Defining the relevance of surgical margins. Part two: Strategies to improve prediction of recurrence risk.

Due to the complex nature of tumour biology and the integration between host tissues and molecular processes of the tumour cells, a continued reliance on the status of the microscopic cellular margin should not remain our only determinant of the success of a curative-intent surgery for patients with cancer. Based on current evidence, relying on a purely cellular focus to provide a binary indication of treatment success can provide an incomplete interpretation of potential outcome. A more holistic analysis of the cancer margin may be required. If we are to move ahead from our current situation - and allow treatment plans to be more intelligently tailored to meet the requirements of each individual tumour - we need to improve our utilisation of techniques that either improve recognition of residual tumour cells within the surgical field or enable a more comprehensive interrogation of tumour biology that identifies a risk of recurrence. In the second article in this series on defining the relevance of surgical margins, the authors discuss possible alternative strategies for margin assessment and evaluation in the canine and feline cancer patient. These strategies include considering adoption of the residual tumour classification scheme; intra-operative imaging systems including fluorescence-guided surgery, optical coherence tomography and Raman spectroscopy; molecular analysis and whole transcriptome analysis of tissues; and the development of a biologic index (nomogram). These techniques may allow evaluation of individual tumour biology and the status of the resection margin in ways that are different to our current techniques. Ultimately, these techniques seek to better define the risk of tumour recurrence following surgery and provide the surgeon and patient with more confidence in margin assessment.

Scar revision for incompletely or narrowly excised soft tissue sarcomas in dogs.

Objective: Describe clinical features of dogs undergoing scar revision for incompletely or narrowly excised soft tissue sarcomas (STSs) in the absence of gross disease and to determine local recurrence rates following scar revision. Animals: Thirty-three dogs with 33 scars. Procedures: Medical records were reviewed to collect data on signalment, tumor details, pre-surgical diagnostic tests, surgical and pathologic findings for both the initial and revision surgeries, and clinical outcomes. Descriptive statistics were generated. Results: For the initial excision, cytology was performed before surgery in 45.5% (15/33) of dogs, and information on surgical margins was rarely reported [4.0% (1/25) of circumferential and 12.0% (3/25) of deep margins]. Microscopic evidence of residual STS was identified in 18.2% of scars. Recurrence occurred in 3.0% (1/33) of dogs [median follow-up of 1127 d (1 to 3192 d)]; this dog had had no evidence of residual tumor in the scar revision pathology. Conclusions: Despite the low identification rate of residual tumor, the local tumor recurrence rate was 3.0%, which is lower than what is historically reported for incompletely or narrowly excised STSs. Clinical relevance: Scar revision for incompletely or narrowly excised STSs resulted in durable tumor remission in the dogs of this study. Pre-surgical diagnostic tests were not often performed in this study; these may be considered before the first excision to plan surgical margins for potentially reducing the incidence of incomplete or narrow excision. Surgical reports should include details on circumferential and deep margins to guide pathologic interpretation and future scar revision, if required.

