National Cancer Institute Of Canada Research Articles

CheckMate 743: A Glimmer of Hope for Malignant Pleural Mesothelioma

CheckMate 743: A Glimmer of Hope for Malignant Pleural Mesothelioma

Editorial introductions

Editorial introductions

The Beginnings of the Canadian Cooperative Clinical Cancer Trials Program and the AmericanInfluences, 1962-76.

Clinical cancer research in Canada entered a new phase in 1971. In that year, the National Cancer Institute of Canada agreed to initiate and support a multidisciplinary cooperative clinical trials program. The first collaborative randomized controlled trial (RCT) for the treatment of advanced Hodgkin's disease was launched in medical centres across the country in December 1971. Simultaneously, in the United States, the National Cancer Act came into effect. To what extent were these Canadian and American developments coincidental? I argue that the cooperative clinical trials program in Canada was timed to coincide with the US declaration of war on cancer, but it was not its corollary. Against the background of this American anti-cancer campaign, the cooperative clinical trials program emerged as a link between the strong radiotherapy tradition in Canada and the new trial infrastructure of chemotherapeutic regimes in the United States. The evolution of the Hodgkin's disease trial serves as a good example to demonstrate how growing collaboration among Canadian and American physician-investigators brought about a large-scale national study. The latter became a prototype of further cooperative oncological RCTs in Canada during the 1970s.

Editorial introductions

Editorial introductions

Management of elderly patients with glioblastoma-multiforme-a systematic review.

The management of elderly patients with glioblastoma-multiforme (GBM) remains poorly defined with many experts in the past advocating best supportive care, in view of limited evidence on efficacy of more aggressive treatment protocols. There is randomised evidence (NORDIC and NA-O8 studies) to support the use of surgery followed by adjuvant monotherapy with either radiotherapy (RT) using hypofractionated regimes (e.g. 36 Gy in 6 fractions OR 40 Gy in 15 fractions) or chemotherapy with temozolomide (TMZ) in patients expressing methylation of promoter for O6-methylguanine-DNA methyltransferase enzyme. However, the role of combined-modality therapy involving the use of combined RT and TMZ protocols has remained controversial with data from the EORTC(European Organisation for Research and Treatment of Cancer)-NCIC(National Cancer Institute of Canada) studies indicating that patients more than 65 years of age may not benefit significantly from combining standard RT fractionation using 60 Gy in 30 fractions with concurrent and adjuvant TMZ. More recently, randomised data has emerged on combining hypofractionated RT with concurrent and adjuvant TMZ. We provide a comprehensive review of literature with the aim of defining an evidence-based algorithm for management of elderly glioblastoma-multiforme population.

Gender differences in pain and patient reported outcomes: a secondary analysis of the NCIC CTG SC. 23 randomized trial.

Gender differences may contribute to variations in disease presentations and health outcomes. To explore the gender difference in pain and patient reported outcomes in cancer patients with bone metastases undergoing palliative radiotherapy on the National Cancer Institute of Canada (NCIC) SC.23 randomized trial. Patients completed the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life (QOL) bone metastases module (QLQ-BM22) and EORTC QOL Core-15-Palliative (QLQ-C15-PAL) before treatment and at days 10 and 42 after a single 8 Gy radiation treatment. Patient demographics, performance status, analgesic consumption, BM22 and C15 were compared between males and females using the 2-sample t-test for continuous variables or the Chi-squared test for categorical variables. Multiple linear regression models were used to check the difference between gender groups adjusting for the baseline demographics and primary disease sites. There were 298 patients (170 male, 128 female) with median age of 69 years. The most common primary cancer sites were lung, prostate and breast. At baseline, there were no differences in BM22 and C15 scores, except a worse nausea and vomiting score (P=0.03) in females on the C15. In patients with moderate baseline worst pain scores (WPS), females reported worse scores in painful sites of BM22. At day 42, there was no significant difference in response to radiotherapy. Among the responders, females reported better improvement in emotional aspect. In cancer patients with bone metastases undergoing palliative radiotherapy, the majority of symptom presentations, patient reported outcomes, and response to radiation was not significantly different between genders. NCT01248585.

MS 17.02 MAGRIT

MS 17.02 MAGRIT

Editorial introductions

Editorial introductions

Management of multiple myeloma: the impact of ixazomib's approval in Canada.

