E-Manuscript Article Summaries ^†

O. Harold Warwick: Canada’s First Medical Oncologist

D.H. Cowan MD. Department of Medicine, Sunnybrook Health Sciences Centre, University of Toronto, and Cancer Care Ontario, Toronto, Ontario.

KEY WORDS

Harold Warwick, history, medical oncology

URL www.current-oncology.com/index.php/oncology/article/view/425/

E-JOURNAL LINKED ABSTRACT

The genesis of modern medical oncology dates to the early 1940s, when nitrogen mustard was demonstrated to be useful in the treatment of certain hematologic malignancies. Simultaneously, hormone manipulation was also showing promise in patients with prostate and breast cancer. These publications stimulated the interest of Harold Warwick, a young World War II overseas veteran of the Royal Canadian Air Force Medical Corp.

Harold Warwick was born in 1915 in Saint John, New Brunswick. He graduated from McGill Medical School in 1940 as a gold medalist and Rhodes Scholar. After World War II, he started his postgraduate training in medicine in Montreal, and in 1946, he returned to London, England, to study the newly described drug treatment of cancer. At the Royal Cancer Hospital, he carried out and published the first study of a chemotherapeutic agent (nitrogen mustard) in a group of adult patients with a non-hematologic solid tumour.

In 1948, Warwick became executive director of both the Canadian Cancer Society and the National Cancer Institute of Canada. At the same time, he was appointed to the staff of the Toronto General Hospital, which housed the Ontario Radiotherapy Institute (ori). There, he became the first Canadian non–radiation oncologist physician to have a full-time appointment in a Canadian cancer centre.

In 1958, the ori closed; the patients and staff moved to the new Ontario Cancer Institute, incorporating the Princess Margaret Hospital (pmh). Warwick became chief physician and was responsible for developing clinical drug trials of anticancer agents. At the pmh, he carried out his best known drug trial, which demonstrated the usefulness of vinblastine sulphate, particularly in patients with Hodgkin lymphoma.

The years 1961–1971 took Warwick to the University of Western Ontario (uwo) in London, where he served as dean of medicine and then vice-president, health sciences. In 1972, he returned to “doing what I like best, caring for sick people.” He practised as a medical oncologist at the Ontario Cancer Foundation London Clinic until his retirement in 1980.

Harold Warwick, in the late 1940s, followed on the heels of the individuals who first used nitrogen mustard and hormones in treating patients with cancer. Aside from his time at uwo in academic administration, he devoted his entire career to oncology—specifically, the medical aspects of care. Although the subspecialty was not formalized until his later working years, he satisfied all the criteria that now define the discipline; he was Canada’s first medical oncologist.

A Multicentre Open-Label Safety and Efficacy Study of Tetrodotoxin for Cancer Pain

N.A. Hagen MD, B. Lapointe MD, M. Ong–Lam MD, B. Dubuc MD, D. Walde MD, B. Gagnon MD, R. Love, R. Goel MD, P. Hawley MD, A. Ho Ngoc phd, and P. du Souich MD phd. Departments of Oncology, of Family Medicine, and of Medicine, McGill University; Jewish General Hospital; Pain Clinic, Centre hospitalier de l’Université de Montréal–Hôtel Dieu; and Département de Pharmacologie, Faculté de Médecine, Université de Montréal, Montreal, Quebec; Department of Oncology, Sault Area Hospital, Sault Ste. Marie, and Department of Oncology, The Ottawa Hospital, Ottawa, Ontario; Tom Baker Cancer Centre and Departments of Oncology, of Clinical Neurosciences, and of Medicine, University of Calgary, Calgary, Alberta; St. Paul’s Hospital, BC Cancer Agency, and WEX Pharmaceuticals, Vancouver, and Palliative Care, Nanaimo Regional General Hospital, and Department of Family Medicine, University of British Columbia, Nanaimo, British Columbia.

