Search

Objective The purpose of this guideline is to provide guidance on appropriate management of satellite and in-transit metastasis (itm) from melanoma. Methods The guideline was developed by the Program in Evidence-Based Care (pebc) of Ontario Health (Cancer Care Ontario) and the Melanoma Disease Site Group. Recommendations were drafted by a Working Group based on a systematic review of publications in the medline and embase databases. The document underwent patient- and caregiver-specific consultation and was circulated to the Melanoma Disease Site Group and the pebc Report Approval Panel for internal review; the revised document underwent external review. Recommendations "Minimal itm" is defined as lesions in a location with limited spread (generally 1-4 lesions); the lesions are generally superficial, often clustered together, and surgically resectable. "Moderate itm" is defined as more than 5 lesions covering a wider area, or the rapid development (within weeks) of new in-transit lesions. "Maximal itm" is defined as large-volume disease with multiple (>15-20) 2-3 cm nodules or subcutaneous or deeper lesions over a wide area. ■ In patients presenting with minimal itm, complete surgical excision with negative pathologic margins is recommended. In addition to complete surgical resection, adjuvant treatment may be considered. ■ In patients presenting with moderate unresectable itm, consider using this approach for localized treatment: intralesional interleukin 2 or talimogene laherparepvec as 1st choice, topical diphenylcyclopropenone as 2nd choice, or radiation therapy as 3rd choice. Evidence is insufficient to recommend intralesional bacille Calmette-Guérin or CO2 laser ablation outside of a research setting. ■ In patients presenting with maximal itm confined to an extremity, isolated limb perfusion, isolated limb infusion, or systemic therapy may be considered. In extremely select cases, amputation could be considered as a final option in patients without systemic disease after discussion at a multidisciplinary case conference. ■ In cases in which local, regional, or surgical treatments for itm might be ineffective or unable to be performed, or if a patient has systemic metastases at the same time, systemic therapy may be considered. [ABSTRACT FROM AUTHOR]

Background Previous versions of the guideline from the Program in Evidence-Based Care (pebc) at Ontario Health (Cancer Care Ontario) recommended that the use of high-dose interferon alfa 2b therapy be discussed and offered to patients with resected cutaneous melanoma with a high risk of recurrence. Subsequently, several clinical trials in patients with resected or metastatic melanoma found that immune checkpoint inhibitors and targeted therapies have a benefit greater than that with interferon. It was therefore considered timely for an update to the guideline about adjuvant systemic therapy in melanoma. Methods The present guideline was developed by the pebc and the Melanoma Disease Site Group (dsg). Based on a systematic review from a literature search conducted using medline, embase, and the Evidence Based Medicine Reviews databases for the period 1996 to 28 May 2019, the Working Group drafted recommendations. The systematic review and recommendations were then circulated to the Melanoma dsg and the pebc Report Approval Panel for internal review; the revised document underwent external review. Recommendations For patients with completely resected cutaneous or mucosal melanoma with a high risk of recurrence, the recommended adjuvant therapies are nivolumab, pembrolizumab, or dabrafenib-trametinib for patients with BRAF V600E or V600K mutations; nivolumab or pembrolizumab are recommend for patients with BRAF wildtype disease. Use of ipilimumab is not recommended. Molecular testing should be conducted to help guide treatment decisions. Interferon alfa, chemotherapy regimens, vaccines, levamisole, bevacizumab, bacillus Calmette-Guérin, and isolated limb perfusion are not recommended for adjuvant treatment of cutaneous melanoma except as part of a clinical trial. [ABSTRACT FROM AUTHOR]

