E-Manuscript Article Summaries ^†

CML Biology for the Clinician in 2011: Six Impossible Things to Believe Before Breakfast on the Way to Cure

Brian Leber MDCM. McMaster University, Hamilton, Ontario.

KEY WORDS

Leukemia, stem cells, targeted therapy, tyrosine kinase inhibitor, apoptosis

URL www.current-oncology.com/index.php/oncology/article/view/652/

E-JOURNAL LINKED ABSTRACT

Chronic myeloid leukemia (CML) is a model disease in oncology: it is the first human cancer linked to a distinct chromosomal abnormality whose presence is now required for a correct diagnosis. This translocation involving chromosomes 9 and 22 was eventually shown to lead to a fusion gene product that causes constitutive overactivity of a known oncogenic tyrosine kinase. That recognition led to enormous advances in the understanding of the pathophysiology of human malignancies and, more importantly, the identification of a drug target. The introduction of the tyrosine kinase inhibitor imatinib, which interferes with the catalytic activity of the BCR-ABL oncogene encoded by the CML chromosomal translocation, has far exceeded expectations, resurrected hope that fundamental insights from the “war on cancer” can lead to significant therapeutic advances, and pushed other therapeutic modalities for CML such as stem-cell transplantation into distant second place.

The current perception among clinicians is that imatinib and its newer, more potent cousins such as dasatinib, nilotinib, and bosutinib offers superb longterm disease control for most patients, but that cure without transplantation remains elusive. However, several important laboratory-based observations have, over the last few years, have changed this perception such that cure without transplant is now conceivable for some patients. The present article discusses several of those developments, including the realization that the important biologic effect of imatinib is not only to decrease cell proliferation, but also to induce apoptosis. There is now a firm understanding that the commitment to apoptosis achieved with tyrosine kinase inhibitors may be usefully enhanced by additionally targeting Bcl-2.

Furthermore, the progression of CML has recently been demonstrated to be attributable to increased generation of reactive oxygen species, another potential therapeutic target. If this transformation event is controlled (as suggested by intriguing results from a series of patients treated by French investigators), then in a small but significant group of patients, disease might wither away with tyrosine kinase therapy, to the point that treatment can be stopped without recurrence—at least according to early observations. For patients whose disease needs a more direct attack than tyrosine kinase inhibitors alone because of resistance of the CML stem cells, several approaches being investigated in laboratory and animal models seem promising, and some are ripe for clinical testing. Among these direct approaches to manipulating CML stem cell behavior that are proceeding to clinical trial are inhibition of the Hedgehog pathway (by inhibitors of Smoothened), inhibition of 5-lipoxygenase, and suppression of autophagy by hydroxychloroquine. These clever approaches to attacking the disease biology of CML, including its stem cells, raise hope for clinicians that at least one (and perhaps several) will be effective and that true cure of CML without an allogeneic transplantation is a realistic hope for the near future.

Systemic Therapy for Advanced Gastric Cancer: A Clinical Practice Guideline

M. MacKenzie MD, K. Spithoff MSc, D. Jonker MD, and the Gastrointestinal Cancer Disease Site Group. London Health Sciences Centre, London; Cancer Care Ontario’s Program in Evidence-Based Care, Hamilton; and The Ottawa Hospital, Ottawa, Ontario.

KEY WORDS

Advanced gastric cancer, systemic therapy, practice guideline

URL www.current-oncology.com/index.php/oncology/article/view/737/

E-JOURNAL LINKED ABSTRACT

Background: Gastric cancer is the second leading cause of cancer mortality worldwide. Despite low incidence rates for gastric cancer in Ontario, the overall prognosis is bleak, with 5-year survival rates of approximately 23%. Even given the considerable body of research available, uncertainty remains regarding the optimal chemotherapy for advanced gastric cancer. Without a recognized standard treatment, significant geographic variation in practice was apparent.

Methods: In a systematic review, outcomes of interest—overall survival, objective response rate, time to disease progression, adverse effects, and quality of life—were evaluated in connection with various treatments. A practice guideline containing clinical recommendations relevant to patients in Ontario was drafted. The practice guideline was reviewed and approved by the Gastrointestinal Disease Site Group (DSG) and the Report Approval Panel of Cancer Care Ontario’s Program in Evidence-Based Care. External review by Ontario practitioners was obtained through a survey, the results of which were incorporated into the practice guideline.