KEY WORDS

Clinical trial, cancer pain, analgesic, tetrodotoxin, long-term, safety, efficacy, open-label

URL www.current-oncology.com/index.php/oncology/article/view/732/

E-JOURNAL LINKED ABSTRACT

Background: Cancer pain is highly prevalent, and existing treatments are often insufficient to provide adequate relief. Animal studies have suggested that systemically administered tetrodotoxin is a potent analgesic, and open-label and randomized trial results in cancer patients have suggested that this agent is active in cancer pain.

Objectives: We assessed the long-term safety and efficacy of subcutaneous tetrodotoxin treatment in reducing the intensity of chronic cancer-related pain.

Methods: In this multicentre open-label longitudinal trial, 30 μg tetrodotoxin was administered subcutaneously twice daily for 4 days in a heterogeneous cohort of patients with persistent pain despite opioids and other analgesics. “Responder” was defined as mean reduction of 30% or more in pain intensity from baseline, and “clinical responder” as some pain reduction, but less than 30%, plus agreement on the part of both the patient and the physician that a meaningful analgesic response to treatment had occurred.

Results: Of 45 patients who entered the longitudinal trial, 41 had sufficient data for analysis. Of all 45 patients, 21 (47%) met the criteria for “responder” [16 patients (36%)] or “clinical responder” [5 patients (11%)]. Onset of pain relief was typically cumulative over days, and after drug administration ended (end of day 4), the analgesic effect subsided over the course of a few weeks. No evidence of loss of analgesic effect was observed during subsequent treatments (in total, 2526 patient–days), or a maximum of 400 days in 1 patient). One patient withdrew from the study because of adverse events. Toxicity was usually mild (82%) or moderate (13%), and remained so through subsequent treatment cycles, with no evidence of cumulative toxicity or tolerance.

Conclusions: Long-term treatment with tetrodotoxin is associated with acceptable toxicity and resulted in a sustained analgesic effect in just slightly fewer than half of all study patients. After treatment with this agent twice daily for 4 days, followed by careful monitoring, relief of cancer pain persisted; the analgesic effect wore off over the course of weeks. The drug is adequately tolerated; almost all treatment-related adverse events were mild-to-moderate in severity, and there was no evidence of cumulative toxicity. Further study of tetrodotoxin for moderate-to-severe cancer pain is warranted.

Defining the Elements for Successful Implementation of A Small-City Radiotherapy Department

P.S. Craighead MD and P. Dunscombe PHD. Tom Baker Cancer Centre and Medical Physics, Tom Baker Cancer Centre; Cancer Care, Alberta Health Services; and Department of Oncology, University of Calgary, Calgary, Alberta.

KEY WORDS

Qualitative research, radiotherapy, access

URL www.current-oncology.com/index.php/oncology/article/view/741/

E-JOURNAL LINKED ABSTRACT

Aims: Distributed cancer care delivery models have been introduced to bring care closer to home, providing better access to cancer patients needing radiotherapy. Very little work has been done to demonstrate the elements critical for success in implementing a non-centralized approach. Our study was intended to validate the elements important for implementing radiotherapy away from large cities.

Methods and Results: This qualitative research project consisted of two separate components. The first component used a structured interview format with 5 external experts. Input on the expert responses was also requested from internal leaders in Alberta within the medical physics, radiation therapy, and radiation oncology disciplines. These interviews led to the development of a proposed template of the elements needed for a small-city department. The validity of all elements was tested by surveying the staff members of the radiation treatment program in Calgary, a process that allowed for the definition of the resources needed for the proposed department in Lethbridge. Seventy-five staff members contributed to the survey. Elements identified by the experts were also validated by staff, including the importance of transparent connections between tertiary and smaller centres; the essence of balancing complexity of care with access to quality when starting small-city departments; the location and size of departments being a driver for that discussion: and the relevance of training future staff and of retaining current staff.

Conclusions: By using a qualitative research method, we were able to define important elements for a small city radiotherapy department and to validate those elements with a large cohort of staff working in a tertiary centre. This work allowed us to influence the planning of a small-city department in Lethbridge, emphasizing the importance of the elements identified to the service planners. We await the completion of the construction project and the opening of the centre so that we can re-evaluate whether these elements turn out to be as important as suggested. We recommend such an approach to jurisdictions considering a devolution of radiotherapy services.

