Oral Tumors

Oral Tumors

CONTROVERSIES IN CLINICAL ONCOLOGY 0195-5616/96 $0.00 + .20 ORAL TUMORS The Surgeon and the Medical Oncologist K. Ann Jeglum, VMD, and Kenneth Sadan...

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CONTROVERSIES IN CLINICAL ONCOLOGY

0195-5616/96 $0.00 + .20

ORAL TUMORS The Surgeon and the Medical Oncologist K. Ann Jeglum, VMD, and Kenneth Sadanaga, VMD

The objective of this article is not to review the already extensive literature on the biological behavior of oral neoplasms in the dog and cat. Instead, it is aimed at raising the issues confronting the clinician following the diagnosis of a specific tumor type in the oral cavity. It is at the time of reading the histopathology report of an oral biopsy that one applies the biological behavior to the individual tumor patient. The controversy in treatment approach starts with whom is initially consulted for a treatment plan, i.e., the surgeon, the radiation therapist, or the medical oncologist. Historically, the conventional treatment of solid tumors has been surgery after which the end product of the procedure dictates the need for adjuvant therapy. Prior to the advent of more aggressive surgical procedures involving resection of mandible or maxilla, radiation therapy may have been used as a salvage therapy in the more advanced stage disease. In reviewing the veterinary literature, medical approaches to oral tumors, i.e., chemotherapy or biological therapy, have been ignored or anecdotal at best. Adjuvant chemotherapy has been used primarily in cases of surgical and / or radiation failure, postoperatively when inadequate tumor-free surgical borders were obtained, or in the presence of regional and/ or distant metastases. In discussing controversy in the management of oral tumors in the dog and cat, the authors will rely heavily on the current status of "primary" or "neoadjuvant" chemotherapy in solid tumor therapy. AdFrom Veterinary Oncology Services and Research Center, West Chester, University of Pennsylvania School of Veterinary Medicine, Philadelphia, and the Wistar Institute, Philadelphia (KAJ); and the Veterinary Referral Center, Frazer (KS), Pennsylvania

VETERINARY CLINICS OF NORTH AMERICA: SMALL ANIMAL PRACTICE VOLUME 26 • NUMBER 1 • jANUARY 1996

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ditionally, the shared clinical experience of the authors will contribute to the potential application of innovative multimodality therapy. A literature review of surgical management will lay the groundwork for determining the need for improvement. In another article, radiation therapy in the treatment of oral neoplasia will be addressed. RESULTS OF MANDIBULECTOMV IN CANINE ORAL CANCER

There are five comprehensive published papers reporting 438 dogs treated with mandibulectomy or maxillectomy between 1979 and 1991.1· 4 • 6• 9 • 12 Although there are variables between the papers with regards to follow-up time at data evaluation and the detail of reporting, a review of this literature allows some conclusions to be made. Radiographic evidence of bony lysis was present in the majority of dogs. Mandibulectomy and maxillectomy was most successful in benign tumors, the most common being of periodontal origin. Median survivals are approximately 2 years with the majority of dogs having no evidence of recurrence. This procedure could be considered curative in these cases. Schwarz et ql reported 1- and 2-year survival rates for benign versus malignant tumor types as 100% and 45% and 86% and 33%, respectively.9 The malignant tumor types will be summarized by histological type in decreasing numbers of incidence. Postoperative complications included wound dehiscence, prehension dysfunction, tongue lag, medial drift, excessive drooling or salivation, palatal ulceration secondary to malocclusion and pressure necrosis from the canine tooth resulted in tooth extraction. Overall, owners were satisfied with the cosmetic and functional outcome of the surgery. Breed and location of the tumor contributed. Two studies used univariate and multivariate statistical analysis to evaluate the effect of various prognostic factors on the results of mandibulectomy.4• 9 Benign tumors consistently had longer disease-free intervals and the longest survival times. In one study, tumor size and location, presence or absence of radiographic evidence of bony lysis, and type of partial mandibulectomy performed had no effect on survival time.• Dogs with squamous cell carcinoma and amelioblastoma had longer survival than those with melanoma, osteosarcoma, and fibrosarcoma. Although younger dogs when adjusted for tumor type were reported to have longer survival periods, the age group was not defined. In the other study, there were different results and more factors evaluated.9 Dogs with tumors located between PM1 to M3 or caudally to M3 showed an increased risk (2.5 and 4.0 times, respectively) of dying from disease compared with those with tumors located rostrally to PMl.

