E-Manuscript Article Summaries ^†

Monitoring Response and Resistance to Treatment in Chronic Myeloid Leukemia

S. Assouline MD MSc BSc and J.H. Lipton MD PhD. Department of Medicine and Oncology, McGill University, Jewish General Hospital, Montreal, Quebec, and Department of Medical Oncology and Hematology, Princess Margaret Hospital, University of Toronto, Toronto, Ontario.

KEY WORDS

Chronic myeloid leukemia, protein kinase inhibitors, imatinib, drug resistance, drug monitoring

URL www.current-oncology.com/index.php/oncology/article/view/391/

E-JOURNAL LINKED ABSTRACT

Chronic myeloid leukemia (CML) results from expression of the constitutive tyrosine kinase activity of the Bcr-Abl oncoprotein. Imatinib, a tyrosine kinase inhibitor (TKI), is highly effective in the treatment of CML. However, 25%–35% of patients treated with imatinib will fail to respond, will respond suboptimally, or will relapse because of primary or acquired resistance or intolerance. Research activities focusing on the causes of imatinib resistance or decreased responsiveness have identified mutations in the BCR-ABL gene, clonal evolution, amplification of the BCR-ABL gene, low expression of human organic cation transporter 1 protein, and increased expression or activity of Src family kinases as potential mechanisms. Because early response to treatment is predictive for improved long-term outcome, determination of therapeutic response is a crucial component of clinical decision-making for patients with CML.

Cytogenetic response can be monitored using either conventional assessment (bone marrow metaphases) or fluorescence in situ hybridization, although periodic karyotyping should be performed in all patients to detect secondary chromosomal abnormalities arising during therapy. Molecular monitoring of BCR-ABL transcripts in peripheral blood using quantitative reverse-transcriptase polymerase chain reaction is highly sensitive and can be calibrated to a standardized international scale. In cases of inadequate or lost response to treatment, Bcr-Abl mutational assessment is recommended. International recommendations for response have been established based on the achievement of specified levels of response within a defined timeframe. The European LeukemiaNet definition of an optimal response includes complete cytogenetic response (CCyR) by 12 months and major molecular response by 18 months.

For patients who do not respond optimally or who are intolerant to imatinib, dasatinib and nilotinib (newer TKIs with higher in vitro potency compared with imatinib) are established second-line options that are active against most Bcr-Abl mutations. Approximately half the patients who discontinue imatinib because of resistance or intolerance achieve a CCyR on dasatinib or nilotinib. Dasatinib has shown efficacy superior to that with imatinib dose escalation in patients who were resistant to initial imatinib therapy. Although both dasatinib and nilotinib are generally well tolerated, each is associated with a different pattern of adverse events, including pleural effusion for dasatinib and biochemical abnormalities for nilotinib. Monitoring techniques can permit treatment to be tailored to the individual patient based on disease characteristics—for example, according to Bcr-Abl mutation profile or to patient characteristics such as certain comorbid conditions. This approach should benefit patients by increasing the potential for better long-term outcomes.

Rash Rates with EGFR Inhibitors: Meta-Analysis

N. Mittmann PhD and S.J. Seung BSc. HOPE Research Centre, Division of Clinical Pharmacology, Sunny- brook Health Sciences Centre, Toronto, Ontario.

KEY WORDS

Epidermal growth factor receptor inhibitors, meta- analysis, rash

URL www.current-oncology.com/index.php/oncology/article/view/605/

E-JOURNAL LINKED ABSTRACT

The currently marketed epidermal growth factor receptor inhibitors (EGFRIs) have been associated with high rates of dermatologic toxicities. We studied the difference in skin toxicity rates between therapies with EGFRIs and non-EGRFRIs.

We formally reviewed the literature at MEDLINE and EMBASE. Additional searches were conducted using Internet search engines. Studies were eligible if they were randomized controlled clinical trials of EGFRIs, specifically cetuximab and panitumumab, in which at least one arm consisted of a non-EGFRI treatment and in which rash safety data were reported. Differences in incident rash rates were pooled using the random-effects method. Results are summarized as difference in incident rash (EGFRI therapy rate minus the non-EGFRI therapy rate) with corresponding 95% confidence intervals (CIs) for all severity grades of rash and for grades 3 and 4 rash. Sensitivity analyses examining tumour type, severity grade, and comparator were conducted.

