call for RCT that shows chemo or radiation work for VAS

[malernee]

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Subject: sarcomas The very best solution to this problem I think is wide surgical excision to try to get all of the tumor out. While various authors have claimed that additional chemotherapy and/ or radiation is helpful, I find the evidence lacking. In particular, I have not seen any evidence that drugs like acemann or other chemo therapeutic agents work on these tumors . Some work that I have read recently done with a graduate student suggests that radiation may help prolong the time between when a tumor is removed and when it recurs but that does not mean the cats lived longer just that it took longer for the tumor to return. Some vets have found found the 3 year survival of cats with these tumors removed from the shoulder region to be about 30%, not necessarily as a result of surgery. If the tumor does recur it can again be surgically removed. the choice about whether to pursue radiation or not also depends on how much you ' d like to spend as it is quite expensive. I would regard anything beyond surgery as an unproven therapy (though others will certainly disagree with me on this).

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J Am Vet Med Assoc 2001 Feb 15;218(4):547-50
Treatment with a combination of doxorubicin, surgery, and radiation versus surgery and radiation alone for cats with vaccine-associated sarcomas: 25 cases (1995-2000).
Bregazzi VS, LaRue SM, McNiel E, Macy DW, Dernell WS, Powers BE, Withrow SJ
Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins 80523, USA.
[Medline record in process]
OBJECTIVE: To compare use of doxorubicin, surgery, and radiation versus surgery and radiation alone for treatment of cats with vaccine-associated sarcoma. DESIGN: Retrospective study. ANIMALS: 25 cats with vaccine-associated sarcomas. PROCEDURE: Time to first recurrence and survival time were compared between the 2 treatment groups. The number of surgeries (1 or > 1) were compared with respect to time to first recurrence and survival time. RESULTS: Median time to first recurrence was 661 days for the group that received doxorubicin, surgery, and radiation. Median time to first recurrence has not yet been attained for the group treated with surgery and radiation alone. Median survival time was 674 days for the group treated with doxorubicin, surgery, and radiation and 842 days for the group treated with surgery and radiation alone. For time to first recurrence and survival time, significant differences were not detected between cats that had 1 surgery and those that had > 1 surgery. CONCLUSIONS AND CLINICAL RELEVANCE: Significant differences between the 2 treatment groups were not detected. The efficacy of doxorubicin in the treatment of vaccine-associated sarcomas is uncertain.

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Sarcoma Development After Radiotherapy in Two Dogs
Vet Comp Oncol 1[2]:113-119 Jun'03 Case Report 27 Refs

* R. J. Mellanby, M. E. Herrtage, J. Chantry, J. M. Dobson
Queen's Veterinary School Hospital, University of Cambridge, Cambridge, Madingley Road Cambridge C63 OES UK; * e-mail: rjm69@cam.ac.uk
Two dogs were treated with a hypofractionated course of radiotherapy following surgical excision of an intermediate grade mast cell tumour and a round cell tumour, respectively. Both dogs developed a sarcoma of the bone, within the irradiated site, several years after the initial radiotherapy treatment. Bone tumours arising within a previously irradiated area are well recognized late radiotherapy side-effect in humans but have been reported infrequently in dogs. These are the first case reports to describe bone sarcomas in the appendicular skeleton at a site, which had been previously treated by a hypofractionated course of radiotherapy for an unrelated tumour. [Abstract]

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http://www.cancer.org/docroot/CRI/conte ... 0chemicals

Americal Cancer Society
Detailed Guide: Sarcoma - Adult Soft Tissue Cancer
What Are The Risk Factors for Sarcoma?

A risk factor is anything that increases a person's chance of getting a disease such as cancer. Different cancers have different risk factors. For example, exposing skin to strong sunlight is a risk factor for skin cancer. Smoking is a risk factor for cancers of the mouth, throat, lungs, bladder, kidneys, and several other organs. But having a risk factor, or even several, does not mean that a person will get the disease. Scientists have found several risk factors that make a person more likely to develop soft tissue sarcomas. Ionizing radiation: This risk factor accounts for only a small percentage of sarcomas (less than 5%). The most common cause of radiation exposure in patients who develop sarcomas is from radiation given to treat other tumors, such as breast cancer or lymphoma. The average time between radiation exposure and diagnosis of a sarcoma is about 10 years. Radiation therapy techniques have steadily improved over several decades. Treatments now target the cancers more precisely, and more is known about selecting radiation doses. These advances are expected to reduce the number of secondary cancers resulting from radiation therapy. However, oncologists (doctors with special training in the diagnosis and treatment of cancer) prescribe radiation therapy only when its benefits (improved survival rate and relief of symptoms) outweigh the risk of this and other complications.