Donna E Reece speaks to Laura Dormer, Commissioning Editor: Dr Donna E Reece is a Professor of Medicine and Director of the Program for Multiple Myeloma and Related Diseases in the Department of Medical Oncology and Hematology at Princess Margaret Hospital/University of Toronto. She earned a Bachelor of Arts degree at the University of Texas, Austin, and graduated as valedictorian with a medical degree from Baylor College of Medicine, Houston, Texas. She completed an internship in Internal Medicine at the University of Colorado Affiliated Hospitals, a residency and Chief Residency in Internal Medicine at Jewish Hospital, St Louis, and a Fellowship in Hematology/Oncology at Barnes Hospital, Washington University, St Louis, Missouri. She was a fellow and later a leukemia/stem cell transplant staff physician at Vancouver General Hospital/University of British Columbia for over 10 years. She then served as Director of the Outpatient Leukemia/Stem Cell Transplant Program, and later interim director, of the Blood and Marrow Transplant Program of the Markey Cancer Center at the University of Kentucky, Lexington, Kentucky until her appointment to Princess Margaret Hospital in Toronto in 2001. Dr Reece received the David and Molly Bloom Chair in Myeloma Research in 2009. She is currently the co-chair of the Multiple Myeloma Clinical Trials Group of the National Cancer Institute of Canada, member of the Scientific Advisory Board of the International Myeloma Foundation, and member of the Project Review Committee of the MMRC (Multiple Myeloma Research Consortium). She is also the Chief Medical Officer of the Myeloma Canada Research Network and serves on the board of directors of Myeloma Canada. Her career focus has been in the areas of hematopoietic stem cell transplantation, lymphoid malignancies and plasma cell dyscrasias. She has published numerous articles in these areas.

Limited-Stage Small-Cell Lung Cancer: An Age Limit for Combined Modality Therapy?

Limited-Stage Small-Cell Lung Cancer: An Age Limit for Combined Modality Therapy?

Improved survival with the addition of radiotherapy to androgen deprivation: questions answered and a review of current controversies in radiotherapy for non-metastatic prostate cancer.

The contemporary standard of care for locally advanced high-risk prostate cancer includes a combination of dose-escalated radiotherapy (RT) plus androgen-deprivation therapy (ADT). However, 20 years ago, at the inception of the National Cancer Institute of Canada (NCIC) led study (NCIC Clinical Trials Group PR.3/Medical Research Council PR07/Intergroup T94-0110), the survival impact of prostate RT for high-risk disease was uncertain. Recently, Mason, Warde and colleagues presented the final results of this NCIC/MRC study (PMID: 25691677) randomizing 1,205 high-risk prostate cancer patients to ADT + RT vs. ADT alone. These updated results confirm substantial improvements with the addition of RT to ADT for the endpoints of overall survival (OS), disease-free survival (DFS), and biochemical recurrence. Close examination of subtleties of this trial's design highlight some of the most salient controversies in the field of prostate RT, including the risk-stratified roles of ADT, optimal ADT duration, and RT field design in the dose-escalated and intensity-modulated radiotherapy (IMRT) era.

Radiation therapy to the primary tumor in locally advanced prostate cancer is not "closing the barn door after the horse has bolted".

The National Cancer Institute of Canada (NCIC) Clinical Trials Group PR.3/Medical Research Council PR07/ Intergroup T94-0110 (1) was a randomized controlled trial (RCT) of radiation therapy (RT) and androgen deprivation therapy (ADT) vs. ADT alone, for men with locally advanced prostate cancer. The authors defined locally advanced as: (I) T3-4, N0/X, M0; or (II) T1-2 with prostate specific antigen (PSA) > 40 ng/mL; or (III) PSA 20-40 ng/mL and Gleason 8-10. Men were randomized to lifelong ADT vs. ADT + RT, 65-69 Gy in 1.8 Gy fractions, using 3D conformal RT, to the prostate and pelvis or prostate alone. Of the 1,205 patients treated between 1995 and 2005, 602 received ADT alone and 603 received ADT + RT. Overall survival (OS) was significantly improved in the patients allocated to ADT + RT [hazard ratio (HR) =0.70; 95% CI, 0.57-0.85; P<0.001]. Prostate cancer specific mortality (CSM) was improved in the patients allocated to ADT + RT (HR =0.46; 95% CI, 0.34-0.61; P<0.001). Although patients on ADT + RT arm reported a higher rate of gastrointestinal (GI) toxicity, only 2 of 589 patients had grade 3 or greater diarrhea at 24 months after RT.