Sixteen studies met the initial inclusion criteria of randomized controlled trials comparing EGFRI with non-EGFRI therapy. Disease sites included metastatic colorectal cancer, head-and-neck cancer, pancreatic cancer, and non-small-cell lung cancer. Seven publications provided information on all grades of rash severity, which when pooled showed an overall difference in incident rash rate of 0.74 (95% CI: 0.68 to 0.81; p < 0.01) between EGFRI and non-EGFRI therapies. Thirteen studies reported the incidence of grades 3 and 4 rash, which when pooled showed an overall difference in incident rash rate of 0.12 (95% CI: 0.09 to 0.14; p < 0.01). Sensitivity analyses showed that results were generally robust, but sensitive to small samples. Studies showed generally similar rash differences for grades 3 and 4 reactions when only colorectal cancer patients and only active comparators were included. By contrast, studies examining patients with non-small-cell lung cancer showed a rate difference with respect to grades 3 and 4 rash that was higher than the rate difference overall (0.20 vs. 0.12 overall) between EGFRI and non-EGFRI therapies.

Skin toxicities are a common adverse drug reaction seen with EGFRIs. The results from this systematic review provide a pooled value for the difference in rash rates between EGFRI and non-EGFRI therapies in patients diagnosed with a number of solid tumours. The overall risk differences for EGFRI therapy compared with non-EGFRI therapy are 74% for rashes of all severities and 12% for grades 3 and 4 rashes. Rash definitions are not always standardized, and therefore definition standardization is recommended to facilitate appropriate pooling of data.

A New Standard of Care for the Management of Peritoneal Surface Malignancy

F. Mohamed MBChB MD, T. Cecil MD, B. Moran MD MCh, and P. Sugarbaker MD. Basingstoke and North Hampshire Hospital, Basingstoke, Hampshire, U.K., and Washington Cancer Institute, Washington, DC, U.S.A.

KEY WORDS

Cytoreductive surgery, hyperthermic intraperitoneal chemotherapy, HIPEC, carcinomatosis, peritoneal mesothelioma, appendiceal cancer, pseudomyxoma peritonei, colorectal cancer, mitomycin C

URL www.current-oncology.com/index.php/oncology/article/view/663/

E-JOURNAL LINKED ABSTRACT

Background: Early on, the major goal of cancer surgery was clearance of the primary cancer and achievement of an R0 resection. Next, maximal containment during cancer resection was shown to be of utmost importance for optimizing locoregional control. Currently, clearance and containment as goals have been expanded so that the knowledgeable use of cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS plus HIPEC) can be examined as a third crucial requirement for the surgical management of gastrointestinal cancer.

Methods: Clinical and pharmacologic parameters have been used to rethink new requirements for optimal gastrointestinal cancer management. This practice-based evidence from multiple institutions and published manuscripts shows long-term success with the new approach. As quantitative prognostic indicators have evolved, clinical data have been made available for improved selection of patients. Also, the simultaneous (not adjuvant or neoadjuvant) use of locoregional chemotherapy in the perioperative period with the surgical intervention has been widely published. Finally, as experience with this technology has increased, the associated morbidity and mortality have been greatly reduced, making the treatments more widely available throughout the surgical community.

Results: Treatment of mucinous appendiceal neoplasms, including pseudomyxoma peritonei syndrome, has changed markedly since the early 1990s. Comparison of results from prominent institutions suggests that long-term survival is greatly improved with CRS plus HIPEC. For colorectal peritoneal carcinomatosis, no available evidence suggests that systemic chemotherapy alone is a treatment option. By contrast, multiple reports from many different institutions show that, in selected cases, CRS plus HIPEC improves median survival and produces approximately 30% cure rates. Evidence for systemic chemotherapy treatments in peritoneal mesothelioma is also lacking. By contrast, when compared with historical data, CRS plus HIPEC shows approximately 50% long-term survival and marked improvement. Acceptance of medical history in the treatment of liver metastases to reach a standard of care creates a strong rationale for acceptance of CRS plus HIPEC as a standard of care. The treatment results for both conditions as compared in multiple reports are similar. Since 2000, traditional treatments for carcinomatosis do not have publications. Only CRS and HIPEC results have been published.

Conclusions: The options for treatment of peritoneal carcinomatosis have certainly been expanded. Furthermore, clinical data provide selection criteria for delivering optimal treatment using this new standard of care. Recent trends published from multiple institutions suggest that this new treatment is a standard of care at experienced centres managing significant numbers of patients. Alternative management plans have not been forthcoming. Practice-based medicine is a reality for carcinomatosis from appendiceal cancer, colorectal cancer, and peritoneal mesothelioma.

