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New treatment for an aggressive tumor

van Nimwegen SA, Bakker RC, et al.  Intratumoral injection of radioactive holmium (166Ho) microspheres for treatment of oral squamous cell carcinoma in cats. Vet Comp Oncol 2017;0:1-11. 

Feline oral squamous cell carcinomas (FOSSCs) are devastating tumors.  They are frequently advanced when identified and due to their location, even radical surgical resection is unlikely to be curative unless the tumor is small, localized, and sited very rostrally.  Responses of FOSSCs to radiation therapy, chemotherapy, and/or immunotherapy are also largely unrewarding and short-lived.   All treatment modalities that have been attempted have serious side effects on the patient, particularly in terms of tongue function impairment, which in turn has a severe adverse effect on activities crucial to quality of life such as eating and grooming.

Generally FOSSCs are found in the gingiva and tend to invade the underlying bone, the ventral aspect of the tongue, or in the sublingual area.  The etiopathogenesis of FOSSC is largely unknown; possible risk factors include passive tobacco smoke exposure, poor oral hygiene, papillomavirus exposure, and advanced patient age.  These tumors often present as inflamed or ulcerated patches in the oral mucosa rather than mass effects, and it is impossible to definitively identify them as neoplasms without biopsy and histopathology.

In this prospective cohort study of 13 client-owned cats with inoperable, histopathologically confirmed FOSSC with no evidence of locoregional and/or distant metastasis, patients were treated by direct injection of holmium-166 (166Ho) loaded microspheres (10-30 µm in diameter) into their tumors, dubbed “microbrachytherapy” by the authors.  Holmium-166 is a radioactive isotope that is principally a β-particle emitter, but also emits a small fraction of γ radiation.  The β radiation has a short penetration depth, which allows a high radiation dose to be given in a single, very localized treatment without extensive collateral radiation damage to surrounding tissues.  The small amount of γ radiation emitted by this radionuclide allows observation and monitoring of the treated tissues as well as the rest of the body via single-photon emission computed tomography (SPECT). Other physical properties of 166Ho also allow observation of its behavior as well as treatment guidance with computed tomography or magnetic resonance imaging.

Previous studies of 166Ho microbrachytherapy in laboratory animals and veterinary patients, including cats with spontaneous liver tumors, demonstrated that very high tumor-absorbed doses of radiation could be delivered in this way, over 6 times the absorbed dose that can be achieved with external beam radiation, without major associated adverse effects.  In humans 166Ho microspheres are employed in intra-arterial transcatheter radio-embolization treatment of metastatic liver cancer.

Patients enrolled in this study included 8 males and 5 females (gonadectomy status not reported) with a mean age of 14.3 + 2.0 years.  Ten of the patients had FOSSCs on the ventral aspect of the tongue, in the frenulum, or in the sublingual area.  One patient’s tumor was in the mandibular gingiva, and two had tumors in the maxillary gingiva.  Of the 13 cats enrolled in the study, 11 were discharged from the hospital and subsequently followed up.  Two of the cats died, but not from their FOSSCs, within a week of administration of the 166Ho microbrachytherapy, and were not included in the response and survival analysis.

In those study patients with obvious large tumors that presented as mass effects, partial debulking by laser surgery was first performed prior to administration of the 166Ho microbrachytherapy.  Tumors that were principally infiltrative in their growth pattern were not amenable to surgical debulking.  Prior to treatment, all patients received an esophageal feeding tube and a single prophylactic dose of injectable cefovecin sodium, and all received buprenorphine and meloxicam for analgesia during treatment and hospitalization.  Administration of the 166Ho microbrachytherapy was performed under general anesthesia, and scintigraphy was performed immediately after the treatment to evaluate for any unwanted systemic distribution of the radionuclide.

Patients were followed for 6 months after treatment; follow-up examinations were performed at one week, one month, and 2, 4, and 6 months after discharge from the hospital.  Tumor response to the microbrachytherapy was evaluated under general anesthesia by oral examination and manual caliper measurements, and a complete physical examination was performed as well to evaluate for tumor progression or metastasis, side effects of radiation, and general patient condition. Additional laboratory evaluation or imaging studies were performed in some patients if indicated.  After the 6-month post-treatment follow-up period, all patients were monitored long-term for any suspected side effects or recurrences until their death.

For the 11 cats evaluated in the follow-up period, treatment with the 166Ho microbrachytherapy resulted in maximum tumor response approximately 2 weeks after treatment, generally resulting in enhanced quality of life due to improvement in eating, drinking, and grooming activity, and a less inflamed appearance of the lesion.  The local response rate overall was 55% (6/11 patients), with complete response in three patients, and partial response in the other three patients. One cat with a complete response was still being followed up at the time of publication of this article, at 1304 days post-treatment.  In two of the three patients experiencing a partial response, marginal resection using laser surgery following the 166Ho treatment resulted in a local disease progression-free survival (LDPFS) time of 113 and 132 days.

Median overall survival time for all patients who survived to discharge was 113 days (range 63-341 days).  For those patients who experienced local control of their FOSCCs, median survival time was 296 days.  Those patients with smaller pre-treatment tumor volumes (1.9 + 1.0 cm3) were significantly more likely to be responders to the microbrachytherapy than those with larger tumor volumes (4.2 + 1.7 cm3); smaller tumor volume was also a predictor of longer LDPFS time.  Only one of the cats experienced an adverse event considered to be definitely related to the microbrachytherapy, which was a localized radiation ulcer on the surface of the tongue adjacent to the treated tumor; this lesion healed within three weeks with minimal supportive wound care.

The authors conclude that cats with small unresectable FOSSCs can be curatively treated with high-dose 166Ho microbrachytherapy.  Others will usually experience a significant partial response.  While the overall survival time of cats with FOSSCs treated with 166Ho microbrachytherapy is similar to that reported for those receiving hypofractionated external beam radiation protocols alone or in a multimodal approach, the microbrachytherapy is administered in a single session, is minimally invasive, and does not have the severe side effects associated with external beam radiation and chemotherapy. In addition, microbrachytherapy requires only one episode of general anesthesia, rather than the multiple episodes of general anesthesia required for hypofractionated external beam radiotherapy. Especially in larger FOSSCs, which tended to respond less well to the microbrachytherapy, optimization of the intratumoral spatial distribution of the 166Ho microspheres may result in an improved tumor response rate in the future. [PJS]

See also:

Snyder L. Oral squamous cell carcinoma: like owner, like cat.  Vet J 2012;193:6-7.