Detailed Guide: Sarcoma - Adult Soft Tissue Cancer
What Are The Risk Factors for Sarcoma?

A risk factor is anything that increases a person's chance of getting a disease such as cancer. Different cancers have different risk factors. For example, exposing skin to strong sunlight is a risk factor for skin cancer. Smoking is a risk factor for cancers of the mouth, throat, lungs, bladder, kidneys, and several other organs. But having a risk factor, or even several, does not mean that a person will get the disease. Scientists have found several risk factors that make a person more likely to develop soft tissue sarcomas.

Ionizing radiation: This risk factor accounts for only a small percentage of sarcomas (less than 5%). The most common cause of radiation exposure in patients who develop sarcomas is from radiation given to treat other tumors, such as breast cancer or lymphoma. The average time between radiation exposure and diagnosis of a sarcoma is about 10 years.

Radiation therapy techniques have steadily improved over several decades. Treatments now target the cancers more precisely, and more is known about selecting radiation doses. These advances are expected to reduce the number of secondary cancers resulting from radiation therapy. However, oncologists (doctors with special training in the diagnosis and treatment of cancer) prescribe radiation therapy only when its benefits (improved survival rate and relief of symptoms) outweigh the risk of this and other complications.

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A Review of Clinical Trials: Design and Expected Outcomes
ACVIM 2003
Marlene Hauck, DVM, PhD, DACVIM
Raleigh, NC

INTRODUCTION

The advancement of knowledge in veterinary oncology relies, in part, upon the testing of new (or old) therapies in clinical trials. Just as important is our ability, as the consumer of the veterinary journals reporting these trials, to understand the limits of different types of clinical trials and to avoid the over interpretation of data presented in such studies. The goal of this presentation is to briefly review the different types of clinical trials that are published in the veterinary literature, discuss the basics of trial design and the types of outcomes that can be assessed.

FEASIBILITY STUDIES

These studies are often the first step in the introduction of a new method of treatment in veterinary oncology. The purpose of a feasibility study is not to demonstrate that a treatment is effective, but instead to show that it can be done. Feasibility studies (sometime called "proof of principle") typically report the new methods in detail, with emphasis on repeatability and achievement of endpoints. An example of this type of study is a recent publication by Thrall et al. entitled: Using Units of CEM 43°C T90, local hyperthermia thermal dose can be delivered as prescribed. (Int J Hyperthermia 16:415-428, 2000). This paper described the techniques used to deliver a prescribed heat dose to a tumor, how heat dose was measured and how precise was the delivery. Feasibility studies are often required before any type of clinical trial is undertaken. These types of studies make no effort to determine if a new treatment is beneficial.

DOSE-FINDING STUDIES

Often called phase I trials, dose-ranging or schedule finding, dose-finding studies are designed to determine the optimum dose or schedule of a new therapeutic agent. The classical definition is a study designed to identify the side effects and the maximum dose that can be safely administered. With traditional cytotoxic agents, this type of study is relatively straightforward--the maximum tolerated dose is that at which a predefined level of toxicity is seen. With newer agents that act via non-traditional pathways, the maximum biologically effective dose is the endpoint desired, and the means by which this is measured are more complex. But the goals of the dose-finding study are ultimately the same: determination of the dose to be used in future safety and efficacy trials, the types of toxicity that can be expected and the pharmacokinetics of the new agent. These studies do not have patient benefit as a goal or as an endpoint (other than toxicity). For ethical reasons, patients entered on dose-finding studies are typically those for whom no definitive treatment exists. In veterinary medicine, this sometimes includes patients for whom this is the only financially available treatment.

When reading a report of a dose-finding study, the reader should be able to clearly understand the rationale of the starting dose, the dose escalation scheme, the toxicity measurement scale, number of patients in a cohort (traditionally at least 3) and the means by which the MTD is determined (usually one dose below that which >2 of 3 or >2 of 6 patients experience DLT). Information on the pharmacokinetics and/or pharmacodynamics of the drug is also a critical component of this type of trial. The types of toxicities seen also need to be reported.

SAFETY AND EFFICACY TRIALS

These trials are also known as phase II clinical trials. The goals of these trials are to determine if a new treatment is effective and to further define the toxicity of this new treatment in a wider population. Pharmacokinetics may also be a part of safety and efficacy trials. The optimal dose and schedule may not be know for a new agent (despite dose-finding studies) so multiple safety and efficacy trials may be performed on a novel agent. The cumulative toxicities and effects of multiple doses on PKs are often unknown as well, and these are studied as a part of these trials.