Using a Positive Self-Talk Intervention to Enhance Coping Skills in Breast Cancer Survivors: Lessons from a Community-Based Group Delivery Model

R. Hamilton MSES, B. Miedema PhD, L. MacIntyre, and J. Easley MA. Dalhousie University Family Medicine Teaching Unit, Fredericton, New Brunswick.

KEY WORDS

Cancer survivorship, coping skills, positive self-talk

URL www.current-oncology.com/index.php/oncology/article/view/706/

E-JOURNAL LINKED ABSTRACT

Introduction: Advances in early detection and treatment of cancer have caused mortality rates to decline, resulting in growing numbers of cancer survivors. Cancer survivorship is a distinct phase in the cancer continuum, and it can present with a myriad of challenges, including fatigue, lymphedema, fear of recurrence, anxiety, and depression. The purpose of the present study was to evaluate the effectiveness of a positive self-talk (PST) intervention in enhancing the coping skills and improving the psychological well-being of breast cancer survivors.

Methods: Participants (n = 38) were recruited from 5 support groups in a small eastern Canadian province. Support groups were randomly assigned to either an intervention (n = 20) or a control condition (n = 18). Intervention participants were pre-tested, received a 2-hour PST session and a 10-minute refresher session by telephone, and completed post-test questionnaires 1 month later. Measures included the Profile of Mood States, the Hospital Anxiety and Depression Scale, the Rehabilitation Survey of Problems and Coping, and a workshop evaluation questionnaire. Control participants completed the same questionnaires at an equivalent 1-month interval.

Results: Intervention participants reviewed the workshop favourably. Nearly all participants used the intervention in everyday life, were able to accurately describe how PST works, and found that PST had a considerable impact on their ability to cope with cancer and related sequelae. However, the descriptive findings from the workshop evaluation did not translate into significant differences between the intervention and control groups on the psychometric measures used for evaluation. Although declines in depression and anxiety were observed, the differences between the groups were not statistically meaningful.

Conclusions: The PST intervention was well received, retained, and applied by participants. Participants engaged willingly with the content and expressed a need for this type of workshop because of their continual need to cope with cancer survivorship issues. However, these subjective appraisals of the intervention did not equate to significant psychological change for the participants. Community-based psychological interventions present unique challenges, including time constraints, travel requirements for participants, and diverse experiences with cancer within the group (recency of diagnosis, existing support system, varying prognoses). Despite the observed challenges, incorporation of the modifications proposed in this paper may enable future researchers and health care professionals to effectively target survivors in community-based programs. Enhancements to workshop delivery in community-based settings may help to maximize the psychological benefit of this well-received PST intervention.

Acute Aortic Thrombosis in Patients Receiving Cisplatin-Based Chemotherapy

D.D. Fernandes MD, M.L. Louzada MD MSc, C.A. Souza MD PhD, and F. Matzinger MD. University of Ottawa, Department of Diagnostic Imaging, The Ottawa Hospital–General Campus, Ottawa, and University of Western Ontario, Victoria Hospital, London, Ontario.

KEY WORDS

Acute, arterial, aortic thrombosis, aortic occlusion, cisplatin, cancer

URL www.current-oncology.com/index.php/oncology/article/view/710/

E-JOURNAL LINKED ABSTRACT

The increased risk of thrombosis in patients with active malignancy is well documented and has multiple causes. Chemotherapy is one of the most important risk factors for thromboembolic events, with cisplatin being the most commonly implicated agent. Most cases described in the literature involve the heart (myocardial infarction), brain (ischemic stroke), and lower-limb arteries. Although exceedingly rare, thrombosis of the aorta is a potentially devastating complication in cancer patients receiving cisplatin-based chemotherapy. The mechanism behind cisplatin-induced vascular events remains unknown, but various hypotheses have been proposed, as have potential risk factors.

Acute aortic thrombosis currently has no standardized treatment, but current guidelines suggest using immediate systemic anticoagulation with unfractionated heparin. In patients undergoing embolectomy, initial therapy with unfractionated heparin followed by long-term anticoagulation with a vitamin K antagonist or a low molecular weight heparin is recommended.

We report 4 cases of acute thrombosis of the abdominal aorta in patients receiving cisplatin-based chemotherapy. In all cases, thrombotic events occurred later in the treatment course, with absent or minimal symptoms. Patients were treated conservatively with either low molecular weight or unfractionated heparin. In 1 case, the patient deteriorated and died from multiple organ failure shortly after presentation.

Early diagnosis can be difficult because of nonspecific symptoms, and so a high degree of clinical suspicion is necessary to decrease morbidity and mortality from this rare but serious complication.

