Management of uveal melanoma: a consensus-based provincial clinical practice guideline

Practice Guideline

Management of uveal melanoma: a consensus-based provincial clinical practice guideline


E. Weis, MD MPH*,, T.G. Salopek, MD, J.G. McKinnon, MD§, M.P. Larocque, PhD, C. Temple-Oberle, MD MSc§, T. Cheng, MD§, J. McWhae, MD§, R. Sloboda, PhD, M. Shea-Budgell, MSc#

*Department of Ophthalmology and Visual Sciences, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB;
Department of Surgery, Cumming School of Medicine, University of Calgary, Calgary, AB;
Division of Dermatology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB;
§Department of Oncology, Cumming School of Medicine, University of Calgary, Calgary, AB;
Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB;
#Cancer Strategic Clinical Network, Alberta Health Services, Calgary, AB.


doi: http://dx.doi.org/10.3747/co.23.2859


ABSTRACT

Introduction

Survival in uveal melanoma has remained unchanged since the early 1970s. Because outcomes are highly related to the size of the tumour, timely and accurate diagnosis can increase the chance for cure.

Methods

A consensus-based guideline was developed to inform practitioners. PubMed was searched for publications related to this topic. Reference lists of key publications were hand-searched. The National Guidelines Clearinghouse and individual guideline organizations were searched for relevant guidelines. Consensus discussions by a group of content experts from medical, radiation, and surgical oncology were used to formulate the recommendations.

Results

Eighty-four publications, including five existing guidelines, formed the evidence base.

Summary

Key recommendations highlight that, for uveal melanoma and its indeterminate melanocytic lesions in the uveal tract, management is complex and requires experienced specialists with training in ophthalmologic oncology. Staging examinations include serum and radiologic investigations. Large lesions are still most often treated with enucleation, and yet radiotherapy is the most common treatment for tumours that qualify. Adjuvant therapy has yet to demonstrate efficacy in reducing the risk of metastasis, and no systemic therapy clearly improves outcomes in metastatic disease. Where available, enrolment in clinical trials is encouraged for patients with metastatic disease. Highly selected patients might benefit from surgical resection of liver metastases.

KEYWORDS: Uveal melanoma, ocular melanoma, choroidal melanoma, ciliary body melanoma, iris melanoma, melanoma, ophthalmology, practice guidelines

INTRODUCTION

Melanoma of the uveal tract (that is, iris, ciliary body, and choroid), sometimes called “ocular melanoma,” accounts for 5% of all melanomas and occurs at a rate of about 6 cases per million person–years1,2. Nevertheless, melanoma is the most common primary intraocular malignancy, and after the skin, the uveal tract is the 2nd most common location for melanoma2. Risk factors include white race, light eye color, fair skin, cutaneous and iris nevi and freckles, and an inability to tan36. Despite advances in our understanding of the disease, the overall survival (os) rate has not improved since the early 1970s7. The disease-specific mortality rate at 15 years is 45%8, and no successful treatments for metastatic uveal melanoma have been developed to date9.

Factors associated with poor prognosis include large tumour size, tumour location in the ciliary body, intermediate or epithelioid cell type, proximity to the location of the tumour anterior margin, presence of extraocular extension, high mitotic rate, and lymphocytic infiltration1012. Two genetic tests more precisely identify patients with worse prognosis: testing for monosomy 3 and gene-expression profiling (gep). Monosomy 3, with a gain in chromosome 8q, and gep class 2 are associated with 3-year metastasis-free survival rates of 53% and 50% respectively8,13,14; these genetic variations occur in about 50% of patients13,1518. A prospective validation study of gep class 2 showed that, on multivariate analysis, gep class was the only significant factor14. Subsequent work has demonstrated that tumour size (basal dimension) is an independent predictor of survival for gep class 1 and 2 patients alike19.

The management of uveal melanoma is complex and often requires a multidisciplinary team of specialists. No published Canadian guidelines are available to suggest appropriate strategies for the diagnosis, treatment, and follow-up of patients with uveal melanoma. We therefore aimed to develop a consensus-based, evidence-informed guideline for the management of uveal melanoma. The intended readership includes ophthalmologists, oncologists, and family physicians involved in the follow-up care of patients with this disease. For the purposes of the present guideline, other non-uveal ocular melanomas arising in the conjunctiva, the eyelid, and the orbit are not included.

The aim for the guideline was that it address these questions:

  • ■ How should patients with uveal melanoma be staged at baseline?

  • ■ How should uveal melanoma be managed?

  • ■ What follow-up testing is required for uveal melanoma patients?

METHODS

The literature review process for the guideline was developed based on published guidance from the U.K. National Institute for Health and Clinical Excellence20, the Archives of Pediatrics and Adolescent Medicine21, and the agree Collaboration22. With that methodologic foundation, the guideline recommendations were drafted by an ophthalmologist du-ally appointed to the University of Alberta (Edmonton, AB) and the University of Calgary (Calgary, AB) and by a cancer research methodologist. The guideline was then reviewed by an expert panel of surgical oncologists, radiation oncologists, medical oncologists, and dermatologists and was endorsed by the Alberta Cutaneous Tumour Team.

The evidence base for the guideline was informed by a systematic review of the literature. Using the terms “uveal melanoma,” “ocular melanoma,” and “intraocular melanoma,” PubMed was searched (2000 through December 2014) for English-language publications including clinical trials, meta-analyses, and guidelines. Small studies (that is, fewer than 10 patients) and those that did not report outcomes related to the efficacy of treatments or imaging modalities for uveal melanoma were excluded. Reference lists of key publications were also searched for relevant citations. The U.S. National Guidelines Clearinghouse and the Web sites of individual guideline organizations were searched for clinical practice guidelines relevant to the topic. Throughout the review process, authors were allowed to add new publications to the evidence base if they met the original inclusion criteria.

RESULTS

Eighty-four publications formed the basis for the recommendations. Literature was identified for diagnosis and staging, observation, surgery, brachytherapy, transpupillary thermotherapy (ttt), management of metastatic disease, and follow-up. Among the relevant publications were five guidelines from the U.S. National Cancer Institute23, the American Association of Ophthalmic Oncologists and Pathologists24, the Royal College of Ophthalmologists (United Kingdom)25, the Australian Cancer Network26, and the Université catholique de Louvain27. No Canadian guidelines were identified.