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The anatomic site did not predict histologic type. Dogs with inadequate tumor-free surgical margins were 2.5 times more likely to die than those with complete histologic excision. There was no difference in survival times among the malignant tumor types, although dogs with squamous cell carcinoma showed a trend toward longer survival times. Dogs that received adjuvant therapy following mandibulectomy were 2.5 times likely to die of disease, although 64% of those cases had incomplete surgical resection. The median survival times for dogs with benign tumors was more than 64 months compared with 11 months with malignant tumors. The 1- and 2-year survival times for dogs with benign and malignant tumors was 100% and 45% and 86% and 33%, respectively. For comparitive purposes, Todoroff reported survival times in 361 cases of oral and pharyngeal neoplasmas in the dog. 10 The mean survival times for maiignant melanoma, fibrosarcoma, and squamous cell carcinoma were 3 months, 1 month, and 9 months, respectively. Harvey summarized a compilation of several reports of surgical excision of oral tumors.3 The mean survival times for melanoma, fibrosarcoma, squamous cell carcinomas, and osteosarcoma were 9, 14, 14, and 10 months, respectively. Mean survival times are considered to be a biased estimate versus median times that measure the point of 50% occurrence of the outcome. A few dogs with very long survival times will significantly improve the mean time but not the median. Malignant Melanoma (as in Subsequent Tumor Types)

Sixty-seven of the dogs had malignant melanoma. In the four studies summarized, this tumor type had the poorest prognosis following mandibulectomy due to local recurrence and regional and distant metastases.1· 4• 6• 9 Eighteen of 67 (26.8%) dogs developed local recurrence. Although not specifically documented in all cases, approximately 50% had been regional and/or distant metastases. Thirty-eight (57%) died or were euthanized due to melanoma. The reported median survival times were similar between the studies (6, 7.3, 8, and 9.9). In the authors' opinion, malignant melanoma requires a multimodality therapeutic approach. This will be discussed later in the article. Another site of occurrence of melanoma in the dog's oral cavity is the lip or mucocutaneous junction. These tumors do not have bony involvement and allow a more aggressive resection of surrounding soft tissue. The literature suggests that these melanomas are not as malignant with regards to metastases as gingival tumors. In the authors' clinical experience, oral mucocutaneous melanomas are highly malignant and should be treated similarly to gingival tumors.

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Squamous Cell Carcinoma

Forty-nine dogs with squamous cell carcinoma were treated in the same studies reviewed. The local recurrence rate ranged from 0% to 25%. The survival and disease-free intervals were much more variable between the studies than with melanoma. Schwarz reported a median survival time of 9 months, with 38% of the dogs dying of disease. Kosovsky reported a median disease-free interval of 26 months (range, 6 to 84) with a 91% 1-year survival rate. The differences may be explainable by differences in tumor sites among the studies with the rostral tumors having a more favorable prognosis. Radiation therapy seems to also have a role in the treatment of squamous cell carcinoma with comparable results. The major deciding factors to the clinician would be based on tumor site and stage of disease, availability of radiation therapy, anesthetic risks with multiple radiation treatments and cost factors. Fibrosarcoma

Two studies accounted for the majority of dogs (32/ 38) with fibrosarcoma.•· 9 The median survival times were 10.6 and 11 months respectively. Ther'e was a 50% 1-year survival rate in 19 dogs. Recurrence rates were 31% imd 57% with at least 5 dogs having had rostral mandibulectomy. Sixty-three percent and 62% of the affected dogs died of progressive disease. Palantine fibrosarcomas have the poorest prognosis due to the inability to adequately surgically resect. Osteosarcoma