Capecitabine or Infusional 5-Fluorouracil for Gastroesophageal Cancer: A Cost–Consequence Analysis

A.M. Horgan MB BCh, J.J. Knox MD, G. Liu MD, C. Sahi MD, P.A. Bradbury MB BCh, and N.B. Leighl MD MMSc. Division of Medical Oncology and Hematology, Princess Margaret Hospital, Toronto, Ontario.

KEY WORDS

Capecitabine, cost–consequence analysis, gastroesophageal cancer, infusional 5FU

URL www.current-oncology.com/index.php/oncology/article/view/730/

E-JOURNAL LINKED ABSTRACT

Background: Globally, gastric and esophageal cancers are, respectively, the second and sixth most common causes of cancer-related deaths and an important cause of cancer-related morbidity. In advanced disease, benefits in survival and quality of life outcomes have been shown for chemotherapy compared with best supportive care alone, with ECF [epirubicin 50 mg/m² and cisplatin 60 mg/m² every 3 weeks, plus infusional 5-fluorouracil (5FU) 200 mg/m² daily] being a standard treatment regimen for this disease. The phase III Randomized ECF for Advanced and Locally Advanced Esophagogastric Cancer 2 (REAL-2) trial suggests that, in the ECF regimen, capecitabine (X) can be substituted for infusional 5FU without compromising efficacy. In view of the increasing constraints on health care expenditures, the economic implications of treatment with capecitabine as an alternative to 5FU should be considered.

Methods: We used the published REAL-2 trial data to perform a cost–consequence analysis of ECF compared with ECX. Resources and costs were determined from start of treatment until first progression, and a mean cost per patient on each treatment arm was calculated. This analysis took the perspective of the Canadian public health care system and considered only direct medical resource utilization and costs. Clinical data were extracted from the REAL-2 trial. Costs were determined at Princess Margaret Hospital (Toronto, ON) and are presented in 2008 Canadian dollars. Only grades 3 and 4 toxicities, determined according to the U.S. National Cancer Institute’s Common Toxicity Criteria, version 2.0, were considered.

Results: Drug costs from start of treatment until first progression, including pre- and post-chemotherapy medications and administration costs, totalled $5,344 for ECX compared with $3,187 for ECF. Costs for treatment of adverse events were estimated at $2,621 for ECX compared with $3,397 for ECF. Additional cost associated with insertion of an implanted venous catheter was $873. Total incremental cost of ECX over ECF was $508. On one-way sensitivity analysis, the incremental cost of ECX over ECF was most sensitive to changes in capecitabine cost. A ±20% variation in the cost of capecitabine changed the incremental cost of total treatment in a range from –$46 (savings with ECX) to $1,062 (increased cost with ECX).

Conclusions: In advanced gastroesophageal cancer, capecitabine is an attractive alternative to 5FU. The drug cost itself is greater, but its administration is associated with less consumption of hospital resources. Capecitabine not only fits with patient preference for oral therapy, it avoids the inconvenience and complications of central venous access. Administrators of public or group practice plans should consider these data and support patient and specialist choice to substitute capecitabine for 5FU in the ECF regimen.

Chronic Lymphocytic Leukemia and Breast Cancer As Synchronous Primary in a Male—A Rare Combination

B. Dubashi MD DM, A. Jain MD DM, K. Srinivasan MS, V. Surendrakumar MD, and S. Vivekanandam DMRT. Departments of Medical Oncology, Surgery, Pathology, and Radiotherapy, Jawaharlal Institute of Postgraduate Medical Education and Research, Dhanvantari Nagar, Puducherry, India.

KEY WORDS

Chronic lymphocytic leukemia, male breast cancer, synchronous malignancy

URL www.current-oncology.com/index.php/oncology/article/view/731/

E-JOURNAL LINKED ABSTRACT

Second malignancies are known to be associated with chronic lymphocytic leukemia (CLL). The incidence of male breast cancer is 1%. Synchronous presentation of CLL and various malignancies are rare. We present a rare combination of synchronous primary CLL with breast cancer in a man. The management of dual tumours is challenging. The decisions that have to be made include sequence of the treatment, chemotherapy regimen, and management of complications. Further investigation of genetic features that predispose patients with CLL (or with small lymphocytic lymphoma) to develop other malignant neoplasms is warranted.

Rare Synchronous Primary Large B-Cell Gastric Lymphoma and Huge Retroperitoneal Liposarcoma with Inguinal Hernia in Chronic Hepatitis B Patient

P. Ghimire MBBS MD, G.Y. Wu MD PhD, and L. Zhu MBBS MD. Department of MRI, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, PR China.