DISCUSSION

Diagnosis and Referral

The timely management of uveal melanocytic lesions, including small flat lesions, is vitally important, because any delay in referral of an early melanoma could result in significant growth and subsequent loss of vision, loss of the eye (that is, enucleation), and loss of life because of metastasis. Waiting for observation of growth, even in small melanocytic lesions (≤2 mm thickness) identified as clinically suspicious by an ophthalmologist, can increase the risk of metastasis28,29; such lesions can therefore be offered treatment30.

Because uveal melanoma and indeterminate lesions are complex eye conditions, with diagnoses that are often very difficult for the non-specialist30,31 and because treatment options require the balancing of benefits against complications (that is, risk of observation compared with treatment), international guidelines recommend that patients be provided an evaluation by an eye cancer specialist (that is, ophthalmic oncologist, medical physicist, or radiation oncologist)30 or an ophthalmologist24,25. The provider should be trained in all treatment areas (that is, medical, surgical, radiotherapy, laser therapy, and cancer care) so as to safely follow, discuss, and treat all indeterminate lesions and malignant intraocular lesions.

Ocular ultrasonography (us) can be used to determine tumour size and shape. Orbital or ocular computed tomography (ct) and magnetic resonance imaging (mri) are not commonly used during diagnostic work-up unless other examinations are inconclusive25,31. The differential diagnosis for uveal melanoma includes ephelis, nevus, Lisch nodules, neovascular age-related macular degeneration, congenital hypertrophy of the retinal pigment epithelium, choroidal hemangioma, hemorrhagic detachment of the choroid or retina, melanocytoma, metastasis to the eye from another location, and choroidal osteoma24. Experienced ophthalmologists with a practice focus in oncology are able to diagnose uveal melanoma based predominantly on funduscopy and us (that is, without biopsy) with 98% accuracy32.

Recommendations:

The evaluation and treatment of uveal melanoma and indeterminate intraocular lesions is complex. Observation with subsequent delay in therapy, even in small intraocular malignancies (≤2 mm thickness), can increase in the risk of metastasis. Therefore, all intraocular malignancies and indeterminate lesions should be evaluated by a provider trained in all aspects of care (that is, medical, oncologic, surgical, radiotherapy, laser therapy) to determine appropriate treatment.

Staging

Staging is guided by the American Joint Committee on Cancer system for uveal melanoma10. Staging requires intraocular examination, serum tests, and imaging. Blood work typically consists of complete blood count and liver function tests25. Historically, the most basic baseline imaging for ruling out systemic metastases consisted of plain chest radiography, with abdominal us. However, those tests have since been shown to have low sensitivity33 and have largely been replaced by combined positron-emission tomography (pet)–ct imaging, abdominal mri and chest ct imaging, or ct imaging of chest and abdomen. Whole-body pet-ct imaging has demonstrated good sensitivity (35%–100%) and positive predictive value (88%–100%)3436, and mri has shown the highest sensitivity (67%–92%)36,37.

Controversy surrounds the question whether baseline imaging should be performed in the affected population, because of the premise that metastases cannot be treated and the fact that the yield of positive findings at presentation is low. It should be noted, however, that more than half the affected patients (55%) have abdominal ct findings that require further investigation38, with most being false positives; only 2% of patients have definitive metastasis at staging38. It might therefore be best to clarify the baseline imaging findings early, so as to reduce the challenges of ruling out metastasis at a later date. The treating surgeon should decide on the appropriateness of staging investigations that balance excessive testing with patient stress, additional testing that can arise from false positives, and potentially unnecessary surgery. Patients who demonstrate metastasis at presentation are often spared aggressive treatment of their primary lesion.

Recommendations:

Staging work-up to rule out metastases of uveal melanoma should include serum testing (complete blood count and liver function tests) and diagnostic imaging using one of these schema:

  • ct of chest and abdomen (liver protocol for abdomen)

  • ■ Whole body pet-ct imaging

  • ■ Liver mri and chest ct

If metastasis is suspected, the patient should be referred to a cancer centre.

Primary Management

Observation

Observation is typically reserved for indeterminate lesions, but can be acceptable for rare selected patients with melanoma of the iris and small choroidal melanomas (that is, <3.0 mm apical height and <10.0 mm basal diameter)24. Most patients selected for observation present with a low-grade tumour, have multiple comorbidities, or are at an advanced age and already carry a limited expected survival24.

Risk factors for future growth of indeterminate lesions include tumour thickness greater than 2 mm, subretinal fluid, visual symptoms, orange pigmentation, close proximity to the optic nerve head, absence of drusen, acoustic hollowness on us, and absence of a halo pigmentation pattern3941. If the foregoing risk factors are present, treatment should be considered. Waiting for documented growth of lesions can increase the risk of metastasis by a factor of up to 828, and improved survival has been demonstrated with earlier management29.

The 7th edition of the American Joint Committee on Cancer classification system has demonstrated that tumour size predicts survival42. Furthermore, more recent work has found that, even after controlling for gep, tumour size (that is, basal dimension ≥ 12 mm) is an independent predictor of metastasis at 5 years19. In contrast, several small non-comparative case series have suggested that patients with small indeterminate lesions who are carefully selected by an ophthalmologist can be observed for tumour growth before treatment initiation without adversely affecting survival4347. The American Brachytherapy Society guidelines suggest that patients being observed should be counselled about the small (yet still unquantified) increased risk of metastasis with observation30.

Recommendations:

Observation is not recommended for uveal melanomas except in unique situations. Indeterminate lesions should undergo a complete ophthalmologic assessment of risk factors for future growth. The presence of risk factors necessitates discussion for treatment, including future risk of growth and metastasis balanced with the risk of visual loss from treatment.

Surgery

Local resection of the tumour can preserve the eye, but is best suited for iris melanomas and selected ciliary body melanomas, or anterior small choroidal melanomas23. Enucleation involves surgical removal of the eye; historically, it was the most widely used treatment until recent advances in radiotherapy24,47. Patients with lesions exceeding 10 mm in thickness or 18 mm in diameter (or both) are still offered enucleation as the preferred treatment because of the complications connected to delivering high-dose radiation to the eye. Concerns about enucleation potentially promoting the hematogenous release of tumour cells and possibly leading to increased mortality after enucleation48 have contributed to the development of new management strategies such as radiotherapy and ttt. Subsequently, however, the Zimmerman hypothesis concerning the seeding of tumour during enucleation has been disproved49.