Background For patients who are diagnosed with early-stage cutaneous melanoma, the principal therapy is wide surgical excision of the primary tumour and assessment of lymph nodes. The purpose of the present guideline was to update the 2010 Cancer Care Ontario guideline on wide local excision margins and sentinel lymph node biopsy (SLNB), including treatment of the positive sentinel node, for melanomas of the trunk, extremities, and head and neck. Methods Using Ovid, the medline and embase electronic databases were systematically searched for systematic reviews and primary literature evaluating narrow compared with wide excision margins and the use of SLNB for melanoma of the truck and extremities and of the head and neck. Search timelines ran from 2010 through week 25 of 2017. Results Four systematic reviews were chosen for inclusion in the evidence base. Where systematic reviews were available, the search of the primary literature was conducted starting from the end date of the search in the reviews. Where systematic reviews were absent, the search for primary literature ran from 2010 forward. Of 1213 primary studies identified, 8 met the inclusion criteria. Two randomized controlled trials were used to inform the recommendation on completion lymph node dissection. Key updated recommendations include: ■ Wide local excision margins should be 2 cm for melanomas of the trunk, extremities, and head and neck that exceed 2 mm in depth. ■ SLNB should be offered to patients with melanomas of the trunk, extremities, and head and neck that exceed 0.8 mm in depth. ■ Patients with sentinel node metastasis should be considered for nodal observation with ultrasonography rather than for completion lymph node dissection. Conclusions Recommendations for primary excision margins, sentinel lymph node biopsy, and completion lymph node dissection in patients with cutaneous melanoma have been updated based on the current literature. [ABSTRACT FROM AUTHOR]

Background In Canada, requests for public reimbursement of cancer drugs are predominately initiated by pharmaceutical manufacturers. Clinician-led submissions provide a mechanism to initiate the drug funding process when industry does not submit a request for funding consideration. Although such requests are resource-intensive to produce, Cancer Care Ontario (cco) has the capacity to facilitate clinician-led submissions. In 2014, cco began developing a cancer drug prioritization framework that allocates resources to systematically address a growing number of clinician-identified funding gaps with clinician-led submissions. Methods Cancer site-specific drug advisory committees established by cco consist of health care practitioners whose roles include identifying and prioritizing funding gaps. The committees submit their identified gaps to a cross-cancer-site prioritization exercise in which the requests are ranked based on a set of guiding principles derived from health technology assessment. The requests are then sequentially allocated the resources needed to meet submission requirements. Whether the funding gap is of provincial or pan-Canadian relevance determines where the submission is filed for assessment. Results Since its inception, the cco framework has identified 17 funding gaps in 9 cancer sites. In 4 prioritizations, the framework supported 6 submissions. As of June 2018, the framework had contributed to the eventual funding of more than 9 new drug-indication pairs, with more awaiting funding consideration. Conclusions The cco prioritization framework has enabled clinicians to effectively and systematically identify, prioritize, and fill funding gaps not addressed by industry. Ultimately, the framework helps to ensure that patients can access evidence-informed and cost-effective therapies. The framework will continue to evolve as it encounters new challenges, including funding requests for rare indications. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors have revolutionized care for many cancer indications, with considerable effort now being focused on increasing the rate, depth, and duration of patient response. One strategy is to combine immune strategies (for example, ctla-4 and PD-1/L1-directed agents) to harness additive or synergistic efficacy while minimizing toxicity. Despite encouraging results with such combinations in multiple tumour types, numerous clinical challenges remain, including a lack of biomarkers that reliably predict outcome, the emergence of therapeutic resistance, and optimal management of immune-related toxicities. Furthermore, the selection of ideal combinations from the myriad of immune, systemic, and locoregional therapies has yet to be determined. A longitudinal network-based approach could offer advantages in addressing those critical questions, including long-term follow-up of patients beyond individual trials. The molecular cancer registry Personalize My Treatment, managed by the Networks of Centres of Excellence nonprofit organization Exactis Innovation, is uniquely positioned to accelerate Canadian immuno-oncology (io) research efforts throughout its national network of cancer sites. To gain deeper insight into how a pan-Canadian network could advance research in io combinations, Exactis invited preeminent clinical and scientific advisors from across Canada to a roundtable event in November 2017. The present white paper captures the expert advice provided: leverage longitudinal patient data collection; facilitate network collaboration and assay harmonization; synergize with existing initiatives, networks, and biobanks; and develop an io combination trial based on Canadian discoveries. [ABSTRACT FROM AUTHOR]

