CCAN's annual conference was held in Long Island, New York on August 20th 2011.  The theme of the day long conference was "Multidisciplinary Approach to the Diagnosis Treatment and Monitoring of NETs." Speakers included several local oncolgists, as well as Dr, O'Dorisio from Iowa,  Dr. Delpassand from Excel Diagnostics in Houston.and Leigh Anne Burns from Ochsner Kenner's Neuroendocrine Program.  It was a full day starting with an introduction to NETs, methods of detection as common ways to treat -  with talks throughout the day on interventional radiology, surgery, blood markers, imaging and PRRT.  As this writer does at many conference I take notes in real time and make them available to the NET Community and while efforts is takn to take  accurate notes – there are certain to be omissions and errors – SO PLEASE talk to your medical professional – do not rely on these notes as a basis for treatment.


Robert Wahmann – Introduction to CCAN

Thanks to CCAN there is a NET Awareness Day in NY and other states. NETs are not as rare as one thinks – Throughout the day you will hear about what NETs are, What to Ask and what your treatment options are.

 


Dr. Hal Gerstein– Cancer Institute of Long Island

NETs are a diverse group of malignancies – that can be categorized as functional (producing something / or non functional)

The number of yearly DX rate is going up – not sure if we are better at dx them or something new is causing them.  The rate is increasing faster than the average of other cancers.

NETs can be undetected for years before either symptom caused by peptide release or obstructions allow for a dx

Locations are Fore, Mid and Hind gut

KI-67 from tissue biopsy is one of the best ways to predict outcome with Ki-67 under 2 and no spread being best and KI-67 >10 with distant mets  being worst.

Median life expectancy with Ki-67>10 and distant spread is 33 months – with KI-67<2 and being local in scope - this increases to 223 months.  With 102 and with regional mets – this is 111 months.

Why no early detection? – Symptoms are wide ranging and could be a number of other issues as well

Carcinoid Syndrome
Flushing – wheezing – usually but not always with mets to the liver

Need to understand patient’s history – Diarrhea not related to eating (night time) one good clue for diagnosis

BIO Markers (please see Interscience Institute website for complete bio markers and how to take tests)
CgA
5HIAA
For all blood test make sure you follow precautions about foods and medications to avoid or false positive can be seen – Do not take PPI for CgA and many fruits and vegs and nuts should be avoided for 5HIAA

Imaging
CT or MR
OSCAN to see functional or not (uptake of octreotide)
Upper Endoscope (PNETs only)
PET

Evolving treatment
Treatment is moving from symptom to control to some reduction in tumors – trying to get to chronic disease.  New drugs approved for some forms of NETs (Evrolimus / Sutent) approved this year for treatment.

 


Dr. Steven Libutti – Surgery In NET Cancer – Montefiore Hospital

 

 

Background NCI researcher in surgical oncology/NETs – Came back to work at new cancer center – Center for NET Cancer –

Prevalence is going up – why not sure

All nets can be stained – look at the tumor’s histology (what are the genes)

Now grouping tumor to molecular makeup not on location (NETs to the lung / not Lung Cancer)

Carcinoid Syndrome – Mostly for people with mets to liver – but can happen with lung and rectum

How do we treat – Many years the only tools were surgery –beginning to change with new agents

Carcinoid tumors can be very small – lymph node involvement may be the only way to detect – even with removal there may be microscopic METs that exists outside the primary area

Imaging – how do we find out where the tumors are even after surgery
OSCAN
FDG PET – more for PNET


CT or MRI is the mainstay for managing

First site of recurrence is in the Liver
Greatest hope is that they are resectable – via surgery or other methods – ablation

Hopkins research – surgical mgt of NET Tumors
Overall median survival – 125 months

Case slide – 1996 – patient presented with PNET – removed a modified whipple (although it should be called a Cameron procedure) – one step process that leaves part of the pancreas intact.  In 2005 after years of following – livers mets showed –resected a lobe – more tumors were found in dissected lobe – no doubt there are micro mets in the other lobe – need to have more management than just surgery