Recommendations:

Enucleation is most often reserved for lesions more than 10 mm in thickness or 18 mm in diameter (or both) because of complications secondary to radiation, including the risk of severe vision loss and loss of the eye. Selected ciliary body lesions and iris lesions might be amenable to excision (that is, iridocyclectomy and iridectomy respectively).

Brachytherapy

Radiotherapy has largely replaced enucleation for tumours of suitable location and dimension (that is, less than 10 mm in thickness and 18 mm in largest basal diameter). Larger tumours carry a risk of vision loss and radiation complications because of neovascular glaucoma; however, radiotherapy is sometimes used in patients with large tumours and a strong preference for attempting eye-sparing treatments. Radiotherapy options include episcleral brachytherapy, charged-particle external-beam radiotherapy (that is, protons, carbon ions, or helium ions), and photon-based radiosurgery [that is, linear accelerator, Gamma Knife (Elekta, Stockholm, Sweden), or CyberKnife (Accuray, Sunnyvale, CA, U.S.A.)].

Brachytherapy has become the treatment of choice based on the results of the Collaborative Ocular Melanoma Study (coms), a randomized controlled trial in 1317 patients that showed equivalent survival for brachytherapy and enucleation5052. Brachytherapy provides accurate and continuous administration of radiation and has the added benefit of vision preservation and improved cosmesis53. The most commonly used isotopes include 125I, 103Pd, and 106Ru5456. The choice of isotope is often based on tumour depth. High-risk indeterminate lesions that carry a greater than 50% risk of growth could be offered brachytherapy in selected cases28,40,57.

The coms trial found that the risk of treatment failure (that is, tumour growth, recurrence, or extrascleral extension) with 125I was low (10.3%; 95% confidence interval: 8.0% to 13.2%). Predictors of failure included older age, greater tumour thickness, and proximity of the tumour to the foveal avascular zone54. The reported local control rate with 103Pd is also quite high (96.7%), with only 14 of 400 patients requiring secondary enucleation55. A retrospective analysis of patients with uveal melanomas 16 mm or less in basal diameter and large height by the coms criteria also reported a low recurrence rate with 125I (7%)58. Local failure after radiation for posterior uveal melanoma should be re-treated with either enucleation or brachytherapy59. In some centres, minimal margin recurrence can also be treated with ttt60.

Recommendations:

Lesions best suited for brachy-therapy include high-risk indeterminate lesions and lesions less than 10 mm in thickness and 18 mm in maximum diameter; larger tumours can be offered brachytherapy in selected cases. Selected ciliary body lesions less than 10 mm thick without an extensive circumferential growth pattern and selected iris lesions can also be considered for brachytherapy.

Transpupillary Thermotherapy

Transpupillary thermotherapy uses an infrared laser through a dilated pupil. Because of high recurrence rates, ttt is generally not used as a primary treatment for uveal melanoma; rather, it is used as an adjunct to radiotherapy or to treat medium-risk nevi or indeterminate lesions. Because of penetrance limitations, ttt is best suited for small lesions (<3.0 mm in apical height and <16.0 mm in largest basal diameter)23. The recurrence rate for primary treatment of small melanomas with ttt is as high as 29%, significantly higher than the rates seen with plaque brachytherapy61,62. The role for ttt as an adjunct to radiotherapy is based on data from a retrospective case-matched comparative study (n = 36) and a retrospective observational study (n = 21) that were conducted in parallel to compare ttt alone with ttt plus plaque radiotherapy. The data showed that the local failure rate with ttt alone was 29% (that is, 6 patients); in the radiotherapy plus ttt group, regression was rapid, with no local failures, and no patient experienced metastasis63. Transpupillary thermotherapy can also be used to treat marginal recurrence after brachytherapy60; a complete response rate of 29% has been reported64.

Recommendations:

Because of a relatively high rate of local recurrence, ttt is not recommended as a primary therapy for uveal melanoma. In choroidal melanoma, to reduce the risk of local recurrence after radiotherapy or as a primary treatment for medium-risk nevi, ttt can be offered as an adjunct treatment in select cases.

Medical Management in the Setting of High-Risk or Metastatic Disease

No studies to date have shown any benefit from adjuvant therapy in reducing metastasis rates in patients at high risk for future metastasis (gep class 2 and monosomy 3). Furthermore, most systemic therapies for metastatic uveal melanoma (largely modelled after therapies for cutaneous melanoma) have failed to demonstrate clinical efficacy in phase ii trials6581. However, immunotherapies, including the anti-ctla4 antibody ipilimumab, have shown some success in retrospective and expanded-access studies8287. Pooling those publications, 188 patients with advanced uveal melanoma treated with ipilimumab experienced 1 complete response, 7 partial responses, and 52 incidences of stable disease. The resulting response rate was 4.3%, with a disease control rate of 31.9%. That response rate is slightly less than the rates reported in phase iii trials of ipilimumab alone or combined with dacarbazine for cutaneous melanoma (10.9% and 15.2% respectively). More than 80% of primary uveal melanomas carry active mutations in the GNAQ or GNA11 genes, which encode for G protein alpha subunits, leading to activation of the mek pathway. Several targeted agents, including the mek inhibitors selumetinib and trametinib, and the C-kit (CD117) inhibitor sunitinib, have demonstrated modest activity in patients with uveal melanoma88,89. Invariably, resistance to those agents develops within months of therapy initiation. Further study in larger trials is warranted.

Recommendations:

There is no evidence to support the use of adjuvant systemic therapy in high-risk patients (monosomy 3, gep class 2, or tumours > 10 mm thick). Evidence to support the use of systemic chemotherapy for the management of metastatic uveal melanoma is lacking. Immunotherapy with ipilimumab and targeted therapy with mek inhibition appear promising, but to date have generally been palliative. Patients should be considered for enrolment in clinical trials.

Surgical Resection in the Setting of Metastatic Disease

Some data suggest that resection of liver metastases from uveal melanoma might prolong survival90,91, including data from a single-arm prospective study in 12 patients who were able to achieve a median recurrence-free survival of 19 months (range: 6–78 months; 5-year recurrence-free survival: 15.6%) and an os of 27 months (range: 11–86 months; 5-year os: 53.3%) after complete resection92. Retrospective data also suggest that, compared with no surgery, resection of liver metastases is associated with a median survival that is increased by a factor of 3.793. Similar data have been reported elsewhere9496. However, the results in those noncomparative cohorts could be influenced by lead-time bias or favourable tumour biology in patients who are candidates for resection. Nevertheless, without intensive screening, detection of metastatic disease that is amenable to surgical resection is uncommon. Surgery to remove metastases is usually reserved for younger patients24.

