Curr. Oncol., Volume 14, Issue 4 (August 2007) – 7 articles

Sunitinib (SU11248) is an orally bioavailable inhibitor that affects the receptor tyrosine kinases involved in tumour proliferation and angiogenesis, including vascular endothelial growth factor (vegf) receptors 1, 2, 3, and platelet-derived growth factor receptors alpha (pdgfra) and beta (pdgfrb). Because angiogenesis is necessary for the growth and metastasis of solid tumours, and vegf is believed to have a pivotal role in that process, sunitinib treatment may have broad-spectrum clinical utility. In the present article, we discuss the biologic and clinical rationales that have recently led the Investigational New Drug Program of the National Cancer Institute of Canada Clinical Trials Group to initiate four phase ii trials testing this agent in the following four different tumour types: relapsed diffuse large cell lymphoma, malignant pleural mesothelioma, locally advanced or metastatic cervical cancer and recurrent epithelial ovarian, fallopian tube, or primary peritoneal carcinoma. Full article

Testing for HER2/neu in breast cancer at the time of primary diagnosis is now the standard of care. Accurate and standardized testing methods are of prime importance to ensure the proper classification of the patient’s HER2/neu status. A meeting of pathologists from across Canada was convened to update the Canadian HER2/neu testing guidelines. This National HER2/neu Testing Committee reviewed the recently published American Society of Clinical Oncology/ College of American Pathologists (ASCO/CAP) guidelines for HER2/neu testing in breast cancer. The updated Canadian HER2/neu testing guidelines are based primarily on the ASCO/CAP guidelines, with some modifications. It is anticipated that widespread adoption of these guidelines will further improve the accuracy of HER2/neu testing in Canada. Full article

Questions: In adult patients with inoperable locally advanced or metastatic soft-tissue sarcoma, do combination chemotherapy regimens containing ifosfamide have an advantage in terms of response rate, time to progression, or survival, as compared with similar regimens without ifosfamide when used as first-line therapy? What are the adverse effects and effects on quality of life of ifosfamide-containing combination chemotherapy as compared with similar regimens without ifosfamide? Perspectives: The prognosis for patients with inoperable or metastatic soft-tissue sarcoma (STS) remains grim. Although the surgical resection of pulmonary metastases may be curative in 15%–30% of patients with isolated slow-growing metastases, most patients receive chemotherapy for palliative purposes. Ifosfamide has documented activity in patients who have received prior treatment with, or who have progressed on, doxorubicin. A number of studies have suggested a schedule and a dose–response relationship for ifosfamide in metastatic STS. Ifosfamide has also been assessed in combination with other drugs such as doxorubicin and dacarbazine (DTIC); results of such studies have led some authors to suggest that polychemotherapy using “appropriate doses” of ifosfamide and doxorubicin may represent the “most effective systemic treatment” in this population. Given the limited effective therapeutic options available for patients with metastatic STS, the Sarcoma Disease Site Group (DSG) felt that a need existed to more specifically evaluate the potential benefits of ifosfamide-containing combination chemotherapy in that setting. The Sarcoma DSG developed an evidencebased series report through systematic review, evidence synthesis, and input from practitioners across Ontario. Outcomes: Outcomes of interest included survival, response rate, adverse events, and quality of life. Methodology: A systematic review and meta-analysis served as the evidentiary base for this clinical practice guideline. The report was reviewed and approved by the Sarcoma DSG, which comprises medical oncologists, radiation oncologists, surgeons, methodologists, and patient representatives. The results of an external review by Ontario practitioners, obtained through a mailed survey, were incorporated into this report. Final approval of the evidence-based series report was obtained from the Report Approval Panel of Cancer Care Ontario’s Program in Evidence-Based Care (PEBC). Results: The current practice guideline reflects a combination of the draft recommendations (based on the evidence identified in a systematic review and meta-analysis) and the external feedback from Ontario practitioners and the PEBC’s Report Approval Panel. Practice Guideline: In patients with metastatic STS, the addition of ifosfamide to standard first-line doxorubicin-containing regimens is not recommended over single-agent doxorubicin. However, in patients with symptomatic, locally advanced, or inoperable STS, in whom tumour response might potentially result in reduced symptomatology or render a tumour resectable, use of ifosfamide in combination with doxorubicin is reasonable. Qualifying Statement: In combination with a doxorubicin-containing regimen, the dose of ifosfamide should not exceed 7.5 g/m², given as either a split bolus or a continuous infusion. Full article

