Dr. Pinder -

Thank you for posting this interesting information and good on Dr. Okunieff for taking a different approach to using SBRT for metastatic disease. I look forward to hearing more about this research as it proceeds.

- Catharine

Dear Dr. Pinder,

Thank you for this article. It is of particular importance to me because my wife now has several options for continued treatment (including various types of radiation) OR non-treatment following her recent, successful chemotherapy treatments. She does seem to fit the “model” patient you refer to that has an indolent lung cancer that has metastasized, in her case, to the adrenal area. My recent post describes our dilemma:

http://cancergrace.org/forums/index.php?topic=2956.0

We are having a tough time parsing all this info and deciding where our heads are at on this, the eve of our meeting with our first of two radiation oncologists. Based on your article, it would seem like taking a shot at this now-shrunken and singular metastasis is a vote in favor of zapping it while it’s down.

Best,
-Roger

Catharine,

Thanks for your comments. I also admire Dr. Okunieff for taking on this work - it is definitely controversial. I hope that continued systematic study of this treatment modality will yield results for patients and further insights into why and in whom it might work.

-Dr. Pinder

Roger,

You are not alone in having a tough time parsing all of the information out there - the oncology community is right there with you. Given the number of options presented to your wife, it is clear that the “right” answer is unknowable. Patients like your wife challenge us all the time. She has had relatively long periods of time between relapses and has responded to local therapy and chemotherapy, leaving her with lots of options, which ultimately is a good thing to have. I am glad you are meeting with the radiation oncologists and hope that they will be able to offer some further insight.

I’d also like to reiterate that the approach I’ve discussed in my post really is experimental at present.

-Dr. Pinder

Interesting work, and I think you did a very good job of identifying the key question of whether the results of favorable outcomes in a minority of patients are directly related to this treatment or whether these are the very people who would do well with any treatment.

I’m certainly much more inclined to consider local therapy such as SBRT or another form of radiation, or rarely surgery, for a patient who has just a single focus of active metastatic disease, and also in someone who has been followed for long enough without progression in other areas to feel some confidence that nothing new is about to appear within a month or two after pursuing the local treatment.

Unfortunately, the trial being done by SWOG and NCCTG for using radiation to treat metastatic disease has such liberal eligibility that I’m afraid it will include a lot of patients who are pretty unlikely to benefit significantly. The discussions I’ve attended made mention of there being up to 3-4 areas of active disease immediately after several cycles of initial treatment. To me, if there are 3 or more areas of involvement, that’s not really “oligometastatic”, and it’s not giving local treatment to patients whose cancer has been shown to be localized over time. If this concept is pursued in people who really aren’t likely to benefit, it’s likely to lead to negative trials that taint the concept when it may actually be valuable for a more restricted population.

-Dr. West

So let the photons begin…

We had two meetings in the past two days covering all of my wife’s available options for radiation therapy. First was the radiofrequency ablationist / cryoablationist who examined her most recent scan. He said that it was indeed possible to burn / freeze the now-shrunken tumor but to hold judgement until we saw the radiation oncologist. The reason for his hesitation was that the tumor’s adjacency to her aorta would compromise the complete heating / cooling of the tumor.

Next, we saw the radiation oncologist who said, to our surprise, that raining his brand of high intensity radiation down on the tumor would be perfect for our situation. “Piece of cake” were the words he used, although the requisite risks and side effects of radiation quickly brought us back down to earth.

I was not able to ask exactly what device he would be using, but it was a CT-guided series of high-intensity zaps, three sessions over a week’s time, each one requiring about a half-day commitment. She will be immobilized using supports molded from casts from her own body. Also a girdle, looking and working like an over-sized blood pressure cuff, will be used to surround her abdomen, where her tumor is located.

Part of his reasoning and optimism was that her NSCLC metastasis was limited to a single site over the life of her cancer, and that her response to chemotherapy was quite good. Proximity to the aorta was not an obstacle.

How does this apply to Dr. Okunieff’s presentation? Perhaps it lends weight to the notion that a person who has a slower-growing cancer (as she does) that has spawned one (or only a limited number of) metastatic site(s) over a “long” period of time, is less likely to be plagued with micrometastases, and if that is so, then eliminating these sites through high-intensity focused radiation could mean a cure for more people than the current standard of care allows.

