surveillance following treatment of primary ocular...

Surveillance following treatment of primary ocular melanoma

Introduction

• 50% of UM patients relapse with predominantly liver metastases

• Risk of metastatic disease can be predicted relatively accurately through use of clinicopathological features & molecular genetics

• Surgical management of liver metastases offers the only real likelihood of long-term disease control at present (Frenkel et al. 2009; Mariani et al., 2009; Marshall et al., 2013).

• Introduction of surveillance programmes for patients with a high-risk of developing disease with hope of demonstrating survival benefit.

• Optimal screening method, timing, patient selection and overall advantage of surveillance remain under debate

Aims of surveillance in UM patients

• To identify patients who have relapsed. – i.e. who have developedmetastatic disease.

The GDG agreed that the aim is to detect small volume, pre-clinicaldisease rather than first identifying large volume metastatic disease,clinically detectable.

• Aim – to detect metastatic disease as early as possible.

The GDG agreed that there is a need to qualify whether early detectionmakes a difference. There is evidence in Section 7 that small volumetreatment has better outcome. Early treatment increases benefit andlines of treatment

PICO Questions

1. Should all patients be offered surveillance?

2. Should there be a risk-adapted strategy for surveillance?

3. If so, what is a high-risk and or low-risk uveal melanoma?

4. What is the optimal imaging modality for surveillance?

5. What is the interval?

6. What is the duration of surveillance?

Inclusion & exclusion criteria for selecting evidence

• Inclusion criteriaCase control studiesCase series > 3 patientsReview articles combined with case reports Expert opinionAdult patients only

• Exclusion criteriaPreclinical and animal studiesCase reports (1-3 cases)Review articles without any original case information

Inclusion & exclusion criteria for selecting evidence:Results (preamble)

• No randomized or nonrandomized comparative clinical trial

e.g. of total post-treatment survival in subgroups assigned to regular periodic surveillance for metastasis versus no surveillance testing.

• No studies were found that addressed Question 6:

i.e. the duration of surveillance review.

1. Should all patients be offered surveillance?

Authors Year Method Studies Surveillance tools

Outcome Comment

Augsbsurgeret al.

Am J Ophthal

2011 Literaturereview; expertopinion

31/4222,Small, retrospective

Variable

Differing strategies

Levels of specific biomarkers reported when metastasis was first confirmed (n = 14)

% of patients with abnormal results on surveillance testing (n=13)

Values of diagnostic markers assoc. with surveillance regimen (7)

Survival time after metastasis detection (7)

Total survival time after initial diagnosis/Tx (3)

% of patients whose metastatic tumors were detected by presymptomatic testing (5)

Surveillance regimensemployed by different groups (1)

Relationship with other prognostic factors for UM metastasis (1)

Failed to find a survival benefit assoc. with regular surveillance

No RCT performed

Authors Yr Method No. of pts

Surveillance tools

Outcome Comment

Eskelin et al. 1999 Retrospective 46

1985-1996

LFTCXRAbdom US

59% with metsasymptomatic

80% hepatic mets only

Recommends biannual screening

Combination of US and LFTs

CXR of no use

Maeda 2007 Retrospective 1592000-2005

MRI5.2 + 1.7 years (range, 1.2–6.6 yrs)

Biopsy/resection

13% with asymptomatic abnormalities; 9% proven mets

Resulted in initiation of Tx

No improved survival

Kim et al 2010 Retrospective

90 asympt.

259 symptoms

LFTs

-> CT of liver, if abnLFTs

Median time from primary UM diagnosis to met diagnosis was 31.4 mo in asymptomaticgroup vs 40.3 mo in symptomatic group

Presymptomatic detection of metastatic UM by routine surveillance testing seems to confer a survival advantage only in the first year after diagnosisof metastasis.

Authors Yr Method No. of pts

Surveillance tools

Outcome Comment

Eskelin et al. 1999 Retrospective 46

1985-1996

LFTCXRAbdom US

59% with metsasymptomatic

80% hepatic mets only

Recommends biannual screening

Combination of US and LFTs

CXR of no use

Maeda 2007 Retrospective 1592000-2005

MRI5.2 + 1.7 years (range, 1.2–6.6 yrs)

Biopsy/resection

13% with asymptomatic abnormalities; 9% proven mets

Resulted in initiation of Tx

No improved survival

Kim et al 2010 Retrospective

90 asympt.

