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Research Corner Abstracts by Tom Swartz and Bruce Shriver
In This Issue
The effect of an unplanned excision of a soft-tissue sarcoma on prognosis The Royal Orthopaedic Hospital Oncology Service in Birmingham UK had a policy of re-excising a tumor bed after being presented with a case where an unplanned excision of a soft-tissue sarcoma took place. In this study, the authors investigated whether this policy was justified.
Between April 1982 and December 2005, 2201 patients were referred to their hospital with the diagnosis of soft-tissue sarcoma, of whom 402 (18%) had undergone an unplanned excision elsewhere. A total of 363 (16.5%) were included in this study. Each patient was routinely restaged and the original histology was reviewed. Re-excision was undertaken in 316 (87%). We analyzed the patient, tumor and treatment factors in relation to local control, metastasis and overall survival.
The authors report that residual tumor was found in 188 patients (59%). There was thus no residual disease in 128 patients of whom 10% (13) went on to develop a local recurrence. In 149 patients (47%), the re-excision specimen contained residual tumor, but it had been widely excised. Local recurrence occurred in 30 of these patients (20%). In 39 patients (12%), residual tumor was present in a marginal resection specimen. Of these, 46% (18) developed a local recurrence. A final positive margin in a high-grade tumor had a 60% risk of local recurrence even with post-operative radiotherapy. Metastases developed in 24% (86). The overall survival was 77% at five years. Survival was related to the grade of the tumor and the finding of residual tumor at the time of re-excision. The authors thus concluded that their policy of routine re-excision after unplanned excision of soft-tissue sarcoma was justified because of the high risk of finding residual tumor.
Radiological and pathological diagnosis of paediatric bone tumours and tumour-like lesions Primary bone tumors are rare but account for a significant proportion of cancers occurring in childhood and adolescence. Malignant bone tumors need to be distinguished not only from their benign counterparts but also from tumor-like lesions, many of which are developmental or reactive in nature and are found commonly in the pediatric population. Taking note of the age of the patient and the site of the lesion within bone (aided by several imaging techniques including plain radiographs, ultrasound, computed tomography, bone scintigraphy and magnetic resonance imaging) is essential for pathological diagnosis. Immunohistochemistry, cytogenetics, molecular analysis and other techniques are now powerful diagnostic tools in bone pathology. This review article aims to provide an approach to the radiological and pathological diagnosis of pediatric bone tumors. It also provides a brief overview of some of the more common bone tumors and tumor-like lesions, both benign and malignant, which occur in childhood and adolescence.
Radiological features of synovial cell sarcoma Synovial cell sarcoma tumors have common radiological features with a variety of both benign and malignant lesions. However, there is a variety of imaging findings that can suggest a pre-biopsy diagnosis of synovial cell sarcoma. This article is a pictorial review which aims to describe the imaging features of synovial sarcoma in a series of cases with various age ranges and tumor locations. In addition, the pathology, staging, prognosis and management of synovial sarcoma is briefly discussed.
Gastrointestinal stromal tumor (GIST) has emerged as a clinically distinct type of sarcoma with frequent overexpression and mutation of the c-Kit oncogene and a favorable response to imatinib mesylate [also known as STI571 (Gleevec)] therapy. However, a significant diagnostic challenge remains in the differentiation of GIST from leiomyosarcomas (LMSs). To improve on the diagnostic evaluation and to complement the immunohistochemical evaluation of these tumors, the investigators of this study performed a whole-genome gene expression study on 68 well characterized tumor samples. Using bioinformatic approaches, they devised a two-gene relative expression classifier that distinguishes between GIST and LMS with an accuracy of 99.3% on the microarray samples and an estimated accuracy of 97.8% on future cases. They validated this classifier by using RT-PCR on 20 samples in the microarray study and on an additional 19 independent samples, with 100% accuracy. Thus, their two-gene relative expression classifier is a highly accurate diagnostic method to distinguish between GIST and LMS and has the potential to be rapidly implemented in a clinical setting. The success of this classifier is likely due to two general traits, namely that the classifier is independent of data normalization and that it uses as simple an approach as possible to achieve this independence to avoid overfitting. They expect that the use of simple marker pairs that exhibit these traits will be of significant clinical use in a variety of contexts.