Phase II trials are typically performed on a defined patient population (disease), with a specified intervention (treatment) and a defined outcome of interest (how efficacy is determined). Prior to the start of the trial, the definition of effective must be made--i.e., what response rate indicates a new agent has activity against a given disease. The patient population for safety and efficacy studies is typically patients who have failed front-line therapy and for whom definitive treatment is unavailable. Alternatively, safety and efficacy trials can be performed with patients with extremely poor prognoses. The types of outcomes used to assess efficacy include intermediate endpoints, such as tumor response, serum marker levels, 6-month survival etc. These are intermediate endpoints because they may or may not be predictive of increases in patient survival. Quality of life measurements are also used in phase II trials. The critical aspect of the intermediate endpoint used in a safety and efficacy trial is that it should be unambiguously associated with clinical improvement. Therefore short-term tumor shrinkage is not usually a valid endpoint for a safety and efficacy trial unless it absolutely results in clinical improvement of the patient.

In addition to the above parameters, a safety and efficacy study should be hypothesis based. Traditionally, this includes a null hypothesis (response rate is 'low' and further evaluation is not warranted) and an alternative hypothesis (response rate is 'high' and further evaluation is warranted). Low and high rates of response are defined based upon the patient population under study. Ideally, these studies also include early stopping rules in the instance of a low response rate. It is also important that the sample size tested be adequate to draw accurate conclusions about the efficacy of a new agent. There are alternative designs for phase II trials, including 'randomized' trials where patients are assigned to different treatment groups. The goal with this type of study is not the formal comparison of the different treatment groups, but the selection of the most promising agent for further study.

When reading a report of a safety and efficacy trial, the appropriate definitions are important--patient population, intervention tested, endpoint measured and definitions of low and high 'response' rates. If early stopping rules are employed, these should be clearly spelled out. Overinterpretation of the results of safety and efficacy trials is not unusual, and must be cautioned against. These types of trials do not predict the superiority of one treatment over another; their goal is to identify promising therapeutics for further study. In this type of study, the use of a historical control group is for the purpose of defining a 'high' rate of response, not to demonstrate superiority of the new treatment versus the old treatment. These types of questions are answered with the next type of trial:

COMPARATIVE EFFICACY TRIALS

These trials, also known as phase III trials, are exactly what they are entitled: they compare the efficacy of a new treatment versus a standard treatment (or no treatment, depending upon the disease). These types of trials are involve randomly assigning patients with a given to disease to two or more treatment groups, then comparing the impact of the treatment on survival. These trials are the only trials that can tell, with some degree of confidence, whether one treatment is better than another. These trials involve many patients (since improvements in survival are typically quite low, large numbers of patients must be treated in order to detect the differences), multiple institutions (to allow accrual at a reasonable rate) and long term follow-up. Due to the high numbers of patients and expense of performing these types of trials, they are currently rarely performed in veterinary medicine. This may change as veterinary oncology becomes more sophisticated in our approach to the development of new treatments, but the dearth of comparative efficacy trials should not allow us to claim that phase II trials are adequate to make treatment decisions regarding the "best" treatment choice (at least not without understanding the inaccuracies behind that choice).

THE MAGIC p < 0.05 LEVEL OF SIGNIFICANCE

Early in our training we are told that if something has a p-value <0.05 it is 'statistically significant', different from whatever it is being compared with and that statement of difference carries a 95% chance of being correct. This is true in a study designed to test exactly one pair of variables, but after that it gets somewhat less decisive. In a brief communication by Ian F. Tannock in the JNCI, Dr. Tannock suggests that there are at least 3 factors that result in a report of a clinical trial being a false positive: 1) publication bias (more likely that a positive trial will be published); 2) the low probability that a new treatment will result in significant therapeutic gain which implies that the prevalence of true positives is low; and 3) the performance of multiple significance tests. When you consider that, by chance alone, 1 in 20 tests for significance will be positive, one begins to understand why 'significant' results must be carefully evaluated.

Twenty tests may seem like a lot, but when you consider that many comparative efficacy trials have multiple endpoints, perform subgroup analyses or serially test trial participants, the numbers rise quickly. This is an even greater problem if the trial endpoints are not clearly defined initially, which may lead the author of a study to present the most 'impressive' results as the primary endpoint. In addition, without predefined stopping points and total accrual numbers, positive interim results may not be confirmed with additional patients. In the report by Tannock mentioned above, an assessment was made of the number of comparisons (both reported and unreported) made in 32 published human clinical trials. His estimate of the median number of statistical comparisons performed (and not necessarily reported) was 86 per publication. When he included serial reports (abstracts) of these trials as well as the published report, the median estimated number of statistical comparisons was 95.