Association of adverse events and survival in colorectal cancer patients treated with adjuvant 5-fluorouracil and leucovorin: Is efficacy an impact of toxicity?

BackgroundAdverse events associated with 5-fluorouracil (5FU) based adjuvant therapy in colorectal cancer (CRC) patients may predict survival. We studied whether haematological (leucopenia, neutropenia, thrombocytopenia) or non-haematological (mucositis, diarrhoea, nausea/vomiting, hand-foot syndrome or other toxicity) adverse events were associated with disease-free survival (DFS) or overall survival (OS) in a large patient material treated with 5-fluorouracil based adjuvant chemotherapy. Patients and methodsData from two prospective randomised adjuvant trials were combined to achieve a dataset of 1033 radically operated stage II and III CRC patients treated with either monthly 5FU and leucovorin (LV) as bolus injections (Mayo or modified Mayo) or bi-monthly with bolus and continuous infusion (LV5FU2 or simplified LV5FU2). Toxicities were recorded at each treatment cycle according to NCI-C CTC (the Common Toxicity Criteria of the National Cancer Institute of Canada). The worst toxicity grade was taken into account. The median follow-up time of patients was 6.05years. Results47% of patients developed neutropenia, 54% nausea/vomiting and 43% mucositis. Any grade neutropenia was associated with improved DFS (hazard ratio (HR) 0.81), any grade nausea/vomiting with improved DFS (HR 0.79) and OS (HR 0.62) and mucositis with improved DFS (HR 0.74) and OS (HR 0.72). Patients experiencing no predefined toxicity had the worst outcome. ConclusionSpecific adverse events related to adjuvant fluorouracil chemotherapy are associated with improved DFS and OS in early stage CRC patients.

Intermittent versus continuous androgen deprivation therapy.

Androgen deprivation therapy (ADT) has been the standard of care for metastatic prostate cancer for decades; however, the choice of continuous or intermittent administration is a matter of debate. Two large phase III trials have reported results comparing these 2 forms of ADT administration. The National Cancer Institute of Canada (NCIC) PR-7 trial studied men with an increasing prostate-specific antigen (PSA) level and no evidence of metastatic disease after definitive or salvage radiation therapy and radical prostatectomy. The Southwest Oncology Group 9346 trial studied men with newly diagnosed hormone-sensitive metastatic disease. The primary end point in both trials was overall survival with a noninferiority design. The NCIC trial showed that the overall survival in men treated with intermittent ADT was not inferior to that of men treated with continuous ADT, but the SWOG trial was inconclusive regarding noninferiority. Certain domains of quality of life were better in the intermittent arms of both trials. If using ADT in the setting of biochemical relapse, intermittent ADT should be strongly considered over continuous ADT, except perhaps in patients with Gleason score of 8 or higher. In men with metastatic disease, continuous ADT remains the standard of care, because the SWOG trial did not establish noninferiority of intermittent ADT with respect to survival. However, for those with significant side effects from ADT, establishing the risk group, as determined by PSA value after 7 months of ADT or the presence of pain at diagnosis, may help guide the choice of intermittent versus continuous ADT in men with metastatic disease.

Guidelines for the first line management of classical Hodgkin lymphoma

The guideline group was selected to be representative of UK-based medical experts and patients’ representatives. MEDLINE and EMBASE were searched systematically for publications in English from January 1990 to June 2013 using the key words Hodgkin, Lymphoma, Treatment, Chemotherapy and Radiotherapy. References from relevant publications were also searched. The writing group produced the draft guideline, which was subsequently revised by consensus by members of the Haemato-Oncology Task Force of the British Committee for Standards in Haematology (BCSH). The guideline was then reviewed by a sounding board of approximately 50 UK haematologists and the BCSH and comments incorporated where appropriate. The ‘GRADE’ system was used to quote levels and grades of evidence, details of which can be found in Appendix I. The objective of this guideline is to provide healthcare professionals with clear guidance on the management of patients with classical Hodgkin Lymphoma (HL). The guidance may not be appropriate for all patients with HL and in all cases individual patient circumstances may dictate an alternative approach.