Surgical resection in combination with chemotherapy might offer some benefit to patients with metastatic disease. A prospective study of aggressive hepatic surgery and implantation of an intra-arterial catheter for the delivery of chemotherapy (for example, fotemustine or dacarbazine–platinum, or both, for 4–9 cycles) in 75 patients with liver metastases demonstrated complete responses in 27.5% and significant tumour reductions in 49.3%. Median os was 10 months in patients who received complete surgery plus chemotherapy97. Similar findings have been reported elsewhere98. Further study incorporating new agents, especially immunotherapeutic agents, will be of interest, and clinical trial participation is encouraged. Until longer os is achieved, intrahepatic treatment should be considered experimental.

Recommendations:

Highly selected patients should be considered for surgical resection of potentially resectable liver metastasis. Most patients with metastatic disease will present with diffuse involvement of the liver and therefore will not qualify for surgical resection.

Ablation in the Setting of Metastatic Disease

Ablative techniques—that is, thermoablation99 and radio-frequency ablation (rfa)100—have been used in the setting of metastatic uveal melanoma. Data from a retrospective study in 8 patients with liver metastasis from ocular melanoma revealed a success rate of 50% with surgery or rfa, or both. In that series, 1 patient underwent left lateral segmentectomy, and 3 received combinations of left lateral segmentectomy, wedge resection, and rfa of 2–4 lesions. Median survival was 46 months in patients who underwent surgery alone or in conjunction with rfa to address all liver lesions101.

Recommendation

The data are insufficient to provide guidance on the role of ablative techniques in the setting of uveal melanoma metastatic to liver. Further study is required.

Follow-Up

No high-level studies are available to inform the most appropriate monitoring for patients who have undergone treatment for uveal melanoma. As such, no consensus has been reached within the ophthalmic or oncologic community about the role of surveillance for detection of metastases in those patients. Because evidence concerning surgical resection has suggested improved survival102, there is a trend toward the use of rigorous follow-up in high-risk patients. The median time to develop liver metastases is approximately 2.5 years; management of metastatic disease might therefore achieve more favourable outcomes when the metastasis is detected early102.

Clinical characteristics and tumour genetics predict survival. A customized follow-up routine based on the patient’s risk category is therefore recommended. Ultrasonography has demonstrated high specificity (100%), but low sensitivity (14%) for the detection of uveal melanoma liver metastases33. The use of us in the follow-up of high-risk patients should therefore complement other, more sensitive, tests. Several studies have looked at the use of various imaging modalities in detecting metastases, particularly in the liver, at follow-up34,103107. Magnetic resonance imaging offers consistently good sensitivity (92%–96%); the sensitivity of pet-ct is variable (35%–100%). In a head-to-head comparison of mri and pet-ct, sensitivity was higher with mri (67% vs. 41%, p = 0.01), and positive predictive value was slightly higher with pet-ct (95% vs. 100%, p = 0.01)35. The authors concluded that mri was superior to pet-ct for detecting liver metastases from uveal melanoma. In a cohort of 188 high-risk patients, 6-monthly mri of the abdomen detected metastases before symptoms in 92% of patients, resulting in 14% of patients qualifying for liver resection104. Consensus-based guidelines recommend that follow-up consist of annual history and physical exam, liver function tests, pet-ct or mri of abdomen, plain radiography of chest, and liver us2527. High-risk patients require more frequent imaging. To date, no data on the impact of follow-up on survival are available.

Recommendations:

Low-risk patients (that is, gep class 1a or 1b; no monosomy 3 detected; or tumour <9 mm thick and no genetic assessment) should receive annual liver us and a physical exam, indefinitely; follow-up can be transitioned to the family physician at 5 years. High-risk patients (that is, gep class 2; monosomy 3 detected; or tumour ≥9 mm thick and no genetic assessment) should receive an annual physical exam, indefinitely, plus imaging every 6 months, consisting of liver us alternating with abdominal or liver mri, for 10 years. If the body habitus limits us, other modalities should be considered. Follow-up can be transitioned to the family physician at 5–10 years.

CONCLUSIONS

The management of uveal melanoma and indeterminate intraocular lesions is complex and requires multidisciplinary input by experienced specialists with training in ophthalmologic oncology. With appropriate care, many patients can recover from their malignancy. However, more work is needed to understand the role of systemic therapy in the prevention and management of metastatic disease. Enrolment of patients into clinical trials should be encouraged whenever trials are available.

ACKNOWLEDGMENTS

The authors acknowledge Dr. E. Rand Simpson (Princess Margaret Hospital, Toronto, ON) for his review of this guideline. They also thank the Guideline Utilization Resource Unit (CancerControl Alberta, Alberta Health Services) for support with guideline development.

CONFLICT OF INTEREST DISCLOSURES

We have read and understood Current Oncology’s policy on disclosing conflicts of interest, and we declare that we have none.

REFERENCES

1. Singh AD, Topham A. Incidence of uveal melanoma in the United States: 1973–1997. Ophthalmology 2003;110:956–61.
cross-ref  pubmed  

2. Egan KM, Seddon JM, Glynn RJ, Gragoudas ES, Albert DM. Epidemiologic aspects of uveal melanoma. Surv Ophthalmol 1988;32:239–51.
cross-ref  pubmed  

3. Gallagher RP, Elwood JM, Rootman J, et al. Risk factors for ocular melanoma: Western Canada Melanoma Study. J Natl Cancer Inst 1985;74:775–8.
pubmed  

4. Weis E, Shah CP, Lajous M, Shields JA, Shields CL. The association of cutaneous and iris nevi with uveal melanoma: a meta-analysis. Ophthalmology 2009;116:536–43.e2.
cross-ref  pubmed  

5. Weis E, Shah CP, Lajous M, Shields JA, Shields CL. The association between host susceptibility factors and uveal melanoma: a meta-analysis. Arch Ophthalmol 2006;124:54–60.
cross-ref  pubmed  

6. Shah CP, Weis E, Lajous M, Shields JA, Shields CL. Intermittent and chronic ultraviolet light exposure and uveal melanoma: a meta-analysis. Ophthalmology 2005;112:1599–607.
cross-ref  pubmed  

7. Singh AD, Turell ME, Topham AK. Uveal melanoma: trends in incidence, treatment, and survival. Ophthalmology 2011;118:1881–5.
cross-ref  pubmed  

8. Kujala E, Makitie T, Kivela T. Very long-term prognosis of patients with malignant uveal melanoma. Invest Ophthalmol Vis Sci 2003;44:4651–9.
cross-ref  pubmed  

9. Gragoudas ES, Egan KM, Seddon JM, et al. Survival of patients with metastases from uveal melanoma. Ophthalmology 1991;98:383–9.
cross-ref  pubmed  

10. Malignant melanoma of the uvea. In: Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A, eds. AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer; 2009: 547–59.