In 29 cases of osteosarcoma, the median survival times were 7 and 13.6 months. Forty-five percent and 56% of the dogs died of progressive disease. Seven dogs in other studies were reported to have a 6-month median survival. Oral osteosarcoma should be considered a highly malignant tumor and requires more than surgical excision to improve overall, long-term prognosis. The authors are encountering a new population of anaplastic sarcomas in the oral cavity of Golden Retrievers. These are very aggressive locally and highly metastatic. Surgical intervention in these tumors is debatable. RESULTS OF MAXILLECTOMY IN CANINE ORAL CANCER

Aggressive maxillary surgery for the management of maxillary tumors has historically been the primary means of treatment. Various

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adjuvant forms of therapy has been applied to those diseases where inadequate removal, local disease, and metastasis has occurred. Wallace et al report a median disease-free interval of 21.5 months with a 72% 1-year survival time with tumors of dental origin.U Salisbury et aF report similar results with a median disease-free period of 23.5 months and Schwartz et al8 report a greater than 30-month median survival time of dogs with benign oral tumors. We have learned over the past several years that aggressive partial maxillectomies and reconstruction for canine oral tumors can be performed and well tolerated by the canine patient. This approach has enhanced cure rates for benign and local disease. Clearly the efficacy of aggressive maxillectomies and mandibullectomies in the management of benign oral tumors have demonstrated excellent results. However, the relatively low survival times and development of recurrence and metastasis in dogs with malignant maxillary tumors following maxillary surgery appears to be the norm. The argument in favor of surgery has been in the areas of palliation (local disease control), cytoreduction, functional, and cosmetic acceptance. Complications that have been reported include wound management (i.e., swelling), anorexia (transient), tooth-induced mucosal ulcerations from malocclusion, anemia, partial dehiscence, and local recurrence. Malignant maxillary tumors have included squamous cell carcinoma, melanoma, fibrosarcoma, and osteosarcoma. Various prognostic factors have been reviewed with different results. Wallace reports various median survival times for each of these malignant oral tumors concluding tumor size or location and type of partial maxillectomy performed did not affect survival times. In contrast, Schwartz reports no difference in survival times among different tumor types and concluded that tumor location, the integrity of the surgical margins and the use of adjuvant therapy significantly affects survival times. 8 In this article, adjuvant therapy consisted of radiotherapy, combined hyperthermia and radiation therapy, chemotherapy, nonspecific chemotherapy, or combinations of the previously mentioned. Schwartz also reports the use of adjuvant therapy as a negative prognostic indicator, which was a reflection of those cases in which there was inadequate tumor-free surgical margins or when local or distant metastasis was found. 8 This negative indication was a reflection of advanced disease and, therefore, the use of chemotherapy should not be considered a poor prognostic factor by itself. It has been to this salvage role that chemotherapy has been traditionally applied. Our experience with surgical maxillectomies has been consistent with the literature. Of those patients with malignant maxillary tumors having surgery and postoperative chemotherapy, our experience shows that the majority of patients have been euthanized due to local recurrence and/ or complications associated with distant metastasis. The sur-

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gical procedures have been described. In evaluating maxillary tumors, a prerequisite for determining a comprehensive treatment plan is to have an accurate diagnosis that includes a tumor biopsy and staging. Maxillectomies are well tolerated by the patient with functional results. Most of our experience has been in the mesocephalic breeds. In those cases in which we have performed surgeries in the brachycephalic breeds, we have experienced an increased level of morbidity associated with maxillectomies, requiring extended hospitalization and supportive care. Although there seems to be a contrast in the prognostic factors that seem to affect median survival times, we have seen the influence of inadequate surgical margins as the primary factor responsible for survival times. Clearly tumor size and location is often a working constraint if either of these factors impact on the surgeons ability to establish adequate tumorfree margins. The pattern being caudal disease is worse than cranial disease and that tumor size negatively impacts on this pattern also has been our experience. In other words, rostral disease is better than caudal disease. These patterns correlate to the accessibility of the tumor and the surgeon's ability of obtaining clean margins. Of question is the application of surgery for improving long-term survival. If survival and functional integrity is looked at hand-in-hand, there may .be limitations of surgery if the primary tumor imposes no functional debilitating affects. Once this has been established, we have come to question the efficacy of surgery for malignant tumors when there is a high reliance on adjuvant therapy especially when the primary tumor is inadequately excised. One then questions the efficacy of surgery when it is clearly an exercise in debulking the primary inass leaving significant tumor and pathology behind, the potential for showering tumor, and when surgery is clearly not effective (i.e., the primary maxillary tumor is a caudal disease, is too large to allow for primary closure, is involving the midline of the hard palate, is involving the soft palate, tonsillar and/or pharynx, etc.). Under these advanced circumstances, combined modality therapy more than ever with a multidisciplinary team approach to the management of the patient may provide the optimal chances for survival. FELINE ORAL CANCER