Although the side effects of cancer chemotherapy are well known, "opposite effects" of chemotherapy that enhance the malignancy of the treated cancer are not well understood. In this report, the investigators describe the induction of intravascular proliferation, extravasation, and colony formation by cancer cells, critical steps of metastasis, by pretreatment of host mice with the commonly used chemotherapy drug cyclophosphamide. In contrast, in the unpretreated mice, most cancer cells remained quiescent in vessels without extravasation. HT1080 human fibrosarcoma cells, labeled in the nucleus with green fluorescent protein and red fluorescent protein in the cytoplasm for imaging, were injected into the epigastric cranialis vein of nude mice. Twenty-four hours before cancer cell injection, cyclophosphamide was given i.p. Double-labeled cancer cells were imaged at the cellular level in live mice with the Olympus OV100 Small Animal Imaging System with variable magnification. They found that Cyclophosphamide seemed to interfere with a host process that inhibits intravascular proliferation, extravasation, and extravascular colony formation. Cyclophosphamide did not directly affect the cancer cells because cyclophosphamide had been cleared by the time the cancer cells were injected. Thus, the investigators conclude that this report shows an important unexpected "opposite effect" of chemotherapy that enhances critical steps in malignancy rather than inhibiting them, suggesting that certain current approaches to cancer chemotherapy should be modified.
The glucose transporter protein 1 (Glut-1) overexpression is associated with poor overall survival in various tumors. In this study, the investigators sought to study the prognostic significance of Glut-1 overexpression in patients with bone and soft-tissue sarcomas. A total of 67 patients with bone and soft tissue sarcomas were analyzed. Glut-1 overexpression was found in 56 patients (83%). The patients with Glut-1 overexpression showed significantly poor Overall survival compared with those without Glut-1 overexpression. The presence of metastasis, treatment without surgical resection, tumor differentiation, necrosis, mitotic index and MIB-1 grade were also significantly negative prognostic factors. The presence of metastasis was independently associated with poor Overall survival. The authors conclude that assessment of Glut-1 expression prior to treatment has a predictive potential effect in patients with bone and soft-tissue sarcomas.
This phase I trial was conducted to determine the safety, tolerability, pharmacokinetics, and pharmacodynamics of deforolimus (previously known as AP23573; MK-8669), a nonprodrug rapamycin analog, in patients with advanced solid malignancies. Patients were treated using an accelerated titration design with sequential escalating flat doses of deforolimus administered as a 30-minute intravenous infusion once daily for 5 consecutive days every 2 weeks (QDx5) in a 28-day cycle. Safety, pharmacokinetic, pharmacodynamic, and tumor response assessments were performed. Thirty-two patients received at least one dose of deforolimus (3 to 28 mg/d). Three dose-limiting toxicity events of grade 3 mouth sores were reported. The maximum-tolerated dose (MTD) was 18.75 mg/d. Common treatment-related adverse events included reversible mouth sores and rash. Pharmacodynamic analyses demonstrated mammalian target of rapamycin inhibition at all dose levels. Four patients (one each with non–small-cell lung cancer, mixed müllerian tumor [carcinosarcoma], renal cell carcinoma, and Ewing sarcoma) experienced confirmed partial responses, and three additional patients had minor tumor regressions. Thus, the investigators conclude: The MTD of this phase I trial using an accelerated titration design was determined to be 18.75 mg/d. Deforolimus was well tolerated and showed encouraging antitumor activity across a broad range of malignancies when administered intravenously on the QDx5 schedule. On the basis of these overall results, a dose of 12.5 mg/d is being evaluated in phase II trials.