Results: The literature search identified seventy-two randomized trials that met the inclusion criteria. An a posteriori decision was made to focus on the individual contributions of the fluoropyrimidines, platinum agents, anthracyclines, taxanes, irinotecan, and trastuzumab.

Conclusions: The Gastrointestinal DSG made these recommendations:

• To improve survival, a platinum agent should be included in any combination chemotherapy regimen.
• Within a combination chemotherapy regimen, oral capecitabine is preferred over intravenous 5-fluorouracil (5FU)—that is, epirubicin–cisplatin– capecitabine is preferred over the prior standard regimen, epirubicin–cisplatin–5FU (ECF).
• Epirubicin–oxaliplatin–capecitabine (EOX) is a reasonable alternative to ECF. The choice between ECF and EOX should be based on patient preference.
• Trastuzumab in combination with cisplatin and a fluoropyrimidine (5FU or oral capecitabine) is recommended for advanced gastric cancer positive for the human epidermal growth factor receptor 2 (HER2/neu).

Triple-Negative Breast Cancers: An Updated Review on Treatment Options

K.B. Reddy PhD. Department of Pathology, Wayne State University School of Medicine, Detroit, Michigan, U.S.A.

KEY WORDS

Triple-negative breast tumours, epidermal growth factor receptor, chemotherapy

URL www.current-oncology.com/index.php/oncology/article/view/738/

E-JOURNAL LINKED ABSTRACT

Morphologic features of tumour cells have long been validated for the clinical classification of breast cancers and are regularly used as a “gold standard” to prognosticate outcome in patients. Identification of molecular markers such as expression of the receptors for estrogen (ER) and progesterone (PgR), and the human epidermal growth factor receptor 2 (HER2) has played an important role in determining targets for the development of efficacious drugs for treatment, and has also offered additional predictive value for the therapeutic assessment of patients with breast cancer. More recent technical advancements in identifying several cancer-related genes have provided further opportunities to identify specific subtypes of breast cancer. Among the subtypes, tumours with triple-negative cells are identified by using specific staining procedures for basal markers such as cytokeratins 5 and 6 and the absence of ER, PgR, and HER2 expression. Patients with triple-negative breast cancers have the disadvantage of not benefiting from currently available receptor-targeted systemic therapy. The optimal conditions for therapeutic assessment of women with triple-negative breast tumours and for management of their disease have yet to be validated in prospective investigations. This review addresses the characteristics of basal-like and triple-negative cancers, their similarities, and their differences. Given the absence of known targeted therapy for triple-negative breast cancer, many investigators are targeting surface receptors such as the epidermal growth factor receptor or c-Kit; using agents such as cisplatin that damage DNA or that inhibit the poly(ADP–ribose) polymerase 1 repair enzymes; or inhibiting second messengers such as the mitogen-activated protein kinase pathway and angiogenesis, among others, with some success.

Standard chemotherapy seems to be less effective in triple-negative than in other types of breast cancer, and new therapeutic approaches are needed. The pathways that drive proliferation of these tumors are still poorly understood. As a better understanding of the pathways driving triple-negative breast cancer is achieved, potential new targeted therapeutic agents for these patients will continue to be found.

A Comprehensive Bone-Health Management Approach for Men with Prostate Cancer Receiving Androgen Deprivation Therapy

C.E. Lee PhD PT, W.D. Leslie MD MSc, P. Czaykowski MD MSc, J. Gingerich MD, M. Geirnaert, and Y.K.J. Lau MD PhD. Department of Physical Therapy, School of Medical Rehabilitation, and Departments of Internal Medicine and of Radiology, University of Manitoba; and Departments of Medical Oncology and Haematology and of Pharmacy, CancerCare Manitoba, Winnipeg, Manitoba.

KEY WORDS

Prostate cancer, androgen deprivation therapy, osteoporosis, bone, fracture

URL www.current-oncology.com/index.php/oncology/article/view/746/

E-JOURNAL LINKED ABSTRACT

Androgen deprivation therapy (ADT), achieved by bilateral orchiectomy or by administration of luteinizing-hormone releasing-hormone agonists, is the mainstay of treatment for advanced prostate cancer. Awareness of the potential consequences for bone health from ADT use is increasing. These consequences are of particular importance, because more than 70% of men with prostate cancer are more than 65 years of age and are already at risk for osteoporosis or fragility fracture. This article reviews recent studies on bone health in men with prostate cancer receiving ADT and discusses the current evidence relating to bone-health monitoring and management with regard to Canadian provincial guidelines.