In veterinary medicine, particularly with retrospective analyses, we are no better at resisting the impulse to test a large number of descriptors to see if they 'significantly' predict response, survival, toxicity etc. There is nothing inherently wrong in performing these tests--we need to remember, however, that these results should be used to generate new hypotheses that can then be tested prospectively. The reader is required to assess the degree of confidence that can be place in statistically significant results and ultimately what these results mean clinically.

SUMMARY

Publishing the results of clinical research is the only means by which the veterinary profession will see progress in medicine. As consumers of published reports, we must be cautious in the interpretation of results that is possibly beyond the nature of the study design. It is becoming much more common (and a great step forward) for statisticians to be involved in the design and analysis of clinical trials and their inclusion is likely to improve the quality of the data and reporting as well.

REFERENCES

1. Much of this information was presented by many clinical trialists in a workshop on clinical trial design presented by AACR/ASCO from July 29th-August 4, 2000.

2. Tannock, Ian F. (1996), "False-positive results in clinical trials: multiple significance tests and the problem of unreported comparisons", Journal of the National Cancer Institute, 88:206-207.

3. Tannock, Ian F. (1992), "Some problems related to the design and analysis of clinical trials", International Journal of Radiation Oncology, Biology, Physics, 22:881-5.

4. Pocock, Stuart J., Hughes, Michael D. and Lee, Robert J. (1987), "Statistical problems in the reporting of clinical trials", The New England Journal of Medicine, 317:426-32.

Speaker Information
(click the speaker's name to view other papers and abstracts submitted by this speaker)
Marlene L. Hauck, DVM, Ph.D., DACVIM
Clinical Sciences, CVM/Box 8401
North Carolina State University
4700 Hillsborough St.
Raleigh, NC 27606

Funded by National Institutes of Health

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Retroperitoneal Sarcomas

Grade and Survival

Toni Ferrario, MD; Constantine P. Karakousis, MD, PhD

Background The survival of patients with retroperitoneal sarcomas depends on the feasibility of complete resection and the grade of the tumor.

Hypothesis A high rate of complete resection, wide rather than local excision when feasible, and a policy of prompt reoperation for local recurrence all improve survival.

Methods A review of 130 consecutive patients with retroperitoneal soft tissue sarcomas (1977-2001).

Results The complete resectability rate was 95%, being 99% (78/79) for the primary tumors and 90% (46/51) for tumors referred with local recurrence. Local recurrence after complete resection occurred in 41% (32/79) of those with primary tumors and in 61% (31/51) of those referred with local recurrence (P = .06). The local recurrence rate was 63% after local excision and 39% after wide resection (P = .02). Of 83 patients with relapse, 37 (45%) were rendered surgically disease free. The estimated 5-year (10-year in parentheses) survival from the first surgery at our center was 65% (56%) for patients with primary tumors and 53% (34%) for patients referred with local recurrence (P = .23). For the primary tumors, the 5- and 10-year survival rates were 70% and 60%, respectively, after wide resection and 47% and 39%, respectively, after local excision (P = .04). For the primary tumors, the 5-year survival was 92%, 54%, and 48% for grades I, II, and III, respectively (P = .02). For those referred with local recurrence, the figures were 76%, 45%, and 19% for grades I, II, and III, respectively (P<.001).

Conclusions A high resectability rate (95%) is possible in retroperitoneal sarcomas. The survival estimates are similar to those following resection of extremity soft tissue sarcomas given an effective reoperation policy for local recurrences. Wide resection lowers the local recurrence and improves survival significantly. Survival varies significantly according to the grade of the tumor.

Arch Surg. 2003;138:248-251

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INSTITUTION: Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston 02114, USA.

2) Camphausen K. Moses MA. Beecken WD. Khan MK. Folkman J. O'Reilly MS. Radiation therapy to a primary tumor accelerates metastatic growth in mice. Cancer Research. 61(5):2207-11, 2001 Mar 1. MEDICAL LIBRARY OWNS
UI: 11280788