Cord Stem-Cell Transplantation in Ontario: Do We Need a Public Bank?

A. Gassas MBCHB MSC. Division of Hematology/ Oncology/ Blood and Marrow Transplantation, Hospital for Sick Children, University of Toronto, Toronto, Ontario.

KEY WORDS

Cord stem-cell transplantation, public cord banking, private cord banking, children, Ontario

URL www.current-oncology.com/index.php/oncology/article/view/742/

E-JOURNAL LINKED ABSTRACT

It has been 21 years since the first successful use of umbilical cord blood (ucb) as a source of donor cells for hematopoietic stem cell transplantation. These years marked the success of cord blood transplantation (cbt) as an effective modality in the treatment of children and adults with hematologic malignancies, marrow failure, immunodeficiencies, hemoglobinopathies, and inherited metabolic diseases. Furthermore, transplantation without full human leukocyte antigen matching is possible, and despite a lower incidence of graft-versus-host disease, graft-versus-leukemia effect is preserved. More than 20,000 cbts have been performed worldwide. Ontario is the most populated province in Canada, and cbt numbers have increased dramatically in recent years. Most of the necessary ucb units are purchased from international registries; there is no public cord bank in Ontario. Given the increasing demand for cbt for children and adults who would otherwise have no suitable donors, donating cords to a public bank is the ideal option, especially when parents are not considering banking their child’s cord privately. The Society of Obstetricians and Gynaecologists of Canada produced a detailed paper on cord blood banking in support of altruistic donation but against private banking for autologous use. Documents from the United Kingdom and the United States include references to the odds against a child requiring an autologous transplant as being between 1 in 1000 and 1 in 200,000; however, private cord banking may be crucial for some families who have a genetic disease or an unusual cancer gene so that they can bank the cords of their healthy children for potential future use for an ill sibling. Nonetheless, donating a cord to a public bank is always indicated and will help to increase cord availability—in particular, for ethnic minorities— because the main advantage of the ucb approach is the potential to assist, in a noninvasive manner, members of ethnic groups that are underrepresented in the adult unrelated donor pool. Ontario has the largest number of live births in Canada (approximately 40% of total Canadian live births per year), but there is no option for public cord banking, and cords when not banked privately are wasted. This brief review discusses the pros and cons of private and public cord banking, and also the benefits of establishing a public “mini” or “junior” cord bank within an already established facility in Ontario.

Canadian Recommendations for the Treatment of Recurrent or Progressive Glioblastoma Multiforme

J.C. Easaw MD PhD, W.P. Mason MD, J. Perry MD, N. Laperrière MD, D.D. Eisenstat MD MA, R. Del Maestro MD PhD, K. Bélanger MD, D. Fulton MD, and D. Macdonald MD for the Department of Oncology, Tom Baker Cancer Centre and the University of Calgary, Calgary, and Department of Medicine, Cross Cancer Institute, and University of Alberta, Edmonton, Alberta; CancerCare Manitoba, Manitoba Institute of Cell Biology, and Departments of Pediatrics, of Anatomy, and of Ophthalmology, University of Manitoba, Winnipeg, Manitoba; Departments of Radiation Oncology and of Medicine, and Crolla Family Brain Tumor Research Centre, University of Toronto, and Princess Margaret Hospital, Toronto, and Department of Medicine, London Regional Cancer Center, and University of Western Ontario, London, Ontario; Departments of Neurology and Neurosurgery and of Oncology, McGill University, and Brain Tumor Research Centre, Montreal Neurological Institute and Hospital, Montreal, Quebec, Centre Hospitalier de l’Université de Montréal Hemalology/Medical Oncology Professeur de Clinique, and Hôpital Notre-Dame, Montréal, Quebec.