Questions: Should patients with confirmed single brain metastasis undergo surgical resection? Should patients with single brain metastasis undergoing surgical resection receive adjuvant wholebrain radiation therapy (WBRT)? What is the role of stereotactic radiosurgery (SRS) in the management of patients with single brain metastasis? Perspectives: Approximately 15%–30% of patients with cancer will develop cerebral metastases over the course of their disease. Patients identified as having single brain metastasis generally undergo more aggressive treatment than do those with multiple metastases; however, in the province of Ontario, management of patients with single brain metastasis varies. Given that conflicting evidence has been reported, the Neuro-oncology Disease Site Group (DSG) of the Cancer Care Ontario Program in Evidence-based Care felt that a systematic review of the evidence and a practice guideline were warranted. Outcomes: Outcomes of interest were survival, local control of disease, quality of life, and adverse effects. Methodology: The MEDLINE, CANCERLIT, EMBASE, and Cochrane Library databases and abstracts published in the proceedings of the annual meetings of the American Society of Clinical Oncology (1997–2005) and American Society for Therapeutic Radiology and Oncology (1998–2004) were systematically searched for relevant evidence. The review included fully published reports or abstracts of randomized controlled trials (RCTS), nonrandomized prospective studies, and retrospective studies. The present systematic review and practice guideline has been reviewed and approved by the Neurooncology DSG, which comprises medical and radiation oncologists, surgeons, neurologists, a nurse, and a patient representative. External review by Ontario practitioners was obtained through an electronic survey. Final approval of the guideline report was obtained from the Report Approval Panel and the Neuro-oncology DSG. Results: Quality of Evidence The literature search found three RCTS that compared surgical resection plus WBRT with WBRT alone. In addition, a Cochrane review, including a meta-analysis of published data from those three RCTS, was obtained. One RCT compared surgical resection plus WBRT with surgical resection alone. One RCT compared WBRT plus SRS with WBRT alone. Evidence comparing SRS with surgical resection or examining SRS with or without WBRT was limited to prospective case series and retrospective studies. Benefits Two of three RCTS reported a significant survival benefit for patients who underwent surgical resection as compared with those who received WBRT alone. Pooled results of the three RCTS indicated no significant difference in survival or likelihood of dying from neurologic causes; however, significant heterogeneity was detected between the trials. The RCT that compared surgical resection plus WBRT with surgical resection alone reported no significant difference in overall survival or length of functional independence; however, tumour recurrence at the site of the metastasis and anywhere in the brain was less frequent in patients who received WBRT as compared with patients in the observation group. In addition, patients who received WBRT were less likely to die from neurologic causes. Results of the RCT that compared WBRT plus SRS with WBRT alone indicated a significant improvement in median survival in patients who received SRS. No quality evidence compares the efficacy of SRS with surgical resection or examines the question of whether patients who receive SRS should also receive WBRT . Harms Pooled results of the three RCTS that examined surgical resection indicated no significant difference in adverse effects between groups. Postoperative complications included respiratory problems, intracerebral hemorrhage, and infection. One RCT reported no significant difference in adverse effects between patients who received WBRT plus SRS and those who received WBRT alone. Practice Guideline: Target Population The recommendations that follow apply to adults with confirmed cancer and a single brain metastasis. This practice guideline does not apply to patients with metastatic lymphoma, small-cell lung cancer, germ-cell tumour, leukemia, or sarcoma. Recommendations Surgical excision should be considered for patients with good performance status, minimal or no evidence of extracranial disease, and a surgically accessible single brain metastasis amenable to complete excision. Because treatment in cases of single brain metastasis is considered palliative, invasive local treatments must be individualized. Patients with lesions requiring emergency decompression because of intracranial hypertension were excluded from the RCTS, but should be considered candidates for surgery. To reduce the risk of tumour recurrence for patients who have undergone resection of a single brain metastasis, postoperative WBRT should be considered. The optimal dose and fractionation schedule for WBRT is 3000 cGy in 10 fractions or 2000 cGy in 5 fractions. As an alternative to surgical resection, WBRT followed by SRS boost should be considered for patients with single brain metastasis. The evidence is insufficient to recommend SRS alone as a single-modality therapy. Qualifying Statements No high-quality data are available regarding the choice of surgery versus radiosurgery for single brain metastasis. In general, the size and location of the metastasis determine the optimal approach. The standard WBRT regimen for management of patients with single brain metastasis in the United States is 3000 cGy in 10 fractions, and this treatment is usually the standard arm in randomized studies of radiation in patients with brain metastases. Based solely on evidence, the understanding that no reason exists to choose 3000 cGy in 10 fractions over 2000 cGy in 5 fractions is correct; however, fraction size is believed to be important, and therefore 300 cGy daily (3000/10) is believed to be associated with fewer long-term neurocognitive effects than 400 cGy daily (2000/5) in the occasional long-term survivor. For that reason, many radiation oncologists in Ontario prefer 3000 cGy in 10 fractions. No data exist to either support or refute that preference; therefore, finding a resolution to this issue is not currently possible. The Neuro-oncology DSG will update the recommendations as new evidence becomes available. Full article