Quality of Life in MAP.3 (Mammary Prevention 3): A Randomized, Placebo-Controlled Trial Evaluating Exemestane for Prevention of Breast Cancer

Exemestane, a steroidal aromatase inhibitor, reduced invasive breast cancer incidence by 65% among 4,560 postmenopausal women randomly assigned to exemestane (25 mg per day) compared with placebo in the National Cancer Institute of Canada (NCIC) Clinical Trials Group MAP.3 (Mammary Prevention 3) trial, but effects on quality of life (QOL) were not fully described. Menopause-specific and health-related QOL were assessed by using the four Menopause-Specific Quality of Life Questionnaire (MENQOL) domains and the eight Medical Outcomes Study Short Form Health Survey (SF-36) scales at baseline, 6 months, and yearly thereafter. MENQOL questionnaire completion was high (88% to 98%) in both groups at each follow-up visit. Change scores for each MENQOL and SF-36 scale, calculated at each assessment time relative to baseline, were compared by using the Wilcoxon rank-sum test. Clinically important worsened QOL was defined as a MENQOL change score increase of more than 0.5 (of 8) points and an SF-36 change score decrease of more than 5 (of 100) points from baseline. Exemestane had small negative effects on women's self-reported vasomotor symptoms, sexual symptoms, and pain, which occurred mainly in the first 6 months to 2 years after random assignment. However, these changes represented only a small excess number of women being given exemestane with clinically important worsening of QOL at one time or another; specifically, 8% more in the vasomotor domain and 4% more each in the sexual domain and for pain. No other between-group differences were observed. Overall, slightly more women in the exemestane arm (32%) than in the placebo arm (28%) discontinued assigned treatment. Exemestane given for prevention has limited negative impact on menopause-specific and health-related QOL in healthy postmenopausal women at risk for breast cancer.

Treatment of newly diagnosed malignant glioma in the elderly people: new trials that impact therapy

Glioblastoma (GB), World Health Organization Grade 4 glioma, is the most common malignant primary brain tumour with an annual incidence of 12,943 cases in the United States . It is a tumour of the elderly people with a median age of onset of 64 years, although children and young adults are also affected. GB is associated with a poor prognosis; despite best treatment, most community-based patients will not survive 1 year . Cures are rare and overall survival rates at 2 and 5 years are 26-48% and 12%, respectively, in highly selected, contemporary, clinical trial eligible patients . For protocol eligible US patients, the median survival is 16-17 months, which is partly a reflection of improved supportive care, recognition of pseudoprogression, exclusion of patients undergoing biopsy only and availability of bevacizumab at recurrence . Initial treatment for patients with high performance [Karnofsky Performance Status (KPS) > 60 and age < 71 years) consists of maximal safe surgical resection followed by adjuvant focal, external beam radiotherapy (RT) with concurrent temozolomide (TMZ) chemotherapy and post-RT TMZ for 6 months . TMZ and carmustine (BCNU) biodegradable wafer (Gliadel) are the only adjuvant chemotherapies that have improved survival in randomised GB clinical trials . The current standard treatment is based upon a European Organization for Research and Treatment of Cancer (EORTC) and National Cancer Institute of Canada (NCIC) randomised, phase 3 trial of 573 patients with newly diagnosed GB (age 19-71 years and World Health Organization Performance Status ≤ 2) that compared RT alone [total dose 60 Gray (Gy)] to TMZ chemotherapy in combination with RT (total 60 Gy), followed by 6 months of post-RT TMZ (4,6,8).

Editorial introductions

Editorial introductions

MO‐F‐108‐01: Deformable Dose Reconstruction to Evaluate Image‐Guidance Strategies in Free‐Breathing Liver SBRT

