1. Shyam B. Paryani M.D., M.S., M.H.A & Nitesh N. Paryani, M.D.
Oligometastases: Curing the incurable A multi-generational perspective on cancer cure
Shyam B. Paryani M.D., M.S., M.H.A &
Nitesh N. Paryani, M.D.
May 1st, 2015
16th Annual Cardiovascular & Medicine Symposium
St. Augustine, Florida

2. Outline Terminology & Background A brief historical overview
Cancer cure rates over time
Biological basis for curability of oligometastatic disease
Questions we must ask
Review of evidence – by site
Questions & Discussion

4. Terminology & Background
Oligometastases
Coined by Weishcelbaum and Hellman in 2005
An intermediate state between local and metastatic disease, as per the spectrum hypothesis
Five or less sites of distant disease and primary can be controlled
Oligorecurrence
Less than or equal to five lesions
Primary under controlled
Possibility of rendering patient disease free once again

5. Terminology & Background
Radiosurgery or Stereotactic Body Radiotherapy
The concept of giving high doses of radiation over a few treatments
Focusing the beam on the tumor and a small rim of healthy tissue
Like surgery, but non-invasive
Side effects usually minimal; treatment well tolerated
Originally pioneered in Japan, now widely accepted and utilized

6. Historical Overview Must look back before we can look forward
How did we come to current understanding of cancer behavior?
Remember, the world was once flat…

7. History 1907 – Halsted, our favorite cocaine addicted surgeon
Locoregional spread through surrounding tissue
Cancer can be cured if diagnosed early…
…and treated with aggressive surgery

8. History 70 years later, Fisher model
Cancer is always a systemic disease
Mets always present
Can happen early in disease course
Systemic therapy is the cornerstone
Aggressive local therapy may not be as necessary

9. History The Spectrum hypothesis
Disease ranges between local and disseminated at time of diagnosis
Progression occurs as a result of acquired somatic mutations and chromosomal rearrangements during the course of the disease
“Seed and soil” phenomenon
Tumor dormancy is possible, likely due to immune response
Some cancers may never metastasize

10. Radiation Oncology Evolution
1960s
1980s
Late 1990s
2000s 2D
3D Conformal
IMRT
IGRT
Stereotactic Treatments
T R E N D – I M P R O V I N G P R E C I S I O N
The point of this slide is to show that over the past 45 years, Varian has continued to innovate and to move radiation therapy towards our ultimate goal: conforming radiation doses as closely as possible to the exact size and shape and location of the tumor.
This precision has been accomplished primarily with new digital technology and accessories for the medical linear accelerator which is the basic treatment machine.
As you can see here, new accessories for state of the art treatment techniques, have added significantly to our ASP over the recent years. In the past 7 years, ASPs have climbed from ~$1.2M to $1.9M for IMRT, and it is now moving towards $2.4M for IGRT and $3M for our top of the line stereotactic systems.

11. PARYANI PARADIGM SHIFT
FROG has been around for over 50 years to see these changes in knowledge, and is constantly adapting!

14. Biologic Rationale
Multiple studies have evaluated genetic differences between patients with oligo- and polymetastatic disease.
Multiple (>100) genetic differences between tumor cells from each cohort
Polymetastatic tumors also have more cell-cycle regulatory genes active
A preliminary 11-gene classifier exists to distinguish poly from oligometastatic
More research is needed

15. Other Factors to Consider
Number of mets
Prognostic of survival in most studies
Several studies have found 4 mets the “critical number”
Disease free interval – for oligorecurrence
Lymph node status – those without do better
Nomograms – there are many
microRNA profile – under investigation

16. Questions to ask Do patients with limited metastatic disease exist?
Do a subset of these patients behave differently; do they have a slower natural history? – true oligomets.
Does aggressive treatment improve outcomes?
How can we make sure these patients get they treatment they need?

17. Do they exist? And if so, are there ones with a more indolent course?
I think we can all agree yes on this....

19. Favorable subset
Singh et al., IJROBP 2005 showed that prostate cancer with patients with <= 5 mets have similar survival to those without mets (~75% 5 year, 45% 10 year), and better survival than those with > 5 mets (45% and 18%).
Dorn et al., IJROBP 2011 showed similar differences for breast patients (60% vs 12% 5 year)
Torok et al presented their data at ASTRO 2013 for lung: 13 month median survival vs 7 month for oligomet patients

20. You don’t always spell things correctly either

21. Evidence by site
Liver
Lung
Spine/bone
CNS

22. Liver Frequent site of mets for GI/sarcoma/breast
Surgery, SBRT, RFA all utilized for limited mets
10 year follow up exists for hepatic resection with limited mets for colorectal cancer
Survival up to 28% (JCO 2007)
5 year data for breast cancer
Ranges from 21-61%
Neuroendocrine tumors can see 95% survival

24. Liver All of these studies centered on resection
From the pre-SBRT era, of course, but…

26. Evidence by site
Liver
Lung
Spine/bone
CNS

27. Lung Most extensively studied site of oligomets
Pastorino et al looked at 5206 cases
Multiple primaries, all with resected lung mets
5 year OS 36% R0 resection vs 13% R+

28. Lung

30. Evidence by site
Liver
Lung
Spine/bone
CNS

31. Bone Bone mets account for 20% of mets
We know bone only breast cancer patients live longer
Surgery is much more invasive and disabling for many bone lesions
SBRT is increasingly being adopted in this site

34. Evidence by site
Liver
Lung
Spine/bone
CNS

35. CNS Most commonly studied in NSCLC patients
First large series of patients with synchronous resections of pulmonary lesions and CNS primary date back to 1976
10 year survival was 15%
Pooling together retrospective series, survival has been as high as 30% at 5 years

39. PARYANI PARADIGM SHIFT
Chance to cure those who we thought were incurable
Or at least, prolong their lives and improve the quality
Changing the paradigm in the battle against cancer
These patients need to be evaluated by experienced and innovative radiation oncologists
Not just given chemo, and wait to die
We stand ready to help your patients beat their cancer
And remain humbled by the opportunity to provide cancer care to this community for over 50 years