ABSTRACT: The surgical removal of a primary tumor can result in the rapid growth of metastases. The production of angiogenesis inhibitors by the primary tumor is one mechanism for the inhibition of metastatic tumor growth. The effect of curative radiotherapy to a primary tumor known to make an inhibitor of angiogenesis and the effects on distant metastases has not been studied. We here show that the eradication of a primary Lewis lung carcinoma (LLC-LM), which is known to generate angiostatin, is followed by the rapid growth of metastases that kill the animal within 18 days after the completion of radiation therapy. The right thighs of C57BL/6 mice (n = 25) were injected s.c. with 1 x 10(6) LLC-LM cells. Animals were randomized to one of five groups: no irradiation, 40 Gy in one fraction, 30 Gy in one fraction, 40 Gy in two 20 Gy fractions, or 50 Gy in five 10 Gy fractions. Tumors were clinically eradicated in each treatment group. All of the surviving animals became dyspneic and
were killed within 14-18 days after the completion of radiation therapy. Examination of their lungs revealed >46 (range, 46-62) surface metastases in the treated animals compared with 5 (range, 2- in the untreated animals. The lung weights had increased from 0.2 g (range, 0.19-0.22 g) in the controls to 0.58 g (range 0.44-0.84) in the experimental animals. The most effective dose regimen was 10 Gy per fraction for five fractions, and serial experiments were conducted with this fractionation scheme. Complete response of the primary tumor was seen in 25 of 35 (71%) mice. The average weight of the lungs in the nonirradiated animals was 0.22 g (range, 0.19-0.24 g) and in the irradiated animals was 0.66 g (range, 0.61-0.70 g). The average number of surface metastases increased from five per lung (range, 2-13) in the control animals to 53 per lung (range, 46-62) in the irradiated animals. Both differences were statistically significant with P < 0.001. If the nontumor-bearing leg was
irradiated or the animals were sham-irradiated, no difference in the number of surface metastases or lung weights was observed between the control group and the treated group. Urinary levels of matrix metalloproteinase 2, the enzyme responsible for angiostatin processing in this tumor model, were measured and correlated with the viability and size of the primary tumor. Administration of recombinant angiostatin prevented the growth of the metastases after the treatment of the primary tumor. In this model, the use of radiation to eradicate a primary LLC-LM tumor results in the growth of previously dormant lung metastases and suggests that combining angiogenesis inhibitors with radiation therapy may control distant metastases.

INSTITUTION: Joint Center for Radiation Therapy, Harvard Medical School, Boston, Massachusetts 02115, USA.

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1: Ann Surg. 1990 Jul;212(1):51-9. Related Articles, Links


Management of primary and recurrent soft-tissue sarcoma of the retroperitoneum.

Jaques DP, Coit DG, Hajdu SI, Brennan MF.

Department of Surgery and Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021.

From 1982 to 1987, 114 patients underwent operation at Memorial Sloan-Kettering Cancer Center for soft-tissue sarcoma of the retroperitoneum. A retrospective analysis of these patients defines the biologic behavior, surgical management of primary and recurrent disease, predictive factors for outcome, and impact of multimodality therapy. Complete resection was possible in 65% of primary retroperitoneal sarcomas and strongly predicts outcome (p less than 0.001). The rate of complete resection was not altered by histologic type, size, or grade of tumor. These patients had a median survival of 60 months compared to 24 months for those undergoing partial resection and 12 months for those with unresectable tumors. Forty-nine per cent of completely resected patients have had local recurrence. This is the site of first recurrence in 75% of patients. These patients undergo reoperation when feasible. Complete resection of recurrent disease was performed in 39 of 88 (44%) operations, with a 41-month median survival time after reoperation. Tumor grade was a significant predictor of outcome (p less than 0.001). High-grade tumors (n = 65) were associated with a 20-month median survival time compared to 80 months for low-grade tumors (n = 49). Gender, histologic type, size, previous biopsy, and partial resection versus unresectable tumors did not predict outcome by univariate analysis. Adjuvant radiation therapy and chemotherapy could not be shown to have significant impact on survival. Concerted attempt at complete resection of both primary and recurrent retroperitoneal soft-tissue sarcoma is indicated.

PMID: 2363604 [PubMed - indexed for MEDLINE]

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J Clin Oncol. 2003 Jul 15;21(14):2719-25. Related Articles, Links


Localized extremity soft tissue sarcoma: improved knowledge with unchanged survival over time.

Weitz J, Antonescu CR, Brennan MF.

Department of Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021, USA.