Roger

Roger,

Thanks for the update on your wife and for your comments. Your last paragraph is exactly the reasoning that is driving this research. There are patients who seem to present over and over with metastases in a single site/organ. Do these patients just have a biologically more indolent cancer or is early treatment “catching” them and preventing their disease from spreading? We don’t know yet (suspect the former). Dr. West’s point is well-taken. If we liberalize criteria for SBRT for oligomets, we may be treating patients who have no chance or benefiting and may dilute the results of the studies. I would have no enthusiasm for doing SBRT in someone who presented with 3 new mets within a month or two of completing chemo.

Another really interesting rationale for treating oligometastatic disease with SBRT is that even stable mets may potentially seed other sites. So far, this has not been proven but is an interesting hypothesis. I hope very much that this treatment is successful for your wife.

-Dr. Pinder

Dr Pinder,

Thanks for the kind words.

From my lay perspective it seem like stringent criteria for Dr. Okunieff’s study could easily be established to filter out most or all of the non-indolent cancers.

Limit the study participants to those who have a maximum of two sites of metastasis (not including a single primary tumor) determined treatable by resection or SBRT. No previous cancers. Acid test: no further metastasis detectable by PET and MRI brain scan at the 36-month mark.

I know I am talking out of my hat loudly at this point, but it seems fairly straightforward to me to come up with a relevant cross-section of participants, even retroactively.

-Roger

We always walk a fine line between trying to get the appropriate patients on a study and becoming so stringent that we would never be able to accrue enough patients to test the hypothesis. I think if we waited 36 months, there would be so few lung cancer patients who met the criteria that we would not be able to complete the study. It makes sense, though, to at least allow a reasonable amount of time to prove that the patient is not going to develop widespread metastases. It’s hard to say where the cutoff should be but I would tend to agree with you that a patient with 5 metastases is different from one with 1 or 2.

Hi Dr. Pinder,
I want to compare Dr. Okunieff’s data of 20% overall survival with the WJTOG 0203: Overall Survival data. In that trial, overall survival was at 20% at 60 months and there were 2 arms, either chemotherapy followed by Iressa or chemotherapy alone. It seems to me as a patient to say that localized therapy may not be necessary to achieve long-term survival.
I am also intrigued by the hypothesis that mets can beget more mets. Since metastatic disease is considered inoperable, I wonder if the hypothesis applies only to patients who had resected primaries and had metachronic metastases. Does it also apply to patients who have both the primary and metastases?
Thanks,
ctrider

The idea that modern systemic therapy results in long-term survival in a growing proportion of patients is one of the reasons for the controversy surrounding treating metastatic disease with local therapy. One of the reasons for the appeal of local therapy (for patients and doctors) is that treatment is brief and if successful, patients may enjoy a long window of time off therapy. If a patient with oligometastatic disease could be treated successfully with either systemic therapy or local therapy, I can definitely see why a patient might choose local therapy.

With respect to the theory of whether metastases beget metastases, we really don’t know at this point and I think this will be very difficult to sort out. We have always considered metastases to be the result of seeding from the primary tumor. Even though they may appear at different points in time after resection of a primary tumor, this could just be a function of different biology within the metastases or the tissue they inhabit. It doesn’t necessarily mean that a met came from another met. Still, no one has disproved the idea that mets could come from mets and I think it is an intriguing hypothesis.

-Dr. Pinder

Hi Doctors,
I do remember seeing in a TV documentary of Dr. Volkman’s research on statins that the primary tumor secretes an anti-angiogenic substance to suppress the growth of metastases. I wonder if 1) metastases do the same 2) whether this is older research at the turn of the century and is now supplanted by newer data.