Révision des cicatrice pour les sarcomes des tissus mous incomplètement ou étroitement excisés chez le chien. Objectif: Décrire les caractéristiques cliniques des chiens subissant une révision de cicatrice pour des sarcomes des tissus mous (STSs) incomplètement ou étroitement excisés en l'absence de maladie macroscopique et pour déterminer les taux de récidive locale après la révision de cicatrice. Animaux: Trente-trois chiens avec 33 cicatrices. Procédures: Les dossiers médicaux ont été examinés pour recueillir des données sur le signalement, les détails de la tumeur, les tests de diagnostic pré-chirurgicaux, les résultats chirurgicaux et pathologiques pour les chirurgies initiales et de révision, et les résultats cliniques. Des statistiques descriptives ont été générées. Résultats: Pour l'excision initiale, une cytologie a été réalisée avant la chirurgie chez 45,5 % (15/33) des chiens, et les informations sur les marges chirurgicales ont été rarement rapportées [4,0 % (1/25) des marges circonférentielles et 12,0 % (3/25) des marges profondes]. Des preuves microscopiques de STS résiduel ont été identifiées dans 18,2 % des cicatrices. Une récidive est survenue chez 3,0 % (1/33) des chiens [suivi médian de 1127 jours (1 à 3192 jours)]; ce chien n'avait eu aucun signe de tumeur résiduelle dans la pathologie de révision de la cicatrice. Conclusions: Malgré le faible taux d'identification de tumeur résiduelle, le taux de récidive tumorale locale était de 3,0 %, ce qui est inférieur à ce qui est historiquement rapporté pour les STS incomplètement ou étroitement excisés. Pertinence clinique: La révision des cicatrices pour les STS incomplètement ou étroitement excisés a entraîné une rémission tumorale durable chez les chiens de cette étude. Les tests diagnostiques pré-chirurgicaux n'ont pas souvent été effectués dans cette étude; ceux-ci peuvent être envisagés avant la première excision pour planifier les marges chirurgicales afin de réduire potentiellement l'incidence de l'excision incomplète ou étroite. Les rapports chirurgicaux doivent inclure des détails sur les marges circonférentielles et profondes pour guider l'interprétation pathologique et la révision future de la cicatrice, si nécessaire.(Traduit par Dr Serge Messier).

Incomplete histological margins following planned narrow excision of canine appendicular soft tissue sarcomas and mast cell tumors, using the residual tumor classification scheme.

OBJECTIVE: To describe the frequency of incomplete histological margins following planned narrow excision (PNE) of mast cell tumors (MCTs) and soft tissue sarcomas (STSs), and to assess the residual tumor classification (R) scheme for reporting histological margins in clinical cases. STUDY DESIGN: Retrospective clinical study. SAMPLE POPULATION: Forty-four client-owned dogs with 47 masses. METHODS: Medical records of dogs undergoing planned narrow excision of STSs and MCTs were reviewed (2016-2019). Histologic specimens were reviewed by a single pathologist and assigned R scoring (histologically incomplete/R1 margins defined as "tumor on ink"). RESULTS: Six out of 23 (26%) MCT PNEs and 10/42 (42%) of STS PNEs resulted in R1 margins. R1 margins were more likely when performing PNE with 6-10 mm lateral measured surgical margins (LMSMs) versus 0-5 mm LMSM for MCTs (1/14 vs 5/9), but not STSs (3/7 vs 7/17) (P = .049). The R scheme resulted in higher retrospective percentage agreement in histological reporting than defining incomplete histological margin as tumor cells within ≤1 mm of the margin (83% vs 68% agreement). Complications occurred in 12/47 surgeries, with none requiring additional surgery. Tumors recurred in 3/18 (17%) STSs and 2/18 (11%) MCTs. CONCLUSION: Fewer R1 margins were obtained when PNE with LMSM of 6-10 mm was performed for mast cell tumors. The use of the R scheme increased agreement in histopathological margin assessment. CLINICAL SIGNIFICANCE: Planned narrow excision is a viable technique for histopathological diagnosis of appendicular soft tissue sarcomas and mast cell tumors for limb salvage.

Evaluation of scar revision after inadequate primary excision of cutaneous mast cell tumors in 85 dogs (2000-2013).

OBJECTIVE: To determine the frequency of residual tumor, and factors associated with local recurrence and disease progression in dogs with incompletely excised mast cell tumors (MCT) following scar revision surgery. STUDY DESIGN: Retrospective study. ANIMALS: Eighty-five dogs. METHODS: Medical records from January 2000 to April 2013 were reviewed. Dogs with scar revision surgery after incomplete primary MCT excision were included. Recorded were signalment; initial tumor size, location and grade; time interval between primary excision and scar revision surgery; presence of MCT in the resected scar; local recurrence, lymph node metastasis, systemic metastasis, and cause of death. RESULTS: Eighty six tumors in 85 dogs were studied. Residual MCT was found in 23 (27%) resected scars. Seven (8%) scars with residual MCT had incomplete or narrow margins. Follow-up was available for 68 dogs (69 tumors; median 403 days; range 4-2939). Local recurrence was reported in three (4%) dogs at 212, 555, and 993 days. Disease progressed in 10 dogs (14.5%) with regional or systemic metastasis at a median of 207 days (64-1583). Margin status and presence of MCT in the resected scar were not associated with local recurrence or disease progression. Lymph node metastasis (p = .004), locoregional recurrence (p = .013), and disease progression (p = .001) were significantly more likely in Grade III tumors. CONCLUSION: Twenty-seven percent of resected scars contained residual MCT, but recurrence was uncommon after surgical revision. CLINICAL SIGNIFICANCE: Clinicians should primarily consider tumor grade when estimating the likelihood of local recurrence and disease progression and determining the need for ancillary treatment of MCT after scar resection.