Objective The purpose of the present work was to develop evidence-based indications for Mohs micrographic surgery in patients with a diagnosis of skin cancer. Methods The guideline was developed by Cancer Care Ontario’s Program in Evidence-Based Care, together with the Melanoma Disease Site Group and the Surgical Oncology Program, through a systematic review of relevant literature, patient- and caregiver-specific consultation, and internal and external reviews. Recommendation 1 Given a lack of high-quality, comparative evidence, surgery (with postoperative or intraoperative margin assessment) or radiation (for those who are ineligible for surgery) should remain the standard of care for patients with skin cancer. Recommendation 2 Mohs micrographic surgery is recommended for patients with histologically confirmed recurrent basal cell carcinoma of the face and is appropriate for primary basal cell carcinomas of the face that are larger than 1 cm, have aggressive histology, or are located on the H zone of the face. Recommendation 3 Mohs micrographic surgery should be performed by physicians who have completed a degree in medicine or equivalent, including a Royal College of Physicians and Surgeons of Canada Specialist Certificate or equivalent, and have received advanced training in Mohs micrographic surgery. [ABSTRACT FROM AUTHOR]

Background Although high-dose interferon (hd-ifn) is the sole approved adjuvant systemic treatment for melanoma in many jurisdictions, it is toxic. We sought to assess the population-level effects of hd-ifn toxicity, particularly neuropsychiatric toxicity, hypothesizing that such toxicity would have the greatest effect on mental health services use in advanced resected melanoma. Methods This retrospective population-based registry study considered all melanoma patients receiving adjuvant hd-ifn in Ontario during 2008-2012. Toxicity was investigated through health services use compatible with hd-ifn toxicity (for example, mental health physician billings). Using stage data reported from cancer centres about a subset of patients (stages iib-iiic), a propensity-matched analysis compared such service use in patients who did and did not receive hd-ifn. Associations between early hd-ifn discontinuation and health services use were examined. Results Of 718 melanoma patients who received hd-ifn, 12% were 65 years of age and older, and 83% had few or no comorbidities. One third of the patients experienced 1 or more toxicity-associated health care utilization events within 1 year of starting hd-ifn. Of 420 utilization events, 364 (87%) were mental health-related, with 54% being family practitioner visits, and 39% being psychiatrist visits. In the propensity-matched analysis, patients receiving hd-ifn were more likely than untreated matched controls to use a mental health service (p = 0.01), with 42% of the control group and 51% of the hd-ifn group using a mental health service in the period spanning the 12 months before to the 24 months after diagnosis. In the multivariable analysis, early drug discontinuation was more likely in the presence of pre-existing mental health issues (odds ratio: 2.0; 95% confidence limits: 1.1, 3.4). Conclusions Stage iib-iiic melanoma patients carry a substantial burden of mental health services use whether or not receiving hd-ifn, highlighting an important survivorship issue for these patients. High-dose interferon is associated with more use of mental health services, and pre-treatment use of mental health services is associated with treatment discontinuation. That association should be kept in mind when hd-ifn is being considered. [ABSTRACT FROM AUTHOR]

Background: This systematic review was completed by the Exercise for People with Cancer Guideline Development Group, a group organized by Cancer Care Ontario's Program in Evidence-Based Care (pebc). It provides background and guidance for clinicians with respect to exercise for people living with cancer in active and post treatment. It focuses on the benefits of specific types of exercise, pre-screening requirements for new referrals, safety concerns, and delivery models. Methods: Using the pebc's standardized approach, MEDLINE and embase were systematically searched for existing guidelines, systematic reviews, and primary literature. Results: The search identified two guidelines, eighteen systematic reviews, and twenty-nine randomized controlled trials with relevance to the topic. The present review provides conclusions about the duration, frequency, and intensity of exercise appropriate for people living with cancer. Conclusions: The evidence shows that exercise is safe and provides benefit in quality of life and in muscular and aerobic fitness for people with cancer both during and after treatment. The evidence is sufficient to support the promotion of exercise for adults with cancer, and some evidence supports the promotion of exercise in group or supervised settings and for a long period of time to improve quality of life and muscular and aerobic fitness. Exercise at moderate intensities could also be sustainable for longer periods and could encourage exercise to be continued over an individual's lifetime. It is important that a pre-screening assessment be conducted to evaluate the effects of disease, treatments, and comorbidities. [ABSTRACT FROM AUTHOR]