Clinical pharmacology of cancer therapies in older adults The authors state that, "Cancer is a disease of older adults. Approximately 60% of cancer diagnoses and 70% of cancer mortalities occur in individuals age 65 and older. As the general population ages and life expectancy increases, the number of older adults with cancer is growing." They further say, "Several unique challenges arise in caring for older adults with cancer. In particular, the physiologic changes associated with aging can have an impact on the pharmacokinetics and pharmacodynamics of cancer therapies. The effects of these age-related changes on drug dosing and tolerance have been understudied, as clinical trials that set the standards for oncology care and drug approval have typically focused on a younger patient population. Few studies have included patients who are frail or who have a poor performance status. In this review, the authors provide an overview of the physiologic changes that accompany aging which have an impact on the pharmacology of anticancer therapies. They also discuss recent studies evaluating the pharmacology of anticancer therapies in older adults. Clinical pharmacology of cancer therapies in older adults, A. Hurria and S. M. Lichtman, British Journal of Cancer (2008) 98, 517-522.
Myeloablative therapy with autologous stem cell rescue for patients with Ewing sarcoma The aim of this study was to identify risk factors associated with PFS in patients with Ewing sarcoma undergoing ASCT; 116 patients underwent ASCT in 1989–2000 and reported to the Center for International Blood and Marrow Transplant Research. Eighty patients (69%) received ASCT as first-line therapy and 36 (31%), for recurrent disease. Risk factors affecting ASCT were analyzed with use of the Cox regression method. Metastatic disease at diagnosis, recurrence prior to ASCT and performance score <90 were associated with higher rates of disease recurrence/progression. Five-year probabilities of PFS in patients with localized and metastatic disease at diagnosis who received ASCT as first-line therapy were 49% (95% CI 30–69) and 34% (95% CI 22–47) respectively. The 5-year probability of PFS in patients with localized disease at diagnosis, and received ASCT after recurrence was 14% (95% CI 3–30). PFS rates after ASCT are comparable to published rates in patients with similar disease characteristics treated with conventional chemotherapy, surgery and irradiation suggesting a limited role for ASCT in these patients. Therefore, ASCT if considered should be for high-risk patients in the setting of carefully controlled clinical trials. Myeloablative therapy with autologous stem cell rescue for patients with Ewing sarcoma, by S L Gardner et al, Bone Marrow Transplantation advance online publication 4 February 2008.
Multimodality treatment of osteosarcoma: Radiation in a high-risk cohort
Purpose: Chemotherapy during radiation and/or bone-seeking radioisotope
therapy (153-samarium; 1 mCi/kg) during radiation may improve osteosarcoma
cancer control. Patients and Methods: We analyzed our preliminary radiation
experience in high-risk, metastatic, and/or recurrent patients during a
consecutive period of 20 months (May 2005-December 2006). Results:
Thirty-nine high-risk osteosarcoma patients had radiotherapy; 119 sites were
irradiated. A median four sites were irradiated per patient (range 1-14).
The median radiation dose and number of fractions of radiation was 30 Gy in
10 fractions (range 10-70 Gy in 4-35 fractions). Chemotherapy, most commonly
ifosfamide or methotrexate, was used in 80% (100/119) radiotherapy courses.
Of 38 painful sites, 29 had improvement (76%), 4 had no change (10%), and 5
had more pain (13%). Objective and potentially durable responses were
documented using PET-CT and bone scans with persistent and sustained
reduction of standard uptake values (SUVs; initial SUV of indication lesion
9.5 became <4 at all subsequent time points) and serial bone scans
[improvement in 29/39 (72%); stable 10/39 (25%), worse 1/39 (3%)]. The
actuarial 4-year survival from development of metastasis was 39%.
Conclusions: Our early results suggest that the use of multimodality therapy
including chemotherapy with radiation in unresectable osteosarcoma may be
beneficial. Multimodality treatment of osteosarcoma: Radiation in a
high-risk cohort,
V5N1 ESUN Copyright © 2008 Liddy Shriver Sarcoma Initiative.
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