Histologic margins and the residual tumour classification scheme: Is it time to use a validated scheme in human oncology to standardise margin assessment in veterinary oncology?

There is no consensus on the definition of a complete histologic excision in veterinary oncology; many definitions have been used in various studies, but these have been arbitrarily selected with no apparent justification. The residual tumour classification scheme, where a complete histologic excision is defined as a histologic tumour-free margin >0 mm, has been used for >40 years in human oncology by all of the major clinical staging organizations and is considered highly prognostic for the vast majority of malignant tumours in people. Because of the widespread use of the residual tumour classification scheme both clinically and in research studies, this standardized approach permits better communication between clinicians, an evidence-based decision-making process for adjuvant treatment options following surgical resection, minimizes exposing patients to unnecessary adjuvant treatments and a better ability to compare local tumour control for specific tumours between different studies. The adoption of the residual tumour classification scheme in veterinary oncology would likely achieve similar outcomes and minimize the prevalent confusion within the veterinary community, amongst both general practitioners and specialists, regarding the definition of what constitutes a complete histologic excision.

Minimal residual disease in canine lymphoma: An objective marker to assess tumour cell burden in remission.

Lymphoma is the most common haematopoietic malignancy in dogs. Since a high proportion of dogs with lymphoma achieve remission soon after initiation of chemotherapy, an objective marker assessing treatment efficacy is required. Following clinical remission, the residual population of tumour cells can be referred to as the minimal residual disease (MRD). MRD traditionally has been detected by cytology and flow cytometry; however, if the burden of malignant cells is low, these methods might not be sufficiently sensitive to detect MRD. As an extension of the development of PCR for antigen receptor gene rearrangements (PARR) in dogs, there has been recent progress in the application of real-time quantitative PCR (RT-qPCR) to canine lymphoma. With the RT-qPCR system, a very high sensitivity (1 cell per 10,000 cells) has been achieved by preparing allele-specific oligonucleotide primers and probes designed from neoplastic clones of each dog. A series of MRD diagnostics studies employing the RT-qPCR system has revealed its usefulness as a prognostic indicator, an objective marker of treatment efficacy and a predictor of relapse for dogs with lymphoma receiving chemotherapy. Introduction of the MRD monitoring system will provide an innovative scientific tool in the development of superior treatments and monitoring strategies for canine lymphoma.

EARLY POSTOPERATIVE MAGNETIC RESONANCE IMAGING FINDINGS IN FIVE DOGS WITH CONFIRMED AND SUSPECTED BRAIN TUMORS.

Early postoperative neuroimaging has been performed in people for over 20 years to detect residual brain tumor tissue and surgical complications. The purpose of this retrospective study was to describe characteristics observed using early postoperative magnetic resonance imaging in a group of dogs undergoing craniotomy for brain tumor removal. Two independent observers came to a consensus opinion for presence/absence of the following MRI characteristics: residual tumor tissue; hemorrhage and ischemic lesions; abnormal enhancement (including the margins of the resection cavity, choroid plexus, meninges) and signal intensity changes on diffusion-weighted imaging. Five dogs were included in the study, having had preoperative and early postoperative MRI acquired within four days after surgery. The most commonly observed characteristics were abnormal meningeal enhancement, linear enhancement at margins of the resection cavity, hemorrhage, and a thin rim of hyperintensity surrounding the resection cavity on diffusion-weighted imaging. Residual tumor tissue was detected in one case of an enhancing tumor and in one case of a tumor containing areas of hemorrhage preoperatively. Residual tumor tissue was suspected but could not be confirmed when tumors were nonenhancing. Findings supported the use of early postoperative MRI as a method for detecting residual brain tumor tissue in dogs.