11. Klintworth GK, Scroggs MW. The eye and ocular adnexa. In: Carter D, Eggleston JC, Mills SE, et al., eds. Diagnostic Surgical Pathology. 3rd ed. Philadelphia, PA: Lippincott Williams and Wilkins; 1999: 994–6.

12. Grossniklaus HE, Green WR. Uveal tumors. In: Garner A, Klintworth GK, eds. Pathobiology of Ocular Disease: A Dynamic Approach. 2nd ed. New York, NY: Marcel Dekker; 1994:1423–77.

13. Kilic E, Naus NC, van Gils W, et al. Concurrent loss of chromosome arm 1p and chromosome 3 predicts a decreased disease-free survival in uveal melanoma patients. Invest Ophthalmol Vis Sci 2005;46:2253–7.
cross-ref  pubmed  

14. Onken MD, Worley LA, Char DH, et al. Collaborative Ocular Oncology Group report number 1: prospective validation of a multi-gene prognostic assay in uveal melanoma. Ophthalmology 2012;119:1596–603.
cross-ref  pubmed  pmc  

15. Coupland SE, Campbell I, Damato B. Routes of extraocular extension of uveal melanoma: risk factors and influence on survival probability. Ophthalmology 2008;115:1778–85.
cross-ref  pubmed  

16. Damato B, Duke C, Coupland SE, et al. Cytogenetics of uveal melanoma: a 7-year clinical experience. Ophthalmology 2007;114:1925–31.
cross-ref  pubmed  

17. Damato B, Dopierala JA, Coupland SE. Genotypic profiling of 452 choroidal melanomas with multiplex ligation–dependent probe amplification. Clin Cancer Res 2010;16:6083–92.
cross-ref  pubmed  

18. Onken MD, Worley LA, Tuscan MD, Harbour JW. An accurate, clinically feasible multi-gene expression assay for predicting metastasis in uveal melanoma. J Mol Diagn 2010;12:461–8.
cross-ref  pubmed  pmc  

19. Walter S, Chao DL, Schiffman JC, Feuer WJ, Harbour JW. Tumor diameter contributes prognostic information that enhances the accuracy of gene expression profile molecular classification in uveal melanoma [abstract 4334]. Invest Ophthalmol Vis Sci 2015;56:. [Available online at: http://iovs.arvojournals.org/article.aspx?articleid=2334273; cited 9 July 2015]

20. U.K. National Institute for Health and Clinical Excellence (nice). How NICE Clinical Guidelines Are Developed: An Overview for Stakeholders, the Public and the NHS. 4th ed. London, U.K.: nice; 2009.

21. Cummings P, Rivara FP. Reviewing manuscripts for Archives of Pediatrics and Adolescent Medicine. Arch Pediatr Adolesc Med 2002;156:11–13.
cross-ref  pubmed  

22. agree Collaboration. Appraisal of Guidelines for Research and Evaluation (agree) instrument. Toronto, ON: agree Collaboration; n.d. [Downloadable from: http://www.agreetrust.org; cited 8 November 2013]

23. United States, Department of Health and Human Services, National Institutes of Health, National Cancer Institute (nci). Intraocular (Uveal) Melanoma Treatment – for health professionals (PDQ) [Web page]. Bethesda, MD: nci; 2015. [Available at: http://www.cancer.gov/types/eye/hp/intraocular-melanoma-treatment-pdq; cited 31 August 2015]

24. Lin AY. Diagnosis and Staging of Uveal Melanoma. Evans, GA: United States and Canadian Academy of Pathology; 2013. [Available online at: http://knowledgehub.uscap.org/site~/102nd/pdf/companion02h02.pdf; cited 17 July 2013]

25. U.K. Royal College of Ophthalmologists. Management of uveal melanoma [Web page]. Liverpool, U.K.: Ophthalmic Research Network; n.d. [Available at: http://www.moorfieldsresearch.org.uk/orntemp/Quality/RGov/Guidelines/Melanoma.htm; cited 17 July 2013]

26. Australian Cancer Network. Clinical Practice Guidelines for the Management of Melanoma in Australia and New Zealand. Ocular and Periocular Melanoma: Supplementary Document. Sydney, Australia: Cancer Council Australia; 2008. [Available online at: http://www.cancer.org.au/content/pdf/HealthProfessionals/ClinicalGuidelines/ManagementofOcularmelanomasupplementarydocument2008.pdf ; cited 17 July 2013]

27. Baurain JF, de Potter P. Practice guidelines in the management of uveal melanoma. The Université catholique de Louvain (Germany). Belg J Med Oncol 2013;7:20–6.

28. Shields CL, Shields JA, Kiratli H, De Potter P, Cater JR. Risk factors for growth and metastasis of small choroidal melanocytic lesions. Ophthalmology 1995;102:1351–61.
cross-ref  pubmed  

29. Shields CL, Furuta M, Thangappan A, et al. Metastasis of uveal melanoma millimeter-by-millimeter in 8033 consecutive eyes. Arch Ophthalmol 2009;27:989–98.
cross-ref  

30. American Brachytherapy Society Ophthalmic Oncology Task Force. The American Brachytherapy Society consensus guidelines for plaque brachytherapy of uveal melanoma and retinoblastoma. Brachytherapy 2014;13:1–14.
cross-ref  pubmed  

31. Law C, Krema H, Simpson ER. Referral patterns of intraocular tumour patients to a dedicated Canadian ocular oncology department. Can J Ophthalmol 2012;47:254–61.
cross-ref  pubmed  

32. Accuracy of diagnosis of choroidal melanomas in the Collaborative Ocular Melanoma Study. coms report no. 1. Arch Ophthalmol 1990;108:1268–73. [Erratum in: Arch Ophthalmol 1990;108:1708]
cross-ref  