Background The use and detailed costs of services provided for people with advanced melanoma (AMEL) are not well known. We conducted an analysis to determine the use of health care services and the associated costs delineated by relevant attributable costs, which we defined for subjects in the province of Ontario. Methods Through the Ontario Cancer Data Linkage Project, a cohort of AMEL patients with diagnoses between 31 August 2005 and 2012 (follow-up to 2013) and with valid International Classification of Diseases (9th revision, Clinical Modification) 172 codes and histology codes was identified. A cohort of individuals with AMEL having a combination of at least 1 palliative, 1 medical oncology, and 1 hospitalization code was generated. The health system services used by this population were clustered into hospitalization, palliation, physician medical visits, medication, homecare, laboratory, diagnostics, and other resources. Overall rates of use and disaggregated costs were determined by phase of care for the entire cohort. Results The mean age for the 2748 individuals in the cohort was 67 years. The greater proportion of the patients were men (65.6%) and were more than 65 years of age (>50%). In this advanced cohort, fewer than 45% of patients were alive 3 years after the malignant melanoma diagnosis. The average annual cost per patient over the time horizon was $6,551. At $15,830, year 1 after diagnosis was the most expensive, followed by year 2, at $8,166. Conclusions Our data provide a baseline for the costs associated with AMEL treatment. Future studies will include newer agents and comparative effectiveness research for personalized therapies. [ABSTRACT FROM AUTHOR]

Background Development of this guideline was undertaken by the Exercise for People with Cancer Guideline Development Group, a group organized by Cancer Care Ontario's Program in Evidence-Based Care (PEBC). The purpose of the guideline was to provide guidance for clinicians with respect to exercise for patients living with cancer, focusing on the benefits of specific types of exercise, recommendations about screening requirements for new referrals, and safety concerns. Methods Consistent with the pebc's standardized approach, a systematic search was conducted for existing guidelines, and systematic literature searches were performed in medline and embase for both systematic reviews and primary literature. Content and methodology experts performed an internal review, which was followed by an external review by targeted experts and intended users. Results The search identified three guidelines, eighteen systematic reviews, and twenty-nine randomized controlled trials with relevance to the topic. The present guideline provides recommendations for the duration, frequency, and intensity of exercise appropriate for people living with cancer. It also provides recommendations for pre-exercise assessment, safety concerns, and delivery models. Conclusions There is sufficient evidence to show that exercise provides benefits in quality of life and muscular and aerobic fitness for people with cancer both during and after treatment, and that it does not cause harm. The present guideline is intended to support the Canadian Society for Exercise Physiology's Canadian physical activity guidelines. The recommendations are intended for clinicians and institutions treating cancer patients in Ontario, and for policymakers and program planners involved in the delivery of exercise programs for cancer patients. [ABSTRACT FROM AUTHOR]

Background Detailed epidemiology for patients with advanced metastatic melanoma in Canada is not well characterized. We conducted an analysis of patients with this disease in the province of Ontario, with the aim being to study the presentation, disease characteristics and course, and treatment patterns for malignant melanoma. Methods In this Canadian observational prospective and retrospective study of patients with malignant melanoma, we used data collected in the Canadian Melanoma Research Network (CMRN) Patient Registry. We identified patients who were seen at 1 of 3 cancer treatment centres between April 2011 and 30 April 2013. Patient data from 2011 and 2012 were collected retrospectively using chart records and existing registry data. Starting January 2013, data were collected prospectively. Variables investigated included age, sex, initial stage, histology, mutation type, time to recurrence, sites of metastases, resectability, and previous therapies. Results A cohort of 810 patients with melanoma was identified from the CMRN registry. Mean age was 58.7 years, and most patients were men (60% vs. 40%). Factors affecting survival included unresectable or metastatic melanoma, initial stage at diagnosis, presence of brain metastasis, and BRAF mutation status. The proportion of surviving patients decreased with higher initial disease stages. Conclusions Using registry data, we were able to determine the detailed epidemiology of patients with melanoma in the Canadian province of Ontario, validating the comprehensive and detailed information that can be obtained from registry data. [ABSTRACT FROM AUTHOR]