Minimal residual disease detection by flow cytometry and PARR in lymph node, peripheral blood and bone marrow, following treatment of dogs with diffuse large B-cell lymphoma.

The most promising techniques for detecting minimal residual disease (MRD) in canine lymphoma are flow cytometry (FC) and polymerase chain reaction amplification of antigen receptor genes (PARR). However, the agreement between these methods has not been established. MRD was monitored by FC and PARR following treatment of dogs affected with diffuse large B-cell lymphoma (DLBCL), comparing results in lymph node (LN), peripheral blood (PB) and bone marrow (BM) samples. The prognostic impact of MRD on time to relapse (TTR) and lymphoma-specific survival (LSS) was also assessed. Fourteen dogs with previously untreated DLBCL were enrolled into the study; 10 dogs eventually relapsed, while four dogs with undetectable MRD were still in remission at the end of the study. At diagnosis, the concordance rate between FC and PARR was 100%, 78.6%, and 64.3% for LN, PB and BM, respectively. At the end of treatment, the agreement rates were 35.7%, 50%, and 57.1% for LN, PB and BM, respectively. At least one of the follow-up samples from dogs experiencing relapse was PARR(+); conversely, FC was not able to detect MRD in seven of the dogs that relapsed. PARR was more sensitive than FC in predicting TTR, whereas the combination of PARR and FC was more sensitive than either technique alone in predicting LSS using PB samples. The results suggest that immunological and molecular techniques should be used in combination when monitoring for MRD in canine DLBCL.

Increase in minimal residual disease in peripheral blood before clinical relapse in dogs with lymphoma that achieved complete remission after chemotherapy.

BACKGROUND: We developed previously a minimal residual disease (MRD) monitoring system in dogs with lymphoma by exploring a highly sensitive real-time PCR system. OBJECTIVES: To identify the change in MRD before clinical relapse in dogs with lymphoma that achieved complete remission after chemotherapy. ANIMALS: Twenty dogs with multicentric high-grade B-cell lymphoma. METHODS: MRD levels in peripheral blood mononuclear cells (PBMCs) were measured by real-time PCR amplifying the rearranged immunoglobulin heavy chain gene. MRD measurement and clinical assessment were performed every 2-4 weeks for 28-601 days after completion of chemotherapy. An increase in MRD was defined as an increase by more than 0.5, calculated by log10 [copy number of MRD per 105 PBMCs], based on the uncertainty level observed in a canine lymphoma cell line. RESULTS: During the follow-up period, 15 dogs relapsed in 28-320 days (median, 120 days) after completion of chemotherapy. An increase in MRD was detected 2 weeks or more before relapse in 14 of the 15 dogs, but an increase in MRD before relapse could not be detected in the remaining 1 dog. The time from increased MRD to clinical relapse was 0-63 days (median, 42 days). In contrast, no increase in MRD was detected in 5 dogs that did not experience clinical relapse. CONCLUSION AND CLINICAL IMPORTANCE: An increase in MRD can be detected before clinical relapse in dogs with lymphoma. Application of early reinduction therapy based on an increase in MRD before clinical relapse may improve treatment outcome in canine lymphoma.

Evaluation of cytoreductive efficacy of vincristine, cyclophosphamide, and Doxorubicin in dogs with lymphoma by measuring the number of neoplastic lymphoid cells with real-time polymerase chain reaction.