Liver transplant not viable on a large-scale population.
Need liver (hard to get) and stay on immunosuppressant rest of life

Schema IHP circuit –   Montefiore one of only two sites in US who do this - it is much like Chemo therapy direct to the liver – hook up the liver to the bypass machine for 60 minutes see the following link for a presentation.
PNETs and Carcinoid
Partial Response of 50%
PR Free is 7 months and overall survival is 48 months
Now trying via percutaneous – having great success

New Drugs that have been approved this year. 
Evrolimus (mTOR inhibitor)
Sutent – another pathway inhibitor

Combined Therapy – Surgery plus Evrolimus

Clinical Trial on SOM230 for Carcinoid with symptoms – This email address is being protected from spambots. You need JavaScript enabled to view it. 718-920-4231

 


Dr. Patrick Malloy, VA New York – Liver Directed Therapy using Y90 Sirspheres

 

Hepatic (liver) tumors result in the largest number of cancer related death and with 1/3 of all NETs presenting with liver mets it is of great importance to treat liver.  Only 10% of patients with liver mets are resectable (?)

Liver directed therapy – introduction of cells, molecules and articles in the blood supply

RFA Slide – effective for limited or focal disease – does not work well for greater spread

Intra-arterial Therapy – how can this work – liver has 2 blood supplies – 75% portal – 25% hepatic -   Tumors have most of their blood delivered via hepatic artery - Tumor always want blood flow – where as normal liver does not – 19x uptake of particle to tumor vs normal liver. 

Y90 Microsphere selection Criteria – Contraindication
Amount of tumor load (under 50%) and bilirubin <2 mg/dl
Metastatic confined to liver
Prior external beam radiation

Y90 – 30 micron in size – smaller – beads can go to other targets – over 50 is too big
Max energy 2.27 MeV – half life 64.1 hours – 2mm effect – 94% of radiation is delivered in 11 days

Glass or Resin are permanent in your body  

One lobe is treated at a time – at first both lobes were done – had a higher complication rate – with one lobe done – very low complication rates

Adverse Events
Fever – right upper quadrant pain -
Non Target Embolization – if the beads escape the liver – this is why it is done as a 2 step procedure – with protective embolization done

 


Leigh Anne Burns – NOLA Nutritionist – Nutrition for NET

Keep eye on portion size

Many things in your diet can help control symptoms and fatigue –

Nutrition problems among NETs
Involuntary weight loss
Muscle Mass Reduction
Reduction in amounts of nutrients
Decrease in immune system

What is weight loss – 1 week >2% , 1 month > 5%, 6 month >10%

Diarrhea and malabsorption
Tumor release
Side effect of meds (sando may stop more than just tumor hormone release)
Due to surgery / tumor the GI Tract may change
Food intolerance

Dietary intervention
High protein High Calorie Dense Diet – you are only hungry for 15 min – you need food ready with easy access
Altered Fiber Diet – Insoluble (whole wheat) – vs Soluble fiber – you need soluble fiber
Low Fat Diet – drop fat in diet – or add enzymes to your diet
Diarrhea Reducing diet – reduce insoluble fiber – perhaps meat
Low tyramine diet – (stop flushing) things that are aged – alcohol / soy sauce / cheese – sometime over ripe fruit – Left over might produce problems as well

CHEW YOUR FOOD…. Start your digestion while chewing

Alterations to improve tolerances
Eat smaller portions – 6 small feeding a day

Nutrition Supplements
Only replace when needed to intake and absorption (ensure, boost)
Modular – Juven, benecal
Specialty – Peptemen – when you can not absorb anything

Medications – Lomitol – Tincture of Opium

Symptoms steatorrhea –
Pancreatic enzyme

Monitoring
Symptom relief / weight stabilize
Increased fat soluble (try morning am or late afternoon sun)
Increase in food selection