KEY WORDS

Glioblastoma multiforme, guidelines, pseudoprogression, re-irradiation, re-operation, chemotherapy, recurrence, progression

URL www.current-oncology.com/index.php/oncology/article/view/755/

E-JOURNAL LINKED ABSTRACT

Given existing clinical equipoise regarding the management of recurrent and progressive glioblastoma multiforme, we reviewed the literature to create a set of recommendations to guide Canadian practice.

Recommendation 1 – Multidisciplinary Approach: The management of patients with recurrent glioblastoma should be individualized and should involve a multidisciplinary team approach, including neurosurgery, neuropathology, radiation oncology, neurooncology, and allied health professionals to optimize treatment outcomes.

Recommendation 2 – Imaging: The standard imaging modality for the assessment of recurrent glioblastoma is Gd-enhanced magnetic resonance imaging (mri). Assessment of tumour recurrence accord with the rano (Response Assessment in Neuro-Oncology) criteria. The optimal timing and frequency of mri after chemoradiation and adjunctive therapy have not been established.

Recommendation 3 – Pseudoprogression: Progression observed by mri after chemoradiation can be pseudoprogression. Accordingly, treated patients should not be classified as having progressive disease by Gd-enhancing mri within the first 12 weeks after the end of radiotherapy unless new enhancement is observed outside the radiotherapy field or viable tumour is confirmed by pathology at the time of a required reoperation. Adjuvant temozolomide should be continued, and follow-up imaging obtained.

Recommendation 4 – Repeat Surgery: Surgery can play a role in providing symptom relief and confirming tumour recurrence, pseudoprogression, or radiation necrosis. However, it is essential to clearly define the treatment goals and the impact on prognosis and patient quality of life before surgical intervention is undertaken. In the absence of level 1 evidence, the decision to reoperate should be made according to individual circumstances, in consultation with the multidisciplinary team and the patient.

Recommendation 5 – Re-irradiation: Radiation therapy is seldom recommended, but can be considered in carefully selected cases of recurrent glioblastoma.

Recommendation 6 – Systemic Therapy: Clinical trials, when available, should be offered to all eligible patients. In the absence of a trial, systemic therapy may be considered, including temozolomide rechallenge or anti-angiogenic therapy. Combination therapy is still experimental, and the optimal drug combination and sequencing have not been established.

Overall, few level 1 studies are available to guide treatment of recurrent glioblastoma multiforme. Our recommendations are an attempt to summarize the literature and provide direction for physicians who treat this aggressive malignancy.

Radiotherapy for Steroid-Resistant Laryngeal Rosai–Dorfman Disease

D. Toguri MEng, A.V. Louie MD, K. Rizkalla MD, J. Franklin MD, G. Rodrigues MD MSc, and V. Venkatesan MBBS. University of Western Ontario, Schulich School of Medicine and Dentistry; London Regional Cancer Program, Department of Radiation Oncology; and Departments of Pathology and of Otolaryngology— Head and Neck Surgery, London Health Sciences Centre, London, Ontario.

KEY WORDS

Rosai–Dorfman disease, histiocytosis with massive lymphadenopathy, radiotherapy

URL www.current-oncology.com/index.php/oncology/article/view/761/

E-JOURNAL LINKED ABSTRACT

Rosai-Dorfman disease (rdd) is a rare benign lymphoproliferative disorder that occurs in children and, less often, in elderly people, in whom it has a greater tendency for extranodal manifestation. Patients typically present with large bilateral painless cervical lymphadenopathy, with or without fever. A diagnosis of rdd may be made by finding the emperipolesis of leukocytes and concurrent histiocytosis upon pathology examination of a biopsied lesion. In the absence of established guidelines for the management of this condition, various therapeutic modalities are used, including radiotherapy. Radiation dosages and fractionation schedules used in the treatment of rdd are seldom reported. Furthermore, advances in the delivery of external-beam radiation warrant reporting of recent radiotherapeutic approaches to the management of rdd.