BACKGROUND: The cytoreductive efficacy of the individual components of multidrug chemotherapy for canine lymphoma is difficult to evaluate after complete remission. OBJECTIVES: To compare the cytoreductive efficacy of vincristine (VCR), cyclophosphamide (CPA), and doxorubicin (DXR) in dogs that received a 6-month modified version of the University of Wisconsin-Madison chemotherapy protocol (UW-25). ANIMALS: Twenty-nine dogs with high-grade B-cell multicentric lymphoma. METHODS: Rearranged immunoglobulin heavy chain gene fragments from lymphoma cells were amplified by polymerase chain reaction (PCR) and sequenced to prepare clone-specific primers and probes for real-time PCR. The number of lymphoma cells in peripheral blood was measured from diagnosis to week 11 of UW-25. RESULTS: The number of lymphoma cells after the 1st administration of VCR, CPA, and DXR in weeks 1-4 was decreased in 29/29 (100%), 15/29 (51.7%), and 26/27 (96.3%) dogs, respectively. The cytoreductive efficacy of CPA was less than that of VCR and DXR. VCR, CPA, and DXR administered in weeks 6-9 were effective in 5/26 (19.2%), 5/20 (25.0%), and 14/19 (73.7%) dogs, respectively, indicating the sustained cytoreductive efficacy of DXR. CPA nonresponders were heavier and exhibited a shorter 1st remission than CPA responders. CONCLUSION AND CLINICAL IMPORTANCE: When using UW-25 for treatment of canine lymphoma, CPA was found to have less cytoreductive efficacy than VCR and DXR. Real-time PCR-based quantification of tumor cells is an objective marker of the efficacy of chemotherapeutic agents.

Monitoring of minimal residual disease (MRD) after multidrug chemotherapy and its correlation to outcome in dogs with lymphoma: a proof-of-concept pilot study.

BACKGROUND: Tumor cell burden in dogs with lymphoma cannot be assessed accurately by diagnostic evaluation during clinical complete remission (CR). Recent advances in polymerase chain reaction (PCR)-based methods enabled us to quantify minimal residual disease (MRD) in canine lymphoma. HYPOTHESIS/OBJECTIVES: To quantify MRD in dogs with lymphoma treated with multidrug chemotherapy and to correlate it with remission duration after chemotherapy. ANIMALS: Seventeen dogs with lymphoma that achieved CR by multidrug chemotherapy. METHODS: Rearranged immunoglobulin heavy chain or T-cell receptor gamma chain gene fragments from lymphoma cells were PCR amplified and sequenced to prepare clone-specific primers and probes for real-time PCR to quantify MRD. MRD in the peripheral blood was monitored during and at the end of a 25-week multidrug chemotherapy protocol. Correlation between MRD at the end of chemotherapy and remission duration after chemotherapy was analyzed. RESULTS: MRD gradually decreased after initiation of multidrug chemotherapy, reached a nadir as low as <0.019-1.0 cells/microL at weeks 4-17, and remained low or slightly increased until week 25. MRD at the end of chemotherapy was negatively correlated with remission duration from the end of chemotherapy to relapse. CONCLUSION AND CLINICAL IMPORTANCE: MRD could be an objective marker to indicate tumor cell burden in dogs with lymphoma even in clinical CR. MRD at the end of chemotherapy could be a prognostic factor to predict remission duration after chemotherapy.

Clonality and phenotyping of canine lymphomas before chemotherapy and during remission using polymerase chain reaction (PCR) on lymph node cytologic smears and peripheral blood.

Polymerase chain reaction (PCR) assays for the immunoglobulin and T-cell receptor genes were utilized to determine phenotype and clonality from lymph node cytologic smears and peripheral blood lymphocytes from 10 dogs with lymphoma, before chemotherapy and during remission. Results were compared with those from 13 dogs with a cytologic diagnosis of lymph node hyperplasia. Clonality was identified in 7 of the lymphomas on the basis of either lymph node cytology or peripheral blood lymphocytes before treatment. No lymph node hyperplasia samples were clonal. In 6 of the dogs with lymphoma, clonality was demonstrated during clinical remission. Detection of PCR clonality during clinical remission is an effective means of identifying minimal residual disease in canine lymphoma and thus additional work is warranted to determine if molecular remission is prognostic or predictive for outcome in well-controlled and well-defined lymphoma subtypes.

Quantitative assessment of minimal residual disease (MRD) in canine lymphoma by using real-time polymerase chain reaction.