33. Hicks C, Foss AJ, Hungerford JL. Predictive power of screening tests for metastasis in uveal melanoma. Eye (Lond) 1998;12:945–8.
cross-ref  

34. Francken AB, Fulham MJ, Millward MJ, Thompson JF. Detection of metastatic disease in patients with uveal melanoma using positron emission tomography. Eur J Surg Oncol 2006;32:780–4.
cross-ref  pubmed  

35. Servois V, Mariani P, Malhaire C, et al. Preoperative staging of liver metastases from uveal melanoma by magnetic resonance imaging (mri) and fluorodeoxyglucose-positron emission tomography (fdg-pet). Eur J Surg Oncol 2010;36:189–94.
cross-ref  

36. Orcurto V, Denys A, Voelter V, et al. 18F–Fluorodeoxyglucose positron emission tomography/computed tomography and magnetic resonance imaging in patients with liver metastases from uveal melanoma: results from a pilot study. Melanoma Res 2012;22:63–9.
cross-ref  

37. Damato B. Progress in the management of patients with uveal melanoma. The 2012 Ashton Lecture. Eye (Lond) 2012;26:1157–72.
cross-ref  

38. Feinstein EG, Marr BP, Winston CB, Abramson DH. Hepatic abnormalities identified on abdominal computed tomography at diagnosis of uveal melanoma. Arch Ophthalmol 2010;128:319–23.
cross-ref  pubmed  

39. Augsburger JJ. Is observation really appropriate for small choroidal melanomas. Trans Am Ophthalmol Soc 1993;91:147–68.
pubmed  pmc  

40. Shields CL, Cater J, Shields JA, Singh AD, Santos MC, Carvalho C. Combination of clinical factors predictive of growth of small choroidal melanocytic tumors. Arch Ophthalmol 2000;118:360–4.
cross-ref  pubmed  

41. Factors predictive of growth and treatment of small choroidal melanoma: coms report no. 5. The Collaborative Ocular Melanoma Study Group. Arch Ophthalmol 1997;115:1537–44.
cross-ref  

42. ajcc Ophthalmic Oncology Task Force. International validation of the American Joint Committee on Cancer’s 7th edition classification of uveal melanoma. JAMA Ophthalmol 2015;133:376–83. [Erratum in: JAMA Ophthalmol 2015;133:493]
cross-ref  

43. Augsburger JJ, Vrabec TR. Impact of delayed treatment in growing posterior uveal melanomas. Arch Ophthalmol 1993;111:1382–6.
cross-ref  pubmed  

44. Lane AM, Egan KM, Kim IK, Gragoudas ES. Mortality after diagnosis of small melanocytic lesions of the choroid. Arch Ophthalmol 2010;128:996–1000.
cross-ref  pubmed  

45. Sobrin L, Schiffman JC, Markoe AM, Murray TG. Outcomes of iodine 125 plaque radiotherapy after initial observation of suspected small choroidal melanomas: a pilot study. Ophthalmology 2005;112:1777–83.
cross-ref  pubmed  

46. Murray TG, Sobrin L. The case for observational management of suspected small choroidal melanoma. Arch Ophthalmol 2006;124:1342–4.
cross-ref  pubmed  

47. Semenova E, Finger PT. Palladium-103 radiation therapy for small choroidal melanoma. Ophthalmology 2013;120:2353–7.
cross-ref  pubmed  

48. Zimmerman LE, McLean IW, Foster WD. Does enucleation of the eye containing a malignant melanoma prevent or accelerate the dissemination of tumour cells. Br J Ophthalmol 1978;62:420–5.
cross-ref  pubmed  pmc  

49. Zimmerman LE, McLean IW. An evaluation of enucleation in the management of uveal melanomas. Am J Ophthalmol 1979;87:741–60.
cross-ref  pubmed  

50. Seddon JM, Gragoudas ES, Egan KM, et al. Relative survival rates after alternative therapies for uveal melanoma. Ophthalmology 1990;97:769–77.
cross-ref  pubmed  

51. Diener-West M, Earle JD, Fine SL, et al. The coms randomized trial of iodine 125 brachytherapy for choroidal melanoma, iii: initial mortality findings. coms report no. 18. Arch Ophthalmol 2001;119:969–82.
cross-ref  pubmed  

52. Collaborative Ocular Melanoma Study Group. The coms randomized trial of iodine 125 brachytherapy for choroidal melanoma: v. Twelve-year mortality rates and prognostic factors. Arch Ophthalmol 2006;124:1684–93.
cross-ref  

53. Jampol LM, Moy CS, Murray TG, et al. on behalf of the Collaborative Ocular Melanoma Study Group (coms Group). The coms randomized trial of iodine 125 brachytherapy for choroidal melanoma: iv. Local treatment failure and enucleation in the first 5 years after brachytherapy. coms report no. 19. Ophthalmology 2002;109:2197–206.
cross-ref  pubmed  

54. Hawkins BS. Collaborative ocular melanoma study randomized trial of I-125 brachytherapy. Clin Trials 2011;8:661–73.
cross-ref  pubmed  

55. Finger PT, Chin KJ, Duvall G on behalf of the Palladium-103 for Choroidal Melanoma Study Group. Palladium-103 ophthalmic plaque radiation therapy for choroidal melanoma: 400 treated patients. Ophthalmology 2009;116:790–6.
cross-ref  pubmed  

56. Papageorgiou KI, Cohen V, Bunce C, Kinsella M, Hungerford JL. Predicting local control of choroidal melanomas following 106Ru plaque brachytherapy. Br J Ophthalmol 2011;95:166–70.
cross-ref  

57. Gragoudas E, Li W, Goitein M, Lane AM, Munzenrider JE, Egan KM. Evidence-based estimates of outcome in patients irradiated for intraocular melanoma. Arch Ophthalmol 2002;120:1665–71.
cross-ref  pubmed  

58. Puusaari I, Damato B, Kivelä T. Transscleral local resection versus iodine brachytherapy for uveal melanomas that are large because of tumour height. Graefes Arch Clin Exp Ophthalmol 2007;245:522–33.
cross-ref  

59. Pe’er J, Stefani FH, Seregard S, et al. Cell proliferation activity in posterior uveal melanoma after Ru-106 brachytherapy: an eortc ocular oncology group study. Br J Ophthalmol 2001;85:1208–12.
cross-ref  