Many studies have showed that prolonged use of ADT leads to the significant bone loss and increased risk of fracture that negatively affect quality of life for these men. However, there is currently no standardized clinical practice guideline in Canada for bone mineral density (BMD) assessment and bone-health management in men with prostate cancer on ADT. Guidelines vary across Canada, from specific or general guidelines in some provinces to no established guidelines in most.

The recommendations for bone-health management in the article are based on current evidence and recommendations from the bone-health literature. Based on a recent recommendation from Osteoporosis Canada, the authors suggest baseline measurement of BMD at initiation of ADT, with periodic reassessment during therapy depending on the initial findings. Although not validated in the ADT population, the Canadian Fracture Risk Assessment (FRAX) tool or the Canadian Association of Radiologists and Osteoporosis Canada semi-quantitative CAROC system could be recommended as part of clinical practice to assess 10-year fracture risk and guide pharmacologic intervention. No consensus has yet emerged on optimal calcium and vitamin D intakes in men with prostate cancer on ADT; however, based on risk and serum level of vitamin D, total daily intake of 1200 mg elemental calcium from all sources and daily supplementation with 800–2000 IU vitamin D should be recommended to men with prostate cancer receiving ADT as suggested by Osteoporosis Canada. Exercises with sufficient bone-loading force have consistently been shown to maintain BMD, muscle strength, and physical function in older men. Men with prostate cancer receiving ADT should therefore be encouraged to engage in regular weight-bearing aerobic, strengthening, and balance exercises. Nevertheless, further studies are needed to define the optimal exercise regimen and the roles of bisphosphonates, denosumab, and selective estrogen receptor modulators in improving bone health in this population.

Prophylactic Feeding Tubes for Patients with Locally Advanced Head-and-Neck Cancer Undergoing Combined Chemotherapy and Radiotherapy—Systematic Review and Recommendations for Clinical Practice

C. Orphanidou MSc,^* K. Biggs BASc MHSc,^† M.E. Johnston BSc,^‡ J.R. Wright MD MSc,^† A. Bowman BASc,^§ S.J. Hotte MD MSc,† A. Esau BHE,|| C. Myers BSc BEd MSc,# V. Blunt BSc RD,^** M. Lafleur RN,^† B. Sheehan MD,^§ and M.A. Griffin BSc RD†† for the Canadian Oncology Nutrition Clinical Practice Guideline Initiative. Oncology Nutrition, BC Cancer Agency, Centre for the Southern Interior, Kelowna, and Oncology Nutrition and Radiation Oncology, BC Cancer Agency, Vancouver Centre, Vancouver, British Columbia; Clinical Nutrition, Tom Baker Cancer Centre, Calgary, Alberta; Patient and Family Support Services, Cancer Care Manitoba, Winnipeg, Manitoba; Supportive Care Program, Radiation Oncology, Medical Oncology, and Nursing, Juravinski Cancer Centre, Hamilton, and Clinical Nutrition, University Health Network (Toronto General Hospital), Toronto, Ontario; technical and methodological consultancy, Dundas, Ontario; and Nutrition Services, Dr. H. Bliss Murphy Cancer Centre, St. John’s, Newfoundland and Labrador.

KEY WORDS

Practice guideline, systematic review, tube feeding, chemoradiation, head-and-neck cancer

URL www.current-oncology.com/index.php/oncology/article/view/749/

E-JOURNAL LINKED ABSTRACT

Malnutrition is common among patients with head- and-neck cancer. When concurrent intensive multimodality treatments are used, severe and often debilitating adverse effects can compromise the patient’s ability to maintain adequate nutrition and hydration. Aggressive enteral feeding regimens are used to address malnutrition and nutritional decline, but there is disagreement about when to initiate tube feeding: before starting chemotherapy and radio-therapy (prophylactic) or in response to nutritional decline during treatment (reactive).

A pan-Canadian multidisciplinary panel, which included oncology and nutrition experts, conducted a systematic review of the literature to determine the benefits and risks of prophylactic feeding tubes for adult patients with squamous cell carcinoma of the head and neck who receive combined chemotherapy and radiotherapy with curative intent. The purpose of the review was to inform recommendations to guide clinical decision-making with regard to the use of prophylactic feeding tubes and the provision of adequate nutrition to this patient population.

A search of the MEDLINE, EMBASE, CINAHL, Health- STAR, and Cochrane Library databases to October 2009 found no eligible randomized controlled trials. Evidence from studies in the target population was limited to seven descriptive studies: two studies with control groups and five studies without. Results from ten controlled studies in patients treated with radiotherapy alone were also reviewed.