Purpose: To evaluate the delivered dose following image‐guidance strategies for liver SBRT. Methods: The delivered dose was reconstructed using deformable image‐registration (DIR) on the retrospectively sorted (4D) cone‐beam CT (CBCT) for 30 SBRT patients (15 with multiple tumors). Plans created on exhale 4D‐CT, for 27–60 Gy/6 fractions, were delivered in free‐breathing after 3D‐CBCT rigid liver alignment. Dose was also reconstructed after simulating two rigid alignment strategies on the exhale 4D‐CBCT: the liver or the tumor directly (using DIR to predict tumor position). Delivered doses were compared to the planned 4D breathing dose, modeled with DIR of 4D‐CT. Results: Residual mean tumor errors &gt;3 mm occurred in nine patients (30%) following free‐breathing 3D‐CBCT (max: 10 mm), and two patients (6.6%) following liver or tumor 4D‐CBCT alignment (maximum: 3.3 mm). With free‐breathing 3D‐CBCT, the delivered minimum tumor doses decreased by more than 1 Gy compared to planned dose for 4 (13%) patients. For 2 of these 4 patients, aligning the liver or tumor on 4D‐CBCT reduced the dose decreases from −1.4 Gy, to within −0.5 Gy. The other 2 patients had multiple tumors and substantial liver deformation, resulting in minimum tumor doses decreases (max: −4.3 Gy) following free‐breathing 3D‐CBCT, that were reduced with either liver (max: −2.7 Gy) or tumor (max: −2.2 Gy) 4D‐CBCT alignment. For normal gastrointestinal tissues receiving &gt;30 Gy, the delivered maximum doses deviated by −11.5 to 2.6 Gy, with one exceeding the planning constraint by 0.7 Gy following free‐breathing 3D‐CBCT. Aligning the liver or tumor on 4D CBCT reduced normal tissue deviations (range: −6.3, 2.7 Gy) without exceeding planning constraints. Conclusion: 4D‐CBCT guidance for liver SBRT has been clinically implemented. The improved correlation between the 4D planning dose and delivered dose can be largely accomplished with 4D alignment of the liver, and should allow for planning margin reduction. This research is supported by the NIH, 5RO1CA124714‐02, and a Canadian Institutes for Health Research Fellowship. Patient data was acquired during clinical trials supported by the National Cancer Institute of Canada, #18207, and CIHR, #202477. K.K. Brock has financial interest in the deformable registration technology through a licensing agreement with RaySearch Laboratories.

Canadian Kidney Cancer Forum 2008

In Canada, at least 4500 people are diagnosed with kidney cancer, and 1 in 3 die of the disease. It is the most lethal genitourinary cancer, and its incidence is increasing. Unlike most human cancers, there is considerable knowledge about specific genetic changes in these cancers. Major advances in treatment are being made owing to new systemic targeted therapies as well as less morbid technologies for localized cancers. The first Canadian Kidney Cancer Forum was held Jan. 31–Feb. 2, 2008, in Mont Tremblant, Quebec, to review these developments and identify opportunities for Canadians. The primary meeting objectives were achieved and included: Achievement of consensus among expert professionals and patients on the management of patients with localized, locally advanced and metastatic renal cell carcinoma, as well as the in the areas of pathology and imaging. Over 3 days, a series of sessions were held to address the different stages of disease and issues. In this issue, we present the consensus statements. Key references in each area were provided by experts and were graded using a modified version of the Oxford Levels of Evidence. During the conference, experts in each area presented, followed by an opportunity for questions and discussion. At the end of the forum, overviews were presented, and participants voted on draft statements developed during the sessions. Stimulation of clinical research in kidney cancer including opportunities for national and international collaboration. To achieve this, the formation of a research network was proposed with the suggested name, Kidney Cancer Research Network Canada. Definition of educational needs to improve kidney cancer care in Canada. This included discussing a national kidney cancer database that will be developed. Initiating the development of a cancer control strategy for kidney cancer to ensure all Canadians have equal access to care to attempt to develop a national approach to the management of this cancer. The Forum was endorsed by the Canadian Urological Association, the Canadian Association of Medical Oncologists and the Canadian Association of Radiation Oncologists, and was supported by grants from the Canadian Institutes of Health Research, the National Cancer Institute of Canada, the Canadian Cancer Society, the Canadian Partnership Against Cancer, several provincial cancer agencies (Cancer Care Ontario, Cancer Care Manitoba, Cancer Care Nova Scotia, Alberta Cancer Foundation) and the Princess Margaret Hospital Foundation, and industry. These groups had been identified by the steering committee as ones that had demonstrated expertise, interest or experience in clinical or research aspects of kidney cancer. They were joined by a small number of invited participants from Europe and the United States to bring an international perspective to the process. Dr. George Browman, representing the Canadian Partnership Against Cancer, contributed expertise in the development and use of guidelines for cancer care. Overall, the participants believe that the forum will have a significant impact on the care of Canadians afflicted with kidney cancer. Given the enormous success of this first meeting, planning for a second meeting in 2009 has commenced.