259 symptoms

LFTs

-> CT of liver, if abnLFTs

Median time from UM diag to met diag was 31.4 mo in asymptomaticgroup vs 40.3 mo in symptom group

Presymptomatic detection of metastatic UM by routine surveillance testing seems to confer a survival advantage only in the first year after diagnosisof metastasis.

Marshall et al

2013 Prospective

2000-2010

188 pts

Median FU of 28.8 months

Study closure @ 5yrs

MRI of high risk pts

LFTs

90 pts with mets

92% asymptom.

38 operable on MRI-> R0 resection in 12 pts

35% pts survived 5 yrs

Hepatic MRI has made it possible to evaluate treatments for metastases at an earlier stage of disease.

Question 2: Should there be a risk-adapted strategy for UM metastasis surveillance?

• Little evidence in literature – only one study to date: Marshall et al. BJO 2013

• Targeted approach:– Is cost effective in NHS setting– Enables studies for comparison of screening techniques

• Comparative studies required

Marshall et al

2013 Prospective

2000-2010

188 pts

Median FU of 28.8 months

Study closure @ 5yrs

MRI of high risk pts

LFTs

90 pts with mets

92% asymptom.

38 operable on MRI-> R0 resection in 12 pts

35% pts survived 5 yrs

Hepatic MRI has made it possible to evaluate treatments for metastases at an earlier stage of disease.

Question 3:If so, what is a high-risk and or low-risk uveal melanoma?

• No consensus on definition in literature (see prognostication Chapter)

• The definition of ‘high risk’ uveal melanoma poses difficulties since not all Centres apply the molecular genetic testing, or only in very few selected cases, e.g. enucleation samples.

• A definition of ‘high risk’ cannot be based only on molecular genetic abnormalities, but must include clinical and histomorphological features of the tumours, when assessable.

Authors Year Method Pts Patients/Outcome Comment

Damato et al. 2008

Ophthalmology

conditional hazard estimating neural network (CHENN)

Training set of 1780,test set of another 874 patients

All-cause survival curves generated by the CHENN matched those produced with Kaplan-Meier analysis (Kolmogorov-Smirnov, P<0.05). In older patients, however, the estimated melanoma-related mortality was lower with the CHENN, which accounted for competing risks, unlike Kaplan-Meier analysis.

Estimation of survival prognosis in patients with choroidalmelanoma requires multivariate assessment of age, sex, clinical tumor stage, cytogenetic melanoma type, and histologicgrade of malignancy

Taktak A et al., 2004 Artificial Neural Networks

2331, split randomly into training and test sets

AI system can match if not better the clinical expert's prediction

Prognostic factor combinations

Kaisermann et al.

2005 ANN 153 pts predicting 5-year mortality

logistic regression reached 86% forecasting accuracy, with a very low LR (0.8), whereas the human expert forecasting ability was <70% (LR, 1.85)

No genetics included


• Combination of parameters is basis of “Liverpool UvealMelanoma Prognostication Online” (LUMPO) model.

www.ocularmelanomaonline.com

2654 UM patients:Training set = 1780Test set = 874

3653 UM patients:Bootstrap re-sampling (200x)Bayesian regularization


• Following discussions at OOG Krakow (March 2014)

• High risk for metastasis could be defined by one or more of the following criteria:

• Large tumour size on USS (>TNM Stage IIIA) with risk of metastasis at 5 years being– Stage IIIA 34%– Stage IIIB 55%– Stage IIIB 74%

• Ciliary body location• Epithelioid cell morphology (when histology available)• Monosomy 3• GEP Class 2

Question 4: What is the optimal imaging modality for surveillance, overall and of the liver?

• Overlap with Staging chapter

• Differing methodologies - USS, CT or MRI (with or without contrast enhancement) or body imaging with CT or PET-CT

• Principal hypothesis behind screening in the surveillance of UM patients is the detection of resectable liver metastases -> liver imaging as the primary modality to detect early disease

• Note: in autopsy studies, 87-90% of UM (advanced) cases with non-liver metastases.

Question 4: What is the optimal imaging modality for surveillance of the liver?

• Liver imaging in metastatic UM


Servois et al. 2010

Eur J SurgOncol.

Retrospective

Comparison of MRI and FDG-PET

15 R0 resection performed in 12 patients

MRI was superior to FDG-PET for staging of liver metastases from UM

Preoperative confirmation remains imperfect

Orcurto et al. 2009Melanoma Res

Retrospective

Comparison of MRI and FDG-PET

Question 4: What is the optimal imaging modality for surveillance outside the liver?