60. Robertson DM. ttt as rescue treatment for choroidal melanoma not controlled with iodine-125 brachytherapy. Ocul Immunol Inflamm 2002;10:247–52.
cross-ref  

61. Pilotto E, Vujosevic S, De Belvis V, Parrozzani R, Boccassini B, Midena E. Long-term choroidal vascular changes after iodine brachytherapy versus transpupillary thermotherapy for choroidal melanoma. Eur J Ophthalmol 2009;19:646–53.
pubmed  

62. Harbour JW, Meredith TA, Thompson PA, Gordon ME. Transpupillary thermotherapy versus plaque radiotherapy for suspected choroidal melanomas. Ophthalmology 2003;110:2207–14.
cross-ref  pubmed  

63. Girvigian MR, Astrahan MA, Lim JI, Murphree AL, Tsao-Wei D, Petrovich Z. Episcleral plaque 125I radiotherapy with episcleral lcf hyperthermia: a prospective randomized trial. Brachytherapy 2003;2:229–39.
cross-ref  

64. Saakian SV, Val’skiĭ VV, Semenova EA, Amirian AG. Transpupillary thermotherapy in the treatment of recurrent and residual choroidal melanomas: preliminary results [Russian]. Vestn Oftalmol 2009;125:11–15.

65. Bhatia S, Moon J, Margolin KA, et al. Phase ii trial of sorafenib in combination with carboplatin and paclitaxel in patients with metastatic uveal melanoma: swog S0512. PLoS One 2012;7:e48787.
cross-ref  

66. Mahipal A, Tijani L, Chan K, Laudadio M, Mastrangelo MJ, Sato T. A pilot study of sunitinib malate in patients with metastatic uveal melanoma. Melanoma Res 2012;22:440–6.
cross-ref  pubmed  

67. Homsi J, Bedikian AY, Papadopoulos NE, et al. Phase 2 open-label study of weekly docosahexaenoic acid–paclitaxel in patients with metastatic uveal melanoma. Melanoma Res 2010;20:507–10.
cross-ref  pubmed  

68. Huppert PE, Fierlbeck G, Pereira P, et al. Transarterial chemoembolization of liver metastases in patients with uveal melanoma. Eur J Radiol 2010;74:38–44.
cross-ref  

69. Fiorentini G, Aliberti C, Del Conte A, et al. Intra-arterial hepatic chemoembolization (tace) of liver metastases from ocular melanoma with slow-release irinotecan-eluting beads. Early results of a phase ii clinical study. In Vivo 2009;23:131–7.
pubmed  

70. O’Neill PA, Butt M, Eswar CV, Gillis P, Marshall E. A prospective single arm phase ii study of dacarbazine and treosulfan as first-line therapy in metastatic uveal melanoma. Melanoma Res 2006;16:245–8.
cross-ref  

71. Schmittel A, Schmidt-Hieber M, Martus P, et al. A randomized phase ii trial of gemcitabine plus treosulfan versus treosulfan alone in patients with metastatic uveal melanoma. Ann Oncol 2006;17:1826–9.
cross-ref  pubmed  

72. Schmittel A, Schuster R, Bechrakis NE, et al. A two-cohort phase ii clinical trial of gemcitabine plus treosulfan in patients with metastatic uveal melanoma. Melanoma Res 2005;15:447–51.
cross-ref  pubmed  

73. Patel K, Sullivan K, Berd D, et al. Chemoembolization of the hepatic artery with bcnu for metastatic uveal melanoma: results of a phase ii study. Melanoma Res 2005;15:297–304.
cross-ref  pubmed  

74. Schmidt-Hieber M, Schmittel A, Thiel E, Keilholz U. A phase ii study of bendamustine chemotherapy as second-line treatment in metastatic uveal melanoma. Melanoma Res 2004;14:439–42.
cross-ref  pubmed  

75. Agarwala SS, Panikkar R, Kirkwood JM. Phase i/ii randomized trial of intrahepatic arterial infusion chemotherapy with cisplatin and chemoembolization with cisplatin and polyvinyl sponge in patients with ocular melanoma metastatic to the liver. Melanoma Res 2004;14:217–22.
cross-ref  pubmed  

76. Alexander HR Jr, Libutti SK, Pingpank JF, et al. Hyperthermic isolated hepatic perfusion using melphalan for patients with ocular melanoma metastatic to liver. Clin Cancer Res 2003;9:6343–9.
pubmed  

77. Alexander HR, Libutti SK, Bartlett DL, Puhlmann M, Fraker DL, Bachenheimer LC. A phase iii study of isolated hepatic perfusion using melphalan with or without tumor necrosis factor for patients with ocular melanoma metastatic to liver. Clin Cancer Res 2000;6:3062–70.
pubmed  

78. Kivelä T, Suciu S, Hansson J, et al. Bleomycin, vincristine, lomustine and dacarbazine (bold) in combination with recombinant interferon alpha-2b for metastatic uveal melanoma. Eur J Cancer 2003;39:1115–20.
cross-ref  

79. Bedikian AY, Papadopoulos N, Plager C, Eton O, Ring S. Phase ii evaluation of temozolomide in metastatic choroidal melanoma. Melanoma Res 2003;13:303–6.
cross-ref  pubmed  

80. Pyrhönen S, Hahka-Kemppinen M, Muhonen T, et al. Chemoimmunotherapy with bleomycin, vincristine, lomustine, dacarbazine (bold), and human leukocyte interferon for metastatic uveal melanoma. Cancer 2002;95:2366–72.
cross-ref  

81. Becker JC, Terheyden P, Kämpgen E, et al. Treatment of disseminated ocular melanoma with sequential fotemustine, interferon alpha, and interleukin 2. Br J Cancer 2002;87:840–5.
cross-ref  pubmed  pmc  

82. Di Giacomo AM, Danielli R, Calabrò L, et al. Ipilimumab experience in heavily pretreated patients with melanoma in an expanded access program at the University Hospital of Siena (Italy). Cancer Immunol Immunother 2011;60:467–77.
cross-ref  

83. Kelderman S, van der Kooij MK, van den Eertwegh AJ, et al. Ipilimumab in pretreated metastatic uveal melanoma patients. Results of the Dutch Working group on Immunotherapy of Oncology (win-o). Acta Oncol 2013;52:1786–8.
cross-ref  pubmed  