PURPOSE: The objective of this study was to define whether survival of patients with extremity soft tissue sarcoma (STS), stratified for known risk factors, has improved over the last 20 years. PATIENTS AND METHODS: From January 1982 to December 2001, 1,706 patients with primary and recurrent STS of the extremities were treated at our institution and were prospectively followed. From this cohort, we selected 1,261 patients who underwent complete macroscopic resection and had one of the following histopathologies: fibrosarcoma, liposarcoma, leiomyosarcoma, malignant fibrous histiocytoma, or synovial sarcoma. Median follow-up was 55 months. Patient, tumor, and treatment factors were analyzed as prognostic factors. RESULTS: The 5-year disease-specific actuarial survival was 79% (78% for patients treated from 1982 to 1986, 79% for patients treated from 1986 to 1991, 79% for patients treated from 1992 to 1996, and 85% for patients treated from 1997 to 2001; P = not significant). For high-risk patients (high-grade, > 10 cm, deep tumors; n = 247), 5-year disease-specific survival was 51% (50% for patients treated from 1982 to 1986, 45% for patients treated from 1986 to 1991, 52% for patients treated from 1992 to 1996, and 61% for patients treated from 1997 to 2001; P = not significant). Tumor depth, size, grade, microscopic margin status, patient age, presentation status (primary tumor versus local recurrence), location (proximal versus distal), and certain histopathologic subtypes were significant prognostic factors for disease-specific survival on multivariate analysis; however, time period of treatment was not. CONCLUSION: Prognosis of patients with extremity STS, stratified for known risk factors, has not improved over the last 20 years, indicating that current therapy has reached the limits of efficacy.

PMID: 12860950 [PubMed - indexed for MEDLINE]

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Ann Surg. 2004 Jun;239(6):903-910. Related Articles, Links


Long-term Results With Resection of Radiation-Induced Soft Tissue Sarcomas.

Cha C, Antonescu CR, Quan ML, Maru S, Brennan MF.

*Surgical Service and daggerDepartment of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York.

INTRODUCTION:: Radiation therapy is increasingly used as adjuvant treatment of many childhood and adult malignancies. Radiation-induced sarcoma is a well recognized if uncommon event. The objective of this study is to determine the prevalence and long-term outcome for patients who develop radiation-induced sarcomas. METHODS:: From July 1982 to December 2001, 4884 adult patients with sarcoma were admitted and treated at our institution and recorded in a prospective database. There were 123 (2.5%) patients who had radiation-induced soft tissue sarcomas. Survival was determined by Kaplan-Meier analysis. Patient, tumor, and treatment characteristics were tested for their prognostic significance by log rank and the Cox proportional hazards model. RESULTS:: The median interval between radiation and development of sarcoma was 103 (6 to 534) months. In 114 patients with radiation-induced sarcoma who underwent curative resection, the 5-year actuarial survival was 41%, with a median survival of 48 months at a median follow-up of 36 months for survivors. The most common malignancy for which radiation was used was breast cancer (29%), followed by lymphoma (16%) and prostate cancer (15%). Malignant fibrous histiocytoma (23%) was the most common histologic diagnosis, followed by fibrosarcoma (15%) and angiosarcoma (15%). High-grade tumors (n = 85; 79%), age > 60 years (n = 61; 50%), and gross positive resection margin (n = 36; 32%) were predictive of poor sarcoma-specific survival on univariate and multivariate analysis. CONCLUSIONS:: The increasing utilization of adjuvant radiation therapy, especially for early-stage breast cancer mandates long-term follow-up to detect radiation-induced sarcoma. Surgical resection remains the primary therapy, but 5-year survival remains approximately 40%.

PMID: 15166970 [PubMed - as supplied by publisher]

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Semin Radiat Oncol. 1999 Oct;9(4):352-9. Related Articles, Links


The reason for confining the use of adjuvant chemotherapy in soft tissue sarcoma to the investigational setting.

Verweij J, Seynaeve C.

Department of Medical Oncology, Rotterdam Cancer Institute (Daniel den Hoed Kliniek), Rotterdam, The Netherlands.

Adjuvant chemotherapy for soft tissue sarcoma has been the subject of many studies. Most studies have been nonrandomized and therefore by definition inconclusive. In addition, most of the 14 performed randomized studies have had small sample sizes. A meta-analysis on the data of these 14 studies suggested a possible survival improvement, albeit not significant. The outcome of the meta-analysis should be interpreted with caution in view of the fact that in 18% of patients, histology data were lacking; ineligibility rates in included studies were high; central pathology was not uniformly performed; and in 6% of patients, sarcomas other than soft tissue sarcomas were included. Because it is generally recommended that meta-analyses of small randomized trials are used only to generate hypotheses for more reliable randomized trials, it is argued that adjuvant chemotherapy in soft tissue sarcomas should remain confined to the investigational setting.