Questions: What is the role of biochemotherapy in the treatment of metastatic malignant melanoma?What are the adverse effects and effects on quality of life of biochemotherapy as a treatment option?For the purposes of this report, "biochemotherapy" is defined as a therapeutic regimen that includes, at a minimum, chemotherapy (either single-agent or combination) and interleukin-2., Perspectives: Although early detection, appropriate surgery, and in some cases adjuvant therapy have improved outcomes, at least one third of patients with early-stage melanoma will develop metastases. Recently, in an effort to potentially maximize outcomes, the combination of chemotherapy and immunotherapy (biochemotherapy) was evaluated. The level of interest that this approach has generated, particularly with regard to the apparently high response rates seen in this otherwise devastating illness, was sufficient to merit closer examination by the Melanoma Disease Site Group (dsg) of Cancer Care Ontario's Program in Evidence-based Care (pebc)., Outcomes: Outcomes of interest include response rate, diseasefree survival, overall survival, quality of life, and incidence of grades 3 and 4 toxicities., Methodology: Evidence was selected and reviewed by three members of the pebc's Melanoma dsg and by two methodologists. The present practice guideline report was reviewed and approved by the Melanoma dsg, which comprises medical and radiation oncologists, surgeons, and dermatologists. External review by Ontario practitioners was obtained through a mailed survey, the results of which were incorporated into the practice guideline. Final approval of the original guideline report was obtained from the pebc's Report Approval Panel., Results: Clinical recommendations were drafted based on the evidence identified through a systematic review. The practice guideline report with draft recommendations was mailed to Ontario practitioners for external review and to the Report Approval Panel. Feedback from both groups was incorporated into this report to create the final practice guideline., Practice Guideline: The recommendations that follow apply to adult patients with metastatic malignant melanoma. Because of the inconsistent results of the available studies with regard to benefit (response, time to progression, and survival) and consistently high toxicity rates, biochemotherapy is not recommended for the treatment of metastatic melanoma.

Questions: What is the role of single-agent temozolomide in the treatment of patients with metastatic melanoma? In comparison with single-agent temozolomide, does the addition of interferon-alpha to temozolomide improve disease-free survival, overall survival, or response rates? In comparison with single-agent temozolomide, does the addition of thalidomide to temozolomide improve disease-free survival, overall survival, or response rates?, Perspectives: Because of its oral route of administration and its ability to cross the blood-brain barrier, temozolomide is a potentially attractive chemotherapy agent for adult patients with unresectable metastatic malignant melanoma. To provide treatment recommendations for this new agent, the Melanoma Disease Site Group (dsg) of Cancer Care Ontario's Program in Evidence-Based Care (pebc) decided to review the available literature on single-agent temozolomide and on temozolomide in combination with interferon-alpha or thalidomide., Outcomes: Outcomes of interest included response rates, disease-free survival, overall survival, quality of life, and adverse effects., Methodology: Evidence was selected and reviewed by two members of the Melanoma dsg and by methodologists. The present practice guideline report was reviewed and approved by the Melanoma dsg, which comprises medical and radiation oncologists, surgeons, and dermatologists. External review was obtained through a mailed survey of Ontario practitioners, the results of which were reflected in revisions to the practice guideline. Final approval of the guideline report was obtained from the Report Approval Panel of the pbec., Practice Guideline: These recommendations apply to adult patients with unresectable metastatic malignant melanoma. It is reasonable to use temozolomide at a dose of 200 mg/m(2) orally for 5 days every 4 weeks as initial systemic treatment for patients with unresectable metastatic malignant melanoma. The addition of moderate-dose interferon-alpha 2b has produced a significantly higher response rate than has single-agent temozolomide in a large randomized phase iii study. However, overall survival was not altered, and grades 3 and 4 hematologic toxicities were higher with the combined treatment. At the present time, the addition of interferon-alpha to temozolomide is not recommended. One randomized phase ii study and six other phase ii studies showed encouraging response rates when thalidomide was combined with temozolomide. However, the doses and schedules of temozolomide in those studies differed from the conventionally prescribed doses and schedules. It is not clear whether the improved response rates were attributable to the small number of patients in the studies, the different temozolomide doses and schedules, or the addition of thalidomide. Further phase iii studies are required to confirm whether a benefit is associated with the combination of temozolomide and thalidomide. Therefore, at this time, it is not recommended that thalidomide be combined with temozolomide., Qualifying Statements: Dacarbazine is the only chemotherapy drug currently approved for the treatment of metastatic malignant melanoma. In large randomized trials, response rates with dacarbazine ranged from 6% to 15%. Almost all responses were partial, with a median response duration of only 7-8 months. Given these disappointing overall results, the consensus among most physicians who are treating patients with metastatic malignant melanoma is that recommending more convenient treatment or experimental treatment to these patients is appropriate. Because of oral dosing, temozolomide is a reasonable choice, particularly for patients who would have difficulty traveling to cancer centres for intravenous chemotherapy. Temozolomide has demonstrated efficacy equal to that of dacarbazine in a randomized phase iii trial. However, unlike dacarbazine, temozolomide is a convenient oral treatment that penetrates the blood-brain barrier and that has shown activity against brain metastases. Although surgery is the preferred treatment modality for patients with solitary brain metastases from melanoma, temozolomide is the preferred chemotherapy for patients with brain metastases who require systemic treatment.

