however, that study did not detect beneficial effects of radiodynamic therapy. It has been suggested that an empty nasal cavity does not emit scattering radiation (19), and that the actual irradiated dose might be smaller than the prescribed dose.

Some treatments should be selected for recurrence after AO-PDT. Conducting surgery at an early tumor stage is important (3). Most recurring tumors were smaller than primary tumors; however, there was no significant difference between re-AO-PDT and preoperative hypofractionated radiotherapy in this sample size. Some dogs survived longer after re-AO-PDT treatment; therefore, re-AO-PDT is recommended for intranasal tumors that recur after initial AO-PDT.

This study had several limitations. First, it included various tumor types, stages, and treatment methods. Second, owing to its retrospective design, minor adverse events may not have been recorded. Third, the follow-up interval in this study was variable and dependent on patient and clinical factors; therefore, recurrence might not have been detected in a timely and thorough manner. Fourth, in this study, not all patients had a CT scan to evaluate for recurrence. In some patients, recurrence was noted by radiographs and/or clinical signs. Therefore, the PFI may be obscure. Fifth, this study did not prove that preoperative hypofractionated radiotherapy was beneficial. Unintended bias may exist in the selection of preoperative radiotherapy in severe cases. The AO-PDT and cribriform plate IORT were safe; however, the combination of preoperative hypofractionated radiotherapy caused some side effects, such as chronic abscesses and pneumocephalus (20). Therefore, the addition of cribriform irradiation after preoperative hypofractionated radiotherapy should be carefully considered.

In conclusion, AO-PDT with cribriform irradiation was a safe and effective treatment for intranasal tumors. However, the recurrence sites were biased to the lateral and caudal (cribriform plate) parts of the nasal cavity. Therefore, AO-PDT techniques should be improved to treat the nasal cavity more uniformly and thoroughly. CVJ

Footnotes

Presented at the Veterinary Cancer Society Annual Conference, Houston, Texas, USA, 2019.

Use of this article is limited to a single copy for personal study. Anyone interested in obtaining reprints should contact the CVMA office (hbroughton@cvma-acmv.org) for additional copies or permission to use this material elsewhere.

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