84. Luke JJ, Callahan MK, Postow MA, et al. Clinical activity of ipilimumab for metastatic uveal melanoma: a retrospective review of the Dana-Farber Cancer Institute, Massachusetts General Hospital, Memorial Sloan-Kettering Cancer Center, and University Hospital of Lausanne experience. Cancer 2013;119:3687–95.
cross-ref  pubmed  pmc  

85. Danielli R, Ridolfi R, Chiarion-Sileni V, et al. Ipilimumab in pretreated patients with metastatic uveal melanoma: safety and clinical efficacy. Cancer Immunol Immunother 2012;61:41–8.
cross-ref  

86. Khattak MA, Fisher R, Hughes P, Gore M, Larkin J. Ipilimumab activity in advanced uveal melanoma. Melanoma Res 2013;23:79–81.
cross-ref  

87. Maio M, Danielli R, Chiarion-Sileni V, et al. Efficacy and safety of ipilimumab in patients with pre-treated, uveal melanoma. Ann Oncol 2013;24:2911–15.
cross-ref  pubmed  

88. Carvajal RD, Sosman JA, Quevedo JF, et al. Effect of selumetinib vs chemotherapy on progression-free survival in uveal melanoma: a randomized clinical trial. JAMA 2014;311:2397–405.
cross-ref  pubmed  pmc  

89. Falchook GS, Lewis KD, Infante JR, et al. Activity of the oral mek inhibitor trametinib in patients with advanced melanoma: a phase 1 dose-escalation trial. Lancet Oncol 2012;13:782–9.
cross-ref  pubmed  pmc  

90. Salmon RJ, Levy C, Plancher C, et al. Treatment of liver metastases from uveal melanoma by combined surgery—chemotherapy. Eur J Surg Oncol 1998;24:127–30.
cross-ref  pubmed  

91. Hsueh EC, Essner R, Foshag LJ, Ye X, Wang HJ, Morton DL. Prolonged survival after complete resection of metastases from intraocular melanoma. Cancer 2004;100:122–9.
cross-ref  

92. Aoyama T, Mastrangelo MJ, Berd D, et al. Protracted survival after resection of metastatic uveal melanoma. Cancer 2000;89:1561–8.
cross-ref  pubmed  

93. Frenkel S, Nir I, Hendler K, et al. Long-term survival of uveal melanoma patients after surgery for liver metastases. Br J Ophthalmol 2009;93:1042–6.
cross-ref  pubmed  

94. Mariani P, Piperno-Neumann S, Servois V, et al. Surgical management of liver metastases from uveal melanoma: 16 years’ experience at the Institut Curie. Eur J Surg Oncol 2009;35:1192–7.
cross-ref  pubmed  

95. Gomez D, Wetherill C, Cheong J, et al. The Liverpool uveal melanoma liver metastases pathway: outcome following liver resection. J Surg Oncol 2014;109:542–7.
cross-ref  

96. Pawlik TM, Zorzi D, Abdalla EK, et al. Hepatic resection for metastatic melanoma: distinct patterns of recurrence and prognosis for ocular versus cutaneous disease. Ann Surg Oncol 2006;13:712–20.
cross-ref  pubmed  

97. Voelter V, Schalenbourg A, Pampallona S, et al. Adjuvant intra-arterial hepatic fotemustine for high-risk uveal melanoma patients. Melanoma Res 2008;18:220–4.
cross-ref  pubmed  

98. Leyvraz S, Piperno-Neumann S, Suciu S, et al. Hepatic intra-arterial versus intravenous fotemustine in patients with liver metastases from uveal melanoma (eortc 18021): a multicentric randomized trial. Ann Oncol 2014;25:742–6.
cross-ref  pubmed  pmc  

99. Al-Jamal RT, Eskelin S, Pyrhönen S, Kivelä T. Long-term progression-free survival in metastatic uveal melanoma after chemoimmunotherapy and consolidation thermoablation. Acta Oncol 2009;48:476–9.
cross-ref  

100. Lieberman S, Goldin E, Lotem M, Bloom AI. Irrigation of the bile ducts with chilled saline during percutaneous radiofrequency ablation of a hepatic ocular melanoma metastasis. Am J Roentgenol 2004;183:596–8.
cross-ref  

101. Derek E, Matsuoka L, Alexopoulos S, Fedenko A, Genyk Y, Selby R. Combined surgical resection and radiofrequency ablation as treatment for metastatic ocular melanoma. Surg Today 2013;43:367–71.
cross-ref  

102. Francis JH, Patel SP, Gombos DS, Carvajal RD. Surveillance options for patients with uveal melanoma following definitive management. Am Soc Clin Oncol Educ Book 2013;382–7.
cross-ref  pubmed  

103. Klingenstein A, Haug AR, Nentwich MM, Tiling R, Schaller UC. Whole-body F-18–fluoro-2-deoxyglucose positron emission tomography/computed tomography imaging in the follow-up of metastatic uveal melanoma. Melanoma Res 2010;20:511–16.
cross-ref  pubmed  

104. Kaiserman I, Amer R, Pe’er J. Liver function tests in metastatic uveal melanoma. Am J Ophthalmol 2004;137:236–43.
cross-ref  pubmed  

105. Marshall E, Romaniuk C, Ghaneh P, et al. mri in the detection of hepatic metastases from high-risk uveal melanoma: a prospective study in 188 patients. Br J Ophthalmol 2013;97:159–63.
cross-ref  

106. Semelka RC, Martin DR, Balci C, Lance T. Focal liver lesions: comparison of dual-phase ct and multisequence multiplanar mr imaging including dynamic gadolinium enhancement. J Magn Reson Imaging 2001;13:397–401.
cross-ref  pubmed  

107. Eskelin S, Pyrhönen S, Summanen P, Prause JU, Kivelä T. Screening for metastatic malignant melanoma of the uvea revisited. Cancer 1999;85:1151–9.
cross-ref  pubmed  


Correspondence to: Ezekiel Weis, Department of Ophthalmology and Visual Sciences, 2319–10240 Kingsway Avenue, Edmonton, Alberta T5H 3V9. E-mail: ezekiel@ualberta.ca

(Return to Top)



Current Oncology, VOLUME 23, NUMBER 1, February 2016








Copyright © 2019 Multimed Inc.
ISSN: 1198-0052 (Print) ISSN: 1718-7729 (Online)