Questions: What is the role of single-agent interleukin-2 (il-2) in the treatment of adults with metastatic melanoma? If there is a role for single-agent il-2, what patient population can appropriately be considered for treatment? If there is a role for single-agent il-2, what dose and schedule are appropriate? What are the toxicities associated with il-2?, Perspectives: Many agents have been investigated for antitumour activity in melanoma, but few have shown promising response rates. Early detection, appropriate surgery, and adjuvant therapy have all improved outcomes, but approximately one third of patients with early-stage disease will nevertheless develop metastases. Single-agent il-2 has attracted much attention over the past several years. A number of randomized trials and many phase ii trials investigating single-agent il-2 suggest that this systemic treatment produces durable responses in melanoma patients. Given the dismal survival of patients with meta-static melanoma and the limited availability of effective treatments, the Melanoma Disease Site Group (dsg) of Cancer Care Ontario's Program in Evidence-Based Care (pebc) felt that the durable responses seen with il-2 treatment warranted closer examination., Outcomes: Primary outcomes of interest included objective response rate, complete response rate, duration of response, toxicity, and quality of life. Secondary outcomes of interest included progression-free survival and overall survival., Methodology: A systematic review was developed, and clinical recommendations relevant to patients in Ontario were drafted. The practice guideline report was reviewed and approved by the Melanoma dsg, which comprises medical oncologists, surgeons, and dermatologists. External review by Ontario practitioners was obtained through a mailed survey, the results of which were incorporated into the practice guideline. Final review and approval of the practice guideline was obtained from the pebc's Report Approval Panel., Results: The present practice guideline reflects the integration of the draft recommendations based on a systematic review of the available evidence with the feedback obtained from external review by practitioners and the Report Approval Panel., Practice Guideline: No studies have compared il-2 to the current standard of care-dacarbazine (dtic)-or to placebo in the treatment of metastatic melanoma. After reviewing and weighing the evidence that does exist, the opinion of the Melanoma dsg is that high-dose il-2 is a reasonable treatment option for a select group of patients with metastatic melanoma: Patients should have a good performance status (Eastern Cooperative Oncology Group 0-1) and a normal lactate dehydrogenase level.Patients should have fewer than three organs involved or have cutaneous and/or subcutaneous metastases only, and no evidence of central nervous system metastases should be present.In this select group of patients, il-2 treatment can produce durable complete remissions. High-dose il-2 is recommended to be given at 600,000 IU/kg per dose, delivered intravenously over 15 minutes, every 8 hours, for a maximum of 14 doses. High-dose il-2 delivery is recommended to be done in a tertiary-care facility by staff trained in the provision of this treatment and with appropriate monitoring. To facilitate treatment and to develop expertise in this therapeutic modality, the dsg recommends that high-dose il-2 programs be established in one or two centres in Ontario., Qualifying Statements: High-dose il-2 has response rates that are similar to those seen with standard chemotherapy. However, unlike chemotherapy, il-2 demonstrates low but durable complete response rates that may lead to years of benefit for patients with metastatic melanoma. Based on the available data assessing prognostic factors and patient selection, patients with non-visceral metastases and fewer metastatic sites have a much higher response rate. In these select patients, high dose il-2 may be considered for first-line therapy. The lack of large randomized trials comparing il-2 to dtic or other chemotherapy means that recommendations for this guideline are based largely on phase ii data and limited phase iii data. Further randomized data will not soon become available, because no randomized trials are currently ongoing or planned. Interleukin-2 is currently widely used in the United States, and it is an approved therapy in both Canada and the United States.