KEY WORDS

Multiple primary neoplasms, primary gastric lymphoma, liposarcoma, synchronous, metachronous

URL www.current-oncology.com/index.php/oncology/article/view/735/

E-JOURNAL LINKED ABSTRACT

Multiple primary neoplasms with synchronous or metachronous presentation are rare, although the incidence has increased recently because of several factors, including carcinogenic substances such as tobacco, alcohol, and dyes; genetic predisposition; immune suppression; various infections; and the sequelae of treatments such as radiotherapy, chemotherapy, or organ transplantation. We present a case of multiple primary neoplasm in a 53-year-old man with chronic hepatitis B who presented with abdominal mass, mild abdominal pain, and inguinal hernia.

Markers for chronic hepatitis B (hepatitis B surface antigen, anti–hepatitis B e-antibody, and anti– hepatitis B core antibody) were positive, with a hepatitis B virus (HBV) DNA level of 7.56×10³ copies per millilitre. The patient’s liver function tests and hematologic profile were within normal limits. Computed tomography imaging of the entire abdomen revealed marked circumferential thickening of the gastric antral wall, with a lobulated inner surface and smooth well-defined outer wall. On enhancement, the thickened wall showed minimal homogeneous enhancement, together with preservation of the perigastric fat plane. Few perigastric lymph nodes were noted. A huge, well-defined heterogeneous abdominal mass measuring 26×12×26 cm, with predominant fat attenuation and no calcification, occupied the retroperitoneum, extending from the infrapancreatic level to the pelvis. This tumour also had thickened irregular septa, with nodular components having an attenuation approximating that of skeletal muscle. The mass displaced the bowel loops laterally and superiorly. Post-contrast imaging showed moderate enhancement of the septa of the retroperitoneal mass.

The patient underwent a distal gastrectomy and wide resection of the retroperitoneal mass with inguinal hernia repair. The gastrectomy specimen confirmed the diagnosis of diffuse large B-cell lymphoma, with invasion to the deeper layer and ulcer formation. Immunohistochemistry revealed positivity for CD20 and negativity for CD79a, CD3, and CD43. Histopathology and immunohistochemistry examination of the resected abdominal mass confirmed the diagnosis of well-differentiated liposarcoma with S100 negativity and CD68 positivity.

Follow-up investigations ruled out any relapse, and patient has been disease-free to the time of writing.

This is a rare case of a primary gastric lymphoma occurring synchronously with another primary malignancy (retroperitoneal liposarcoma) in the same patient. Liposarcoma and non-Hodgkin lymphoma may be related to unidentified familial diseases, or spurious associations may be present. A potential role for HBV in the development of these two primary malignancies can be suggested. Infection with HBV has been linked to the development of B-cell non- Hodgkin lymphoma.

Legalizing Euthanasia or Assisted Suicide: The Illusion of Safeguards and Controls

J. Pereira MBChB MSc. Division of Palliative Care, University of Ottawa; Department of Palliative Medicine, Bruyère Continuing Care; and Palliative Care Service, The Ottawa Hospital, Ottawa, Ontario.

KEY WORDS

Euthanasia, physician-assisted suicide

URL www.current-oncology.com/index.php/oncology/article/view/883/

E-JOURNAL LINKED ABSTRACT

Euthanasia or assisted suicide—and sometimes both— have been legalized in a small number of countries andstates. In all jurisdictions, laws and safeguards were put in place to prevent abuse and misuse of these practices. Prevention measures have included, among others, explicit consent by the person requesting euthanasia, mandatory reporting of all cases, administration only by physicians (with the exception of Switzerland), and consultation by a second physician.

The present paper provides evidence that these laws and safeguards are regularly ignored and transgressed in all the jurisdictions and that transgressions are not prosecuted. For example, about 900 people annually are administered lethal substances without having given explicit consent, and in one jurisdiction, almost 50% of cases of euthanasia are not reported.

Increased tolerance of transgressions in societies with such laws represents a social “slippery slope,” as do changes to the laws and criteria that followed legalization. Although the initial intent was to limit euthanasia and assisted suicide to a last-resort option for a very small number of terminally ill people, some jurisdictions now extend the practice to newborns, children, and people with dementia. A terminal illness is no longer a prerequisite. In the Netherlands, euthanasia for anyone over the age of 70 who is “tired of living” is now being considered. Legalizing euthanasia and assisted suicide therefore places many people at risk, affects the values of society over time, and does not provide controls and safeguards.