Publication Types:
Meta-Analysis

PMID: 10516382 [PubMed - indexed for MEDLINE

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Ocular Metastasis of a Vaccine-Associated Fibrosarcoma in a Cat
Vet Comp Oncol 1[4]:232-240 Dec'03 Case Report 23 Refs

M. Cohen, E.A. Sartin, E.M. Whitley, R.D. Whitley, A.N. Smith *, W.R. Brawner, R. Henderson and E.N. Behrend
* Small Animal Hospital Auburn University, Auburn, AL 36849, USA; email: smith30@auburn.edu
A 6-year-old, neutered male domestic shorthair cat was evaluated for a recurrent vaccine-associated fibrosarcoma. The cat had three excisions of the tumour prior to presentation and was referred for radiation therapy. Ten months following treatment with radiation therapy, the cat was presented again for a cloudy appearance to the eye. An exenteration was performed, and biopsy revealed fibrosarcoma. At the same time, two discrete pulmonary nodules were identified on thoracic radiographs. Two doses of doxorubicin (20 mg/m2) and cyclophosphamide (100 mg/m2) were administered intravenously 3 weeks apart. Despite treatment, the pulmonary nodule doubled in size. This case represents the first antemortem report of ocular metastasis of a vaccine-associated sarcoma and supports the highly aggressive nature of these tumours. [Abstract]

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harvard medical school definitions

http://www.intelihealth.com/IH/ihtIH/WS ... .html#what

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Prognosis for Presumed Feline Vaccine-Associated Sarcoma after Excision: 61 Cases (1986-1996)
J Am Vet Med Assoc 216[1]:58-61 Jan 1'00 Retrospective Study 14 Refs

* A. Elizabeth Hershey, DVM; Karin U. Sorenmo, CMV, DACVIM; Mattie J. Hendrick, VMD, DACVP; Frances S. Shofer, PhD; David M. Vail, DVM, DACVIM
* Dept. of Medical Sciences, School of Veterinary Medicine, University of Wisconsin, Madison, WI 53706
OBJECTIVE: To evaluate time to first recurrence (TFR) and overall survival in cats with presumed vaccine-associated sarcomas (VAS) treated with excision.

DESIGN: Retrospective study.

ANIMALS: 61 cats with presumed VAS.

PROCEDURE: Medical records of cats that received excision as the only initial treatment for presumed VAS were reviewed to evaluate prognosis. Overall survival curves and TFR were determined.

RESULTS: Median TFR was 94 days. Median TFR for tumors treated with excision performed at a referral institution (274 days) was significantly longer than that for tumors excised by a referring veterinarian (66 days). Radical first excision yielded significantly longer median TFR (325 days) than did marginal first excision (79 days). Cats with tumors located on the limbs had longer median TFR (325 days) than cats with tumors located in other sites (66 days). Median overall survival time was 576 days. Significant differences in survival times between groups were not detected. Few cats (13.8%) receiving only surgical treatment had long-term (> 2 years) survival.

CONCLUSIONS & CLINICAL RELEVANCE: Radical first excision of presumed VAS is essential for extended TFR. Current recommendations for vaccination of the distal portions of the extremities are appropriate, because this practice permits radical excision of tumors (amputation) that develop at vaccination sites; however, surgery alone is seldom curative.

________________________
SUMMARY

There has been an increase in incidence of fibrosarcomas developing at typical vaccination sites. These vaccine - related sarcomas (VAS) are characterized by an intense inflammatory infiltrate composed of lymphocytes and macrophages. The proposed mechanism for the formation of sarcomas is that, in genetically susceptible cats, resident fibroblasts undergo neoplastic transformation due to persistent inflammation secondary to vaccine adjuvants. Aluminum adjuvant particles have been found histologically in VAS but it is unknown if they induce the neoplastic transformation or are markers of the neoplastic process.

There is currently little data available as to the efficacy of treatment of VAS. Previous studies have indicated that surgical excision with wide margins results in extended tumor free interval and survival times. In cases of tumors on limbs, amputation was superior to wide excision.

Purpose

determine the prognosis in cats when treated with surgical excision alone
evaluate the effect of primary tumor location
evaluate the effect of marginal, wide and radical surgery
The above factors were all evaluated in relation to the time of first recurrence (TFR)

Population studied

Cases were selected from records of the Veterinary Hospital of the University of Pennsylvania (VHUP) or the University of Wisconsin - Madison Veterinary Medical Teaching Hospital (UWVMTH) from 1986 through 1996. Tumors had been confirmed histologically as sarcomas and cats were included in this study if they had been treated with surgical excision at least once and if follow up information was available. Sarcomas which occurred in areas not associated with vaccination were excluded from the study. Overall, 61 cats were included in the study. Of the 61 cats, 25 also underwent chemo or radiotherapy.