The available evidence was insufficient to draw definitive conclusions about the effectiveness of prophylactic feeding tubes or to support an evidence-based practice guideline. After review of the available evidence, guidelines from other groups, and current clinical practice in Canada, the panel made consensus-based recommendations regarding comprehensive interdisciplinary clinical care before, during, and after cancer treatment in the target population. Because of the limited available evidence, the recommendations are based primarily on the expert opinion of the panel members and their understanding of best clinical practice. The panel distributed the draft evidence summary and recommendations to a cross-section of Canadian clinicians, whose input was incorporated into the final report.

The recommendations cover an interdisciplinary approach to care; nutrition screening and referral; and monitoring during and after combined chemotherapy and radiotherapy.

Key Recommendation: Insertion of a prophylactic feeding tube should be seriously considered when chemoradiotherapy is planned for head-and-neck cancer patients with one or more of these symptoms: significant weight loss (more than 5% in 1 month or more than 10% in 6 months), a body mass index below 18.5, dysphagia, anorexia, dehydration, pain, or other symptoms that interfere with the ability to eat.

Canadian Expert Group Consensus Recommendations: KRAS Testing in Colorectal Cancer

F. Aubin MD, S. Gill MD, R. Burkes MD, B. Colwell, S. Kamel–Reid PhD, S. Koski MD, A. Pollett, B. Samson MD, M. Tehfe MD, R. Wong MD, S. Young PhD, and D. Soulières MD. Nova Scotia Cancer Centre, Halifax, Nova Scotia; Centre Hospitalier de l’Université de Montréal, Montreal, and Hôpital Charles-Lemoyne, Greenfield Park, Quebec; Mount Sinai Cancer Centre and Princess Margaret Hospital, Toronto, Ontario; CancerCare Manitoba, Winnipeg, Manitoba; Cross Cancer Centre, Edmonton, Alberta; and BC Cancer Agency, Vancouver, British Columbia.

KEY WORDS

KRAS mutations testing, BRAF mutations testing, metastatic colorectal cancer, guidelines, consensus recommendations, cetuximab, panitumumab, anti-EGFR therapy

URL www.current-oncology.com/index.php/oncology/article/view/779/

E-JOURNAL LINKED ABSTRACT

Monoclonal antibodies against the epidermal growth factor receptor (EGFR) are used in the treatment of metastatic colorectal cancer (mCRC), but patients whose tumours harbor a KRAS mutation do not benefit from this treatment. The importance of KRAS mutational status in the management of mCRC patients has led to the elaboration of Canadian consensus recommendations on KRAS testing in an attempt to standardize practice across Canada. The guidelines were developed at a Canadian consensus meeting held in Montreal in April 2010. The best available evidence and expertise was used to develop recommendations for various aspects of KRAS testing, including indications and timing for testing, sample requirements, reporting requirements, and acceptable turnaround times.

Tumour KRAS status should be determined whenever anti-EGFR therapy is being considered in the treatment of mCRC. When possible, KRAS testing should be requested in mCRC patients at the start of second-line therapy. Tumor cell enrichment by microor macro-dissection, or selective sampling of the paraffin block by needle core should be used to increase the sensitivity of tumor testing. Mutational analysis should use the primary resection specimen, if available. An endoscopic core biopsy of the primary tumor is preferred over a core biopsy of a distant metastasis. If core biopsy of the primary is not possible, core biopsy of a distant metastasis should be obtained. If every reasonable effort has been made to ascertain KRAS status but that status remains unknown, it would be reasonable to offer the benefit of consideration for anti-EGFR therapy. Testing strategies for KRAS status would be deemed acceptable provided that they satisfy these minimal requirements: a mutation-detection sensitivity between 95% and 99%, and a specificity of 100%. KRAS testing must be reproducible and should be performed by an accredited laboratory that conforms to quality guidelines for KRAS testing and that routinely participates in proficiency testing such as that offered by College of American Pathologists (CAP), with external validation. Routine testing for BRAF mutation status or other potential biomarkers before anti-EGFR therapy is not currently recommended. The absence or presence of KRAS mutation must be reported, and if a mutation is identified, the affected codon should be specified. If available, the specific change should be indicated. The report should specify the assay that was performed. Reports should conform to existing reporting guidelines from the American College of Medical Genetics, CAP, or the Canadian College of Medical Geneticists. Once the specimen is received by the testing laboratory, 10 working days is an acceptable turnaround time for reporting of the results to the ordering physician.