Curr. Oncol., Volume 14, Issue 3 (June 2007) – 6 articles

In medicine, assigning priorities for original ideas and for first implementation of a new type of treatment or technology—radium afterloading, for example—is often difficult. This situation is certainly true for radium therapy, with conflicting claims coming from France, Germany, and the United States about who first implemented it. Moreover, if possible, a distinction must be made between the person who had the idea for a therapy and the person who actually implemented it. These people are not always one and the same. Difficulties in assigning priority also sometimes arise from the lack of a published claim in a medical journal, and extant photographic evidence is typically almost impossible to find some 100 years after the event. The present article tries to solve the problems of priority regarding those who were really responsible for the ideas and implementation of radium therapy, including the technique of afterloading. Full article

Recommendation 1: Management of patients with glioblastoma multiforme (GBM) should be highly individualized and should take a multidisciplinary approach involving neuro-oncology, neurosurgery, radiation oncology, and pathology, to optimize treatment outcomes. Patients and caregivers should be kept informed of the progress of treatment at every stage. Recommendation 2: Sufficient tissue should be obtained during surgery for cytogenetic analysis and, whenever feasible, for tumour banking. Recommendation 3: Surgery is an integral part of the treatment plan, to establish a histopathologic diagnosis and to achieve safe, maximal, and feasible tumour resection, which may improve clinical signs and symptoms. Recommendation 4: The preoperative imaging modality of choice is magnetic resonance imaging (MRI) with gadolinium as the contrast agent. Other imaging modalities, such as positron emission tomography with [¹⁸F]-fluoro-deoxy-D-glucose, may also be considered in selected cases. Postoperative imaging (MRI or computed tomography) is recommended within 72 hours of surgery to evaluate the extent of resection. Recommendation 5: Postoperative external-beam radiotherapy is recommended as standard therapy for patients with GBM. The recommended dose is 60 Gy in 2-Gy fractions. The recommended clinical target volume should be identified with gadolinium-enhanced T1-weighted MRI, with a margin in the order of 2–3 cm. Target volumes should be determined based on a postsurgical planning MRI. A shorter course of radiation may be considered for older patients with poor performance status. Recommendation 6: During rt, temozolomide 75 mg/m² should be administered concurrently for the full duration of radio-therapy, typically 42 days. Temozolomide should be given approximately 1 hour before radiation therapy, and at the same time on the days that no radiotherapy is scheduled. Recommendation 7: Adjuvant temozolomide 150 mg/m², in a 5/28-day schedule, is recommended for cycle 1, followed by 5 cycles if well tolerated. Additional cycles may be considered in partial responders. The dose should be increased to 200 mg/m² at cycle 2 if well tolerated. Weekly monitoring of blood count is advised during chemoradiation therapy in patients with a low white blood cell count. Pneumocystis carinii pneumonia has been reported, and prophylaxis should be considered. Recommendation 8: For patients with stable clinical symptoms during combined radiotherapy and temozolomide, completion of 3 cycles of adjuvant therapy is generally advised before a decision is made about whether to continue treatment, because pseudo-progression is a common phenomenon during this time. The recommended duration of therapy is 6 months. A longer duration may be considered in patients who show continuous improvement on therapy. Recommendation 9: Selected patients with recurrent GBM may be candidates for repeat resection when the situation appears favourable based on an assessment of individual patient factors such as medical history, functional status, and location of the tumour. Entry into a clinical trial is recommended for patients with recurrent disease. Recommendation 10: The optimal chemotherapeutic strategy for patients who progress following concurrent chemoradiation has not been determined. Therapeutic and clinical–molecular studies with quality of life outcomes are needed. Full article

Questions: (1) With respect to outcomes such as survival, response rate, response duration, time to progression, and quality of life, is alemtuzumab a beneficial treatment option for patients with B-cell chronic lymphocytic leukemia (CLL)? (2) What toxicities are associated with the use of alemtuzumab? (3) Which patients are more likely—or less likely— to benefit from treatment with alemtuzumab? Perspectives: Evidence was selected and reviewed by one member of the Hematology Disease Site Group (DSG) of Cancer Care Ontario’s Program in Evidence-Based Care (PEBC) and by methodologists. The practice guideline report was reviewed and approved by the Hematology DSG, which comprises hematologists, medical and radiation oncologists, and a patient representative. As part of an external review process, the report was disseminated to obtain feedback from practitioners in Ontario. Outcomes: Outcomes of interest were overall survival, quality of life, response rates and duration, and adverse event rates. Methodology: A systematic review of the MEDLINE, EMBASE, HealthStar, CINAHL, and Cochrane Library databases was conducted to search for primary articles and practice guidelines. The evidence informed the development of clinical practice recommendations. The evidence review and recommendations were appraised by a sample of practitioners from Ontario, Canada, and were modified in response to the feedback received. The systematic review and modified recommendations were approved by a review body within the PEBC. Results: The literature review found no published randomized controlled trials (RCTS) that evaluated alemtuzumab alone or in combination with other chemotherapeutic agents for the treatment of relapsed or refractory CLL. One RCT evaluated alemtuzumab administered to consolidate a complete or partial response to firstline fludarabine-containing chemotherapy. That study was stopped early because of excessive grades 3 and 4 infection-related toxicity in the alemtuzumab arm. Patients receiving alemtuzumab experienced significantly improved progression-free survival as compared with patients undergoing observation. Six single-arm studies evaluated disease response with administration of alemtuzumab as a single agent in the treatment of patients with relapsed or refractory CLL post-fludarabine. The pooled overall response rate was 38% (complete response: 6%; partial response: 32%). Adverse events associated with the use of alemtuzumab were commonly reported and included serious infusion-related, hematologic, and infection-related toxicities. Recommendation: This evidence-based recommendation applies to adult patients with B-cell CLL. Treatment with alemtuzumab is a reasonable option for patients with progressive and symptomatic CLL that is refractory to both alkylator-based and fludarabine-based regimens. Qualifying Statements: The evidence supporting treatment with alemtuzumab comes principally from case series that evaluated disease response as the primary outcome measure. Patients should be informed that any possible beneficial effect of alemtuzumab on other outcome measures such as duration of response, quality of life, and overall survival are not supported in evidence and currently remain speculative. Treatment with alemtuzumab is associated with significant and potentially serious treatment-related toxicities. Patients must be carefully informed of the uncertain balance between potential risks of harm and the chance for benefit reported in studies. Given the current substantial uncertainty in this balance, patient preferences will likely play a large role in determining the appropriate treatment choice. Given the potential toxicities associated with alemtuzumab, and given the limited nature of the agent’s testing in clinical trials in broad populations of patients with CLL, the use of alemtuzumab in patients with important comorbidities may be associated with excessive risks. Full article

Several large phase iii trials have demonstrated that tamoxifen—and more recently, raloxifene—can effectively reduce the incidence of invasive breast cancer by 50%. However, these selective estrogen receptor modulators can also be associated with several rare, but serious, adverse events. Recently, the third-generation aromatase inhibitors (AIS) have demonstrated excellent efficacy in adjuvant breast cancer trials, and they show particular promise in the breast cancer prevention setting. The National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) has developed a randomized phase III study to determine the efficacy of an AI (exemestane) to reduce the incidence of invasive breast cancer in postmenopausal women at an increased risk for developing breast cancer. The NCIC CTG MAP.3 (ExCel) trial is a double-blind placebo-controlled multicentre, multinational trial. Based on the known preclinical and clinical profile of the AIS, a greater reduction in breast cancer incidence with fewer side effects is hypothesized with this class of agents than with tamoxifen or raloxifene. Full article