• Extrahepatic imaging in metastatic UM


Lorigan et al. 1991

Am J Roentgenol

Retrospective; descriptive

CTMR

110 92% patients with hepatic mets

10 patients developed extrahepatic disease, detected using both technologies

None re superiority

Klingenstein et al.

2010Melanoma Res

FDG-PET CT 11 Hepatic metastases (83%), Osseous (42%), LN (33%), Pulmonary (17%)Adrenal (8%) Muscular metastases (8%).

Six patients showed multiple organ involvement (50%).

Staging

Question 4: What is the optimal imaging modality for surveillance outside the liver?

• Extrahepatic imaging in metastatic UM


Lorigan et al. 1991

Am J Roentgenol

Retrospective; descriptive

CTMR

110 92% patients with hepatic mets

10 patients developed extrahepatic disease, detected using both technologies

None re superiority

Klingenstein et al.

2010Melanoma Res

FDG-PET CT 11 …. Staging

Kurli et al. Am J Ophthalmol 2005

Interventional non-randomized clinical study

PET-CT

20 Mean time from initialdiagnosis to metastasis was 47 months (range 0 to 154)

Liver (100%),bone (50%), lung (25%), lymph nodes (25%),and subcutaneous tissue (25%).

Cardiac, brain, thyroid,and posterior abdominal wall lesions (12.5%).

LFTs abnormal in only 13% pts

Staging

Question 5: What is the optimal surveillance interval ?

• There is very little evidence on which to base decisions regarding either frequency or duration of follow-up.

• General consensus in the field is that 6-monthly imaging is“preferable”.

Question 6: What is the optimal duration of surveillance?

• UM may continue to relapse for many decades following primary diagnosis, with 20-33% of deaths attributed to metastatic recurrence even at 15-42 yrs.

• Anecdotal reports that resection rates in later relapsing patients more favourable: tumour biology?

• No studies in literature, to support or discount lifelong surveillance.

Evidence Statements -1

1. To date, a survival benefit to screening of uveal melanoma patients has not been proven.

2. If a substantial and clinically meaningful survival benefit were truly associated with periodic surveillance testing for UM metastases, such benefit would be demonstrated most convincingly by means of a prospective comparative clinical trial in which subgroups of patients with UM (after treatment of their primary intraocular tumor) were subjected to either regular periodic surveillance testing by some consistent regimen or no surveillance testing at all and then followed until death from any cause.

3. Despite the lack of evidence there is general consensus that surveillance testing is not completely worthless, and indeed is performed in virtually all centres in a periodic manner using differing methods for differing lengths of periods.

4. Surveillance clearly identifies many patients with metastasis at a substantially less advanced metastatic substage than would occur if only postsymptomatic testing were employed.

Evidence Statements - 2

5. Targetted surveillance is likely to bring more benefit. A consensus definition of high-risk UM is required, incorporating clinical, histomorphological and genetic features of the tumours.

6. Most surveillance testing for metastatic UM concentrates on the liver, with the effect that highly-sensitive modalities for liver imaging are chosen.

7. The role of extrahepatic imaging in surveillance is unclear, particularly as the frequency of extrahepatic metastatic relapse remains unknown.

8. Hepatic surveillance of UM has resulted in an increased detection rate of metastases in the liver, resulting in increased loco-regional treatment in some centres and trial recruitment.

Recommendations

1. Surveillance is intuitively advantageous, allowing locoregional management of liver-only metastases, and facilitating early systemic treatment and particularly trial enrolment before the disease burden causes deteriorations in general health and performance status.

2. Surveillance facilitates patient follow-up, provides a link with oncology services and allows a more holistic approach to cancer patients that includes early access to cancer nurse specialists and smooth transition to services such as palliative care at an appropriate stage.

3. Prognostication linked with targeted liver screening of high-risk patients should be the preferred option. This should be carried out within a specialist multidisciplinary team that incorporates expertise from ophthalmology, oncology, cancer nursing and hepatic services.

4. Target high-risk patients and perform 6-monthly surveillance incorporating a clinical review, nurse specialist support, blood for putative circulating biomarkers and non-contrast liver MRI for the first 5 years.

5. Beyond 5 years, patients should be counselled with the option to continue lifelong surveillance with annual follow-up thereafter.

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