Lymphoma is the most common hematopoietic malignancy in dogs. Although a large proportion of dogs with lymphoma can achieve clinical remission by initial chemotherapy, most dogs die as a consequence of tumor relapse. We established a quantitative detection system for minimal residual disease (MRD) in canine lymphoma by using real-time polymerase chain reaction (PCR). A canine T-cell lymphoma-derived cell line, namely, UL-1, was used to examine the specificity and sensitivity of the MRD detecting system. Allele-specific oligonucleotide primers and probes were designed based on the sequence of T-cell receptor gamma chain (TCRgamma) gene fragment of UL-1 cells in conjunction with its downstream sequence, which were obtained from the dog genome database. The real-time PCR system for plasmid DNA containing the TCRgamma gene derived from UL-1 cells and the genomic DNA of UL-1 cells revealed that the system was accurate for 10-100,000 copies per reaction and its sensitivity was 1 cell per 10,000 cells. In order to monitor the kinetics of tumor cell number in canine lymphoma, we quantified the level of MRD in the peripheral blood of 7 dogs with lymphoma under chemotherapy. Since the lymphoma cells from the 7 patients were shown to be B-cell origin from the finding of clonal rearrangement of immunoglobulin heavy chain (IgH) gene, allele-specific oligonucleotide primers and probes were prepared based on the sequence of rearranged IgH gene in each case. The number of peripheral blood tumor cells measured by the real-time PCR was comparable to that estimated by conventional hematological examination in 2 cases of stage V lymphoma. MRD in the peripheral blood was detectable in all 7 cases, even in the complete remission (CR) phase. In the 7 lymphoma dogs, changes in the MRD levels of peripheral blood generally paralleled with the changes in the volumes of lymph nodes. Molecular CR, in which the MRD level was below the detection limit, was not observed in any of these 7 patients under chemotherapy. The MRD level detected by the real-time PCR method described here would be useful for investigating the kinetics of tumor cell growth and its regression in canine lymphoma patients.

Evaluation of primary re-excision after recent inadequate resection of soft tissue sarcomas in dogs: 41 cases (1999-2004).

OBJECTIVE: To determine the efficacy of primary re-excision alone for treatment of soft tissue sarcomas after recent incomplete resection, the frequency and clinical importance of detecting residual tumor in resected scars, and prognostic factors associated with the procedure. DESIGN: Retrospective case series. ANIMALS: 41 dogs. PROCEDURES: Medical records of dogs that had undergone recent incomplete excision of a soft tissue sarcoma at a referring veterinary practice and subsequent re-excision of the scar at the Colorado State University Veterinary Medical Center were reviewed. Owners and referring veterinarians were contacted for follow-up information. Slides from re-excised specimens were reviewed. Dogs that underwent radiation therapy after the re-excision procedure were excluded. RESULTS: 41 dogs met the inclusion criteria, and long-term follow-up information was available for 39 dogs. Median follow-up time was 816 days. Local recurrence of tumor developed in 6 of 39 (15%) dogs, and distant metastasis occurred in 4 of 39 (10%) dogs. Healthy tissue margins of 0.5 to 3.5 cm were achieved at re-excision. Residual tumor was identified in 9 of 41 (22%) resected scars. No tumor-, patient-, or treatment-related variables were associated with local recurrence except for the presence of liposarcoma or fibrosarcoma or whether fine-needle aspiration had been performed prior to surgery. CONCLUSIONS AND CLINICAL RELEVANCE: After incomplete resection of soft tissue sarcomas, resection of local tissue should be performed, even if excisable tissue margins appear narrow. A long-term favorable prognosis is achievable without radiation therapy or amputation. The presence of residual tumor in resected scar tissue should not be used to predict local recurrence.

Comparison of perioperative versus postoperative intratumoral administration of cisplatin for treatment of cutaneous sarcoids and squamous cell carcinomas in horses.