Procedures

Diagnostic work up and clinical staging included: Thoracic or abdominal radiographs, CBC and chemistry profile, viral screening tests, and abdominal ultrasound. Results of chest radiographs were considered the most important criteria for metastasis.

Definitions

Classification of surgical excision:

Marginal: excision with margins < 3 cm in width
Wide: larger excisions of previous surgical excisions or tumors with margins >3 cm
Radical: procedures such as amputation, hemipelvectomy, partial scapulectomy and removal of dorsal spinous processes.
Time of recurrence (TFR) is defined as time of first surgery to recurrence of tumor.

Survival is defined as days from first excision until death.

Results

The following is a brief summary of results; readers should consult full text of article for additional details and graphs.

Signalment

mean and median age of cats was 9 years
54% were castrated males; 46% were spayed females
predominant breed was DSH; DLH (12%) Persian (3%) Siamese (3%)
Metastasis

Overall rate of metastasis was 22.5% (n=9)
3 of the 9 had evidence of metastasis at initial examination at referral
6 of the 9 developed metastasis after or during treatment
8 of the 9 cats had undergone multiple surgeries prior to development of metastasis
Rate if metastasis differed between VHUP (28%) and UWVMTH (14%)
Metastatic lesions included pulmonary lesions, lymph nodes and skin lesions
Time of metastasis ranged from 31- 405 days (medium 265)
Serologic tests (40 of 61 cats were serologically tested for viruses)

1 cat tested positive for FeLV and had multiple recurrences and subsequent pulmonary metastasis
7 cats tested negative for FIV virus
Duration of clinical signs (time between tumor detection and first excision) was recorded in 45 of 61 cats

mean: 2 months
median: 1 month
range: 2 days to 8 months
Primary tumor locations

flank 36%
proximal hind limb 18%
lumbar area 16%
Type of first excision

80% of cats had marginal first excisions
7% had wide first excisions
13% had radical first excisions (amputation)
TFR (time to first recurrence)

mean = 94 days
only 11% treated with excision alone had TFR > 1 year (4 of these cats had amputation; 3 had wide truncal excisions)
TFR was significantly longer when tumors were treated at the referral institution vs. the referring veterinarian
Marginal first excisions: mean TFR = 66 days
Wide first excisions: mean TFR = 419 days
Radical first excisions: mean TFR = 325 days
TFR in cats with radical first excisions was significantly longer than in the combined wide and marginal first excision group
Survival time

Median survival time for all 61 cats was 576 days
Most cats had multiple surgeries and/or additional therapies
Only 5 of 36 cats which did not receive multiple therapies were long term survivors (>1300 days) and 4 of these 5 cats had hind limb amputations. 1 of the 4 cats was euthanized at 1349 days for tumor recurrence at the amputation site
Significant differences in survival was not detected in cats which received surgery and other treatments and cats treated with surgery alone
There were no significant differences in survival:
in cats treated with marginal vs. radical excision;
in cats treated by referring veterinarians and those treated at the referral institution or
between appendicular tumors and other locations.
Discussion

Initial treatment of VAS by aggressive, radical surgery appears to increase the TFR in cats. Those cats treated with radical first excisions had a significantly longer TFR than cats treated with marginal excisions. Wide first excision is also superior to marginal first incision - 3 of 4 cats with truncal sarcomas treated with wide excision had TFR> 1 year.

Location of the tumor affects survival - those on the limbs had significantly longer TFR - this may be because limb tumors could be treated with amputation whereas complete excision of tumors of the trunk is difficult.

Because survival of cats is affected by various owner factors such as decisions of additional treatments, TFR seems be to a better marker of surgical efficacy. Median survival for all cats was 576 days, which is similar to another study in which cats had a median survival time of 600 days. Additional treatments do contribute to longer survival times and cats can have a prolonged period of quality life.

Metastatic rate in this study was 22.4% for all cats but there was a difference in the rate of metastasis between the 2 referral institutions: 14% at UWVMTH vs. 28% at VHUP. This may be because cats referred to UWVMTH more commonly received systemic treatments but the effectiveness of the addition of chemotherapy to surgery as treatment of VAS is inconclusive.

Conclusion

The authors conclude that radical initial excision of VAS is the best way to increase TFR and that current vaccination site recommendation (in the distal limb) is most appropriate because sarcomas at this location can best be treated with amputation. However, the authors point out that surgery alone is seldom curative; these tumors have high metastatic rates and may behave more aggressively than originally thought. Few cats were long term survivors.