The predominant cancer seen in the feline oral cavity has been squamous cell carcinoma. Other tumors have been reported and the prognosis depends on location, whether it is benign or malignant, and the efficacy of surgery. The two most common tumors in the cat are squamous cell carcinoma and fibrosarcoma. Harvey3 reports that 69.5% and Cotter2 reports 75% of all feline oral tumors are squamous cell carcinomas. They respectively report that 6.3% and 18% are fibrosarco-

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mas. Postorino has reported median survival rates of 2 months in cats with oral squamous cell carcinoma having received various modalities of treatment that includes various combinations of surgery, radiation, chemotherapy, and hyperthermia.6 Bradley reports a median survival in five cats with squamous cell carcinoma to be 6 months. Squamous cell carcinomas are typically extremely invasive and can involve the gingiva, tongue, palate, lip, pharynx, and tonsils. Local rostral mandibular disease can, be surgically curative. We have taken up to and including the third premolar on both sides of the mandible with functional results. It is important to note that the morbidity associated with feline mandibular tumors increases with the amount taken at time of the mandibulectomy and, in general, cats are not as tolerant as dogs to mandibulectomies and maxillectomies. Another limitation is the limited amount of soft tissue available for reconstruction following the removal of the primary tumor. There seems to be an increased amount of swelling to the tongue, ranula formation, difficulty in eating associated with mandibulectomies performed in the cat. Hemimandibulectomy up to the third level of the third premolar there is usually a need to provide enteral support until the cat can learn to eat and drink. Concern arises whenever there is a maxillary or caudal mandibular squamous cell carcinoma that often at the time of presentation is usually very invasive and extensive. In our experience, the majority of cases presented have not been good surgical candidates due to the extent of the disease and associated morbidity (pain, anorexia, dehydration). Our past experience has shown that surgical excision of maxillary and caudal mandibular squamous cell carcinoma in the cat is often associated with local recurrence. Therefore, additional modes of therapy need to be explored.

PRIMARY OR NEOADJUVANT CHEMOTHERAPY IN THE MANAGEMENT OF ORAL CANCER

The concept of using chemotherapy as initial treatment prior to any surgical intervention has been applied in humans since the mid-1970s. The primary tumor types have been breast, bone, and head and neck cancers. The trend towards earlier use of chemotherapy has been advanced w ith the improved understanding of the natural history and molecular biology of tumors, identification of more effective chemotherapy agents and protocols and the recognition that chemotherapy has limited efficacy in advanced stage metastatic disease but that the observed antitumor responses warrant its use in earlier stage disease. In veterinary medicine, neoadjuvant chemotherapy has been largely ig-

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Table 1. POTENTIAL ADVANTAGES AND DISADVANTAGES OF NEOADJUVANT OR PRIMARY CHEMOTHERAPY Potential Advantages 1. Decreases the local and regional tumor size thereby improving subsequent surgery and/or radiation therapy; may also allow a less radical surgical approach 2. Improves the effects on micrometastatic disease 3. Allows an in vivo chemotherapy assay to determine response prior to surgery and/or radiation 4. Avoids adverse effects of surgery or radiation via altering vascular access on delivery of adjuvant chemotherapy to local and regional disease Potential Disadvantages 1. Delays control of local and/or regional tumor, resulting in compromise of surgical and/or radiation intervention 2. Allows potential dissemination of micrometastases during ineffective chemotherapy 3. May select for drug-resistant tumor cells 4. Increases toxicity of local treatment