 


AFTERNOON Session

Patient info: 12,000 a year dx in the US – 120,000 living in the US -  ICD 9 code introduced in 2006

Many still do not know about NETs (Dr and patient community) –

Advocate – ADVOCATE – do not treat – bring awareness –

World Net Day – Nov 10, 2010 – first international day of NETs

2010 Warner Advocacy Award – Maryann Wahmann –

Facebook Page CCAN 4,600 members

What can an individual do – Ask your doctor to join NANETS – Start your own support group

Attended, volunteer and support NET Events

Net Cancer Day November 10, 2011 – CCAN will have a flag flown over the US Capital

September 20-22, 2012 National Conference in New Orleans

Dr. Tom O’Dorisio – University of Iowa

Evolution of NETs –  from Gastrin in 1905 – Zollinger-Ellison 1955- Radio Peptide Receptor 1967  - Octreotide 1980 - to Theranostics (Baum) in 2011
Heading towards surgery followed by prrt followed by imaging

Insulin – 1921-22 BantingBest – Insulin replaced in a dog

Zollinger-Ellision 1955 Gastrinoma discovery

Werner Creutzfeldt – Glucagon Peptide 1 GLP1 – Inspiration for Europe preeminence in NETs research and management

University of Iowa Mgt of Treatment Options
Tracking over 1,300 patient tracking
Algorithm of care – Scans first – Surgery - /Sando/ PRRT

Problems with NET interventions
Decisions made using gold standard CTs – but there is a lot going on with symptomatic and asymptomatic changes that are subjective .

In the US calibrations between neuropeptide plasma markers are sorely lacking between commercial – you can read the trends as long as stay with the same lab

Carcinoid Tumors Blood Markers
Serontonin (most sensitive – episodic)
5-H1AA – Almost never elevated without some type of liver mets

CgA – Use the same lab –

Validation of NKA assays in the US and Europe – must be done at ISI LAB – NKA >50 tumor is going to act more aggressively –

Pancreastatin is 100x more sensitive than CgA – very early marker for liver tumor activity

Operative Resection of Primary Tumor valuable even with liver mets

Serotonin and Pancreastatin are good makers to look for unknown primary

Theranostics – Molecular targeting of VECTORS which can be used for both therapy and diagnostics -
Target molecular imaging and therapy  -
Target  <-Vector-à Ga68 or Y90 or LU177 can go in the cage.

With a Ga68 you can quantify uptake and associated  SUV

Enormous benefit being able to use same principle for imaging and diagnostics – Theranostics


Dr. Delpassand – Chairman – Excel Diagnostics – PRRT

Three main decay process
Alpha (very small particles)
Beta (particle for treatment)
Gamma for imaging – wider and can go through tissue

Decrease of blood flow with larger tumor weight
Perhaps one reason Chemo does not work on larger NETs

Crossfire effect of radiolabeled treatment –

Advantages of Targeted Radionuclide Therapy
closer to personalized therapy

Side Effects -
Stem cells of bone marrow is important – Evidence of bone marrow damage appears at 4-6 weeks
Kidney also needs to be protected

Epidemiology
NETs is an orphan disease
Increase in case – is it early diagnosis – more environmental ?

Receptor Binding – Peptide Analog attaches to the tumor cell - once the analog attaches it release the radionuclide in the cage directly to tumor cell damaging the nucleus

PRRT – what has been used – In-111 DTPA  - y90 – lu177
Y90 – Long path length – lots of Energy
LU-177 shorter path length – less energy
IN-111 shortest path length – least energy

Nephrotoxicity related to PRRT
Kidney, spleen and tumor get the highest in PRRT -
Must use amino acid to block radiation