OBJECTIVE: To determine the benefits of reducing the interval between surgical cytoreduction and intratumoral administration of cisplatin. DESIGN: Randomized clinical study. ANIMALS: 70 horses with 89 incompletely resected T2- and T3-stage sarcoids (n = 64) and squamous cell carcinomas (25). PROCEDURE: Horses were given 4 intratumoral treatments of cisplatin at 2-week intervals. The first treatment was given at the time of, or immediately after, surgical resection for horses treated in accordance with the perioperative protocol (group 1). Horses in group 2 were treated with cisplatin after the skin healed following surgical resection in accordance with the postoperative protocol. RESULTS: A difference was not found in duration of overall local tumor control between the 2 groups. Patterns of treatment failures and interval to failure differed between the 2 groups. Length of the surgical scar was the only factor that affected prognosis; an increase in length was associated with a poorer prognosis. A detrimental effect of postoperative treatment was only found in tumors with a high tumor proliferative fraction. Local reactions were similar for the 2 treatment groups, and chronic reactions were not observed. CONCLUSIONS AND CLINICAL RELEVANCE: Intratumoral administration of cisplatin is beneficial for treatment of cutaneous tumors in horses. Tumor repopulation during the interval between surgery and intratumoral administration of cisplatin decreases treatment efficacy. These results provide evidence of rapid tumor repopulation following surgical resection without a lag period for tumors with a high proliferation index. When tumor proliferation index is not known, it may be prudent to use the perioperative protocol.

Radiation therapy and surgery for fibrosarcoma in 33 cats.

Thirty-three cats with histologically confirmed fibrosarcomas were treated with radiation therapy followed by surgery. The median (95% confidence interval) disease free interval and overall survival were 398 (261,924) and 600 (lower limit 515) days, respectively. There were 19 treatment failures; 11 cats had only local recurrence, 4 cats developed metastatic disease, 3 cats had local recurrence followed by metastasis, and 1 cat developed simultaneous local and distant disease. Twelve cats are alive and disease free. Two cats died without evidence of treatment failure. The presence of tumor cells at the margin of resected tissue after radiation was the only variable which influenced treatment success. The median (95% confidence interval) disease free interval in 5 cats with tumor cells at the margin of the resected specimen was 112 (94,150) days versus 700 (lower limit 328) days for 26 cats with negative tumor margins, p < 0.0001. We did not identify a relationship between tumor volume, number of prior tumor excisions, concomitant use of chemotherapy or various descriptors of the radiation therapy technique and disease free interval.

Radiation therapy for incompletely resected canine mast cell tumors.

The records of 56 dogs treated with megavoltage radiation for mast cell neoplasia were reviewed to determine the efficacy of this treatment modality. Total radiation dose ranged from 45 to 57 Gray (Gy), dose per fraction ranged from 3.0 to 4.0 Gy, and radiation treatment time ranged from 14-28 days. Median disease free interval (95% CI) was 32.7 (19-70) months. Median disease free interval for dogs older than 7.5 years was 15 (lower limit 7) months as compared to 62 (lower limit 20) for dogs younger than 7.5 years of age (p = 0.006). Median disease free interval for dogs with measurable disease was 12 (lower limit 5) months as compared to 54 (32-70) months for dogs with microscopic disease (p = 0.006). Radiation treatment time was also significantly related to disease free interval. Median disease free interval for dogs treated longer than 22 days was 12 (7-19) months as compared to greater than 50 (lower limit 20) months for dogs treated in 22 or fewer days (p < 0.001). This appeared to be due to more recurrences in dogs treated with 3-per-week fractionation and suggests that tumor proliferation in the interfraction interval may be important. Sex, tumor location, histologic grade, WHO clinical stage, number of radiation fractions, total radiation dose, and dose-per-fraction, as well as the following "yes/no" variables: steroids given, surgery prior to radiation, lymph nodes irradiated, and development of another mast cell tumor did not appear to influence median disease free interval or survival. Data presented herein support megavoltage radiation as an effective treatment for canine mast cell neoplasia, and suggest that disease free interval in dogs treated with daily fractions may be longer than that achieved with alternating day fractions.

Tumor metastasis: current biologic concepts and their implications for control of residual disease.

Metastatic disease presents an important obstacle to curative cancer therapy. This article reviews cancer biology concepts relevant to the pathogenesis of tumor metastasis and their implications for the surgical oncologist seeking to control or eradicate metastatic disease.