nored. The rationale of neoadjuvant chemotherapy and potential advantages and disadvantages in oral tumors are illustrated in Table 1. There are applications for neoadjuvant chemotherapy and chemotherapy sensitized radiation therapy. These, in turn, may be followed by surgery. To date no controlled studies have been published in the veterinary li.t erature referencing these approaches to cancer management. Given the population of dogs and cats with oral tumors that are prognostically in the poor category as indicated by the above review and factors, the rationale for a modified approach to these patients and application of primary or neoadjuvant chemotherapy is now becoming an approach we have pursued. The authors have been using neoadjuvant chemotherapy in a variety of oral tumors including squamous cell carcinoma, malignant melanoma, and sarcomas. Protocols are given in Table 2. Our results to date have shown objective tumor responses that Table 2. PRIMARY CHEMOTHERAPY PROTOCOLS FOR ORAL TUMORS BAC-Feline Squamous Cell Carcinoma Day 1: Doxorubicin, 25-30 mg/M' IV Bleomycin, 5 units subcutaneously Days 3-6: Cyclophosphamide, 12.5 mg per os Days 8, 15: Repeat bleomycin, 5 units subcutaneously Day 21: Restart cycle with doxorubicin Doxorubicin/Dacarbazine (DTIC)-Canine Oral Sarcomas Day 1: Doxorubicin, 30 mg/M2 IV Days 1-5: Dacarbazine, 200 mg/M' IV Day 10: Complete blood count with differential Day 21: repeat cycle Cisptatin/Dacarbazine (DTIC)-Malignant Melanoma Day 1: Cisplatin, 60 mg/M' IV with NaCI diuresis Days 1- 5: Dacarbazine, 200 mg/M2 IV

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have allowed the patients to have subsequent surgical procedures. We feel that neoadjuvant chemotherapy has a definitive role in the management of oral neoplasia and warrants further investigation. References 1. Bradley RL, MacEwen EG, Loar AS: Mandibular resection for removal of oral tumors. JAVMA 184:460-463, 1984 2. Cotter SM: Oral pharyngeal n~plasms in the cat. JAAHA 17:917-920, 1981 3. Harvey CE: Oral neoplasms. In Harvey CE, Emily P (eds): Small Animal Dentistry. St. Louis, Mosby, 1993, pp 297-311 4. Kosovsky JK, Matthiesen DT, Marretta SM, et al: Results of partial mandibulectomy for the treatment of oral tumors in 142 dogs. Vet Surg 20:397-401, 1991 5. Postorino NC: Feline oral squamous cell carcinoma: A retrospective study in 52 cats. Vet Cancer Society Newsletter 12:6, 1988 6. Salisbury SK, Lantz GC: Long-term results of partial mandibulectomy for the treament of oral tumors in 30 dogs. JAAHA 24:285-294, 1988 7. Salisbury SK, Rkhardson DC, Lantz GC: Partial maxillectomy and premaxillectomy in the treatment of oral neoplasia in the dog and cat. Vet Surg 15:16- 26, 1986 8. Schwartz PD, Withrow SJ, Curtis CR, et a!: Partial maxillary resection as a treatment for oral cancer in 61 dogs. JAAHA 27:617-624, 1991 9. Schwartz PD, Withrow SJ, Curtis CR, et a!: Mandibular resection as a treatment for oral cancer in 81 dogs. JAAHA 27:601-610, 1991 10. Todoroff RJ, Brodey RS: Oral and pharyngeal neoplasia in the dog: A retrospective survey of 361 cases. JAm Vet Med Assoc 175:561-567, 1979 11. Wallace J, Matthiesen DT, Patnaik AK: Hemimaxillectomy for the treatment of oral tumors in 69 dogs. Vet Surg 21:337-341, 1992 12. White RAS, Gorman NT: Wide local excision of acanthomatous epulides in the dog. Vet Surg 18:12-14, 1989 Address reprint requests to K. Ann Jeglum, VMD 739 East Nields Street West Chester, PA 19381