Y90 Dota-Toc
CR 5% PR 18% SD 69%

Indium 111 Octrotide Therapy
500 miliCurrie
Can result in stable disease – (88% were stable)
93 patients treated – 67% carcinoid – 12% pnet
Stable 93%, Partial 2%
Most other studies were done with lower dose
Median survival – 22 -25 months
PNETs had a closer to 40 month median survival

LU-177 Dota-Tate
PD 18% -  SD,PR CR 82%
LU vs I111 more PR and CR with LU 177

LU177 – IND 78,256  Filed June 2007 – Approved August 2010 for Excel Diagnostic
Excel worked with Rotterdam –
25 Patients in a year – No acute renal toxicity –

Patient example – shows great uptake and reduction of liver mets

Predictors of response to PRRT in NET
Needs to respond to OSCAN
Needs good uptake
F-18 FDG PET – give prognostics – FDG uptake is bad prognosticator predictor

Comparing PRRT – More CR and PR with Y90 and LU177  vs Ind111– but good stability with all

Conclusion
PRRT is novel and new
Limited Side Effects (3%)
Improved quality of life
Longer to progression and life 3-6 years

What is available in US

IN111 Yes and covered by most insurance (but not Medicare yet)

LU177 Yes in trail but no insurance coverage till multi center trail – but when the multi center starts – 2012 and may have some challenges with study design – ie random with no crossover

Y90 – not in US

Problem with Data
No Random Data
Administered dosage is different
Uptake  is different

Future PRRT
Treat in earlier stage
Need more data on Max Tolerated dose
Combo Therapy – both with radio nuclide and with other chemo agents
Hepatic artery infusion
PRRT before and/or after surgery as neo-adjuvant


Questions and Answers –

Morning Session

DX of NETs – 1cm mass was not biopsied – treated with Sando – the mass went away – could it be the Sando – maybe but it could have been something else as well.  Imaging must be done properly –

Can SANDO mask marker level (CgA, Gastrin, and others) – markers can go down as much of 50%

After surgery – how do you know if you need additional treatment – very little data on adjuvant (additional therapy) after getting surgical resection – more studies need to be done –

Anti Oxidant – Goes after free radicals – discontinue during active treatment

Foods that need to be avoided on the 5HIAA test – should be avoided in general ? – maybe – no clear evidence

What happens when you only treat one lobe with SirSpheres  - can it change the other lobe prognosis – it might change the direction – i.e. the other lobe might grow faster

Generic Cancer Drug shortages – Can that happen to NETs drug – Octreotide generic can have some shortages due to some manufacturing issues.

Dose the disease decrease Vitamins D,E,A,K – Only supplement with Dr. care

How do you find the correct diet – Google a particular diet – use only big hospital sites.

Inter Arterial chemo -> Dr O’do mentioned that in Germany PRRT was being done inter arterial which may be more directed than using chemo via inter arterial method

Afternoon Session

Can Typical Lung Carcinoid change to Atypical ?  -> No

After cycle of PRRT treatment do you need more? – once you progress you need to look at it all over again

PRRT – is it a last resort?  In the US it is – perhaps once it is approved in US the new standard of care might be – surgery first PRRNT second – (o’do)

Do you stay on LAR after PRRT ? O’do answer Yes -> DelPassand – Can stop is symptoms stop

If you have resectable tumors – should you do PRRT first or surgery – Surgery first if possible

Interfureon does it work – there are studies on this – but it is a challenging drug to take

Goal 1 is stability – try to make this a chronic disease

Food to consume for NETs – High in protein food – egg whites and fish.  Eggs are high in protein – you are at risk for other disease – need to reduce your risk for other disease – back off fruit juice – try the fruit.  Try putting mushrooms in the window and have them absorb the light for VIT D.  Try cooked veg – as they are easier to digest

How do you reduce protein loss – increase carbohydrate – use your muscle

Why transplant held as last resort – you are trading one challenge for another – transplant is life limiting

Affinitor – mTOR inhibitor – has a measurable results – but not one of Dr Gerstein favorites – it is very hard to tolerate.

End of Session