In the case reported here, radiotherapy was used to put steroid-refractory glottic and subglottic Rosai–Dorfman lesions causing stridor and exertional dyspnea in a 92-year-old woman into complete remission, with minimal side effects. The chosen treatment of 25 Gy in 10 fractions, with a boost of 5 Gy to the gross tumour volume in 2 fractions, was delivered using 3-dimensional conformal externalbeam radiotherapy with posterior–anterior, right and left oblique and lateral beams.

The prescribed treatment was well tolerated, with minimal acute toxicity: mild dysphagia and fatigue. Neither a pureed diet nor analgesics were required, and no acute skin toxicity occurred. One week after treatment, fibre-optic examination revealed mild erythema of the laryngeal mucosa and thickened secretions, with complete resolution of the patient’s airway symptoms. One year post radiotherapy, the patient underwent head-and-neck computed tomography, which was negative for lesions in the sites previously affected. Follow-up continued for 2 years without any clinical or radiologic findings suggestive of local recurrence.

A multi-disciplinary approach to the management of primary and recurrent rdd lesions is required to provide good local control and functional results for each individual patient. Reporting of future cases treated with radiotherapy should include detailed descriptions of treatment dose, fractionation, technique, toxicity, and outcome so as to provide clinicians with reliable data on which to base future treatment decisions.

Impact of Tumour Volume on The Potential Efficacy of Therapeutic Vaccines

J.L. Gulley MD PhD, R.A. Madan MD, and J. Schlom PhD. Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, U.S.A.

KEY WORDS

Cancer vaccine, immunotherapy, overall survival, Prostvac, TroVax, Stimuvax

URL www.current-oncology.com/index.php/oncology/article/view/783/

E-JOURNAL LINKED ABSTRACT

With the recent approval by the U.S. Food and Drug Administration (fda) of the first therapeutic vaccine for cancer, the long-awaited goal of harnessing a patient’s immune system to attack cancer is finally realized. However, as researchers in the field of cancer immunotherapy continue to perform randomized definitive studies, much remains to be learned about potential surrogate endpoints and appropriate patient populations for therapeutic vaccines. Multiple randomized immunotherapy studies have suggested limited or no improvement in time to progression, but statistically significant and clinically meaningful improvements in overall survival. Recent examples include randomized phase iii studies of two fda- approved therapies—sipuleucel-T (an autologous cellular therapeutic vaccine targeting pap) and ipilimumab (an anti-CTLA4 monoclonal antibody that takes the “brakes” off the immune system)—and a randomized phase ii study of Prostvac [a poxviral therapeutic vaccine (Bavarian Nordic Immuno-therapeutics, Mountain View, CA, U.S.A.) targeting prostate-specific antigen and containing multiple T-cell costimulatory molecules]. The results of these studies suggest that the kinetics of a clinical response after immunotherapy are substantially different from those after conventional therapy. One biologically plausible hypothesis is that the tumour growth rate undergoes sustained delay—a model that fits the kinetics of a persistent antitumour immune response. If this hypothesis is correct and the clinically significant immune response is maintained, then starting treatment earlier in the course of disease, when total tumour burden is lower, should lead to an earlier sustained divergence from the original growth rate and a greatly improved therapeutic effect.

In addition, larger tumour burdens are associated with negative immune regulatory factors, decreasing the likelihood of a response in those settings. Large tumours often secrete immunosup-pressive cytokines such as transforming growth factor β and interleukin 10, and harbour multiple cells capable of negatively regulating the immune system, such as T-regulatory cells and myeloid- derived suppressor cells. Indoleamine 2,3-dioxy-genase in tumours leads to tryptophan depletion and subsequent functional impairment of immune cells within the tumour microenvironment.

This review addresses available data from clinical trials of immunotherapeutic agents relevant to the selection of appropriate patient populations. The studies reviewed offer several discrete insights, but the weight of collective evidence overwhelmingly supports the use of immunotherapy earlier in the disease course or in patients with less aggressive disease (or both). These findings have important implications for the design of clinical trials of immunotherapeutic agents as monotherapy.