Here is the link:
http://www.pbs.org/wgbh/nova/programs/ht/qt/2805_06.html

I often wonder if this research dovetails with the clinical data that a fair number of resected early stage disease produce metachronous mets and the cure rate of lung cancer is not close to 100%
Thanks,
ctrider

I don’t know that, but that might suggest that there could be a detrimental effect of facilitating cancer progression by treating metastases. I don’t know of any evidence to suggest that, nor have I seen many anecdotal cases that would lead me to suspect it. What we most often see is that, if this is done at a time when there is no evidence of disease elsewhere over a long period of time, we most typically see a few new lesions pop up slowly over time, which I suspect is exactly what we’d have seen if we had just ignored the one area of disease we were following, or rarely we won’t see anything progress over years. The latter could be a cure, if we were fortunate to have killed the last living cancer cell, or it could be a very slow progression in the background that just hasn’t made itself apparent (and may be so slowly growing that it never does).

Much of the work that was being discussed in the PBS piece is very lab-based, so those of us working directly with cancer patients regularly are often not deeply involved with that level of early research and couldn’t comment on how much or little the field of very basic science angiogenesis research (here with “basic” meaning lab-bench based, not “simple”) has changed in the last few years. By the same token, the people who do the lab-based research tend not to spend much time taking care of patients directly.

I have recently (re)joined the faculty of GRACE lead by dear friend Dr. West. I found this article by Dr. Pinder very interesting.

This is an issue that is coming up more and more. With better scans and with improved therapy we are beginning to see patients who have very ‘limited’ areas of metastases and have significant shrinkage in their cancer. Should we consolidate the gains of chemotherapy with radiation or other local treatment such as surgery or radio-frequency ablation or cryotherapy is something that is not completely clear.

I would like to mention my own thoughts on this issue-
1. I agree with Dr. West. Presence of 3-4 sites of metastatic involvement should not be considered ‘limited’
2. I do feel the site of metastases has relevance. So I dont think a patient having a single liver metastases is the same as a patient having a single adrenal metastases.
3. I feel that patients should be considered for ‘local’ therapy after the cancer has been treated by systemic treatment such as chemotherapy or Tarceva. I am more likely to consider ‘local’ treatment in patients whose cancer improved after systemic treatment. This suggests that even if the patient has other tiny areas of cancer that are too small to be seen on the scans they are likely to be controlled for a longer period of time. Therefore doing something for the local treatment for limited area of metastases is likely to control the cancer better. If the patients cancer does not respond to systemic treatment or particularly it grows on systemic treatment I am much more likely to recommend against local treatment even if the metastases are limited.
4. Of course in the future through genetic or other such analyses we may be able to predict which patient’s cancer is likely to be slow growing and therefore more likely to derive benefit from local treatment of metastases.

Would love to read feedback particularly from Dr. Pinder and Dr. West.

Dr. Gadgeel

I think we’re converging on the same principles. What’s interesting is that our previous view of the general doctrine that metastatic lung cancer is an all or none definition is eroding, and we’re less convinced of the prior truism that metastatic means incurable, for NSCLC, at least.

I believe it’s important to not go too far down a slippery slope and change our approach to advanced NSCLC. In the clear majority of patients, this isn’t the question we can feasibly consider.

Overall, my view is that the longer someone has been followed with no evidence of multifocal disease, and the more minimal the cancer was to start with, the more hopeful I would be about pursuing local treatment. And I also consider the challenge of the local therapy: if it’s likely to be well tolerated, I’m more inclined to consider a non-standard and more aggressive approach than if it’s a major surgery in someone who is a very marginal candidate for it.

Finally, I just wanted to add a link to a similar discussion on the forum side, in case people are interested. This is clearly a timely, important topic to both patients and the docs.

-Dr. West

Dr. Gadgeel,

Nice to meet you, thanks for you comments, and Happy New Year!

My wife fits the topic that Dr. Pinder’s post describes almost exactly. She suffers from a single oligometastatic tumor now, three-and-a-half years after her initial diagnosis. Her capsule history: DX July 2006 NSCLC (K-Ras. positive / G12C, position 12); 60% tumor reduction through platinum chemo; subsequent right pneumonectomy. 2007 recurrence in left adrenal gland; subsequent laparoscopic adrenalectomy. 2009 recurrence in adrenal bed (at site of surgery); 60-70% reduction through platinum chemo. No other apparent metastases. Upcoming SBRT (2/2010) to vanquish oligometastatic tumor.

I would like to know what the difference you refer to in your point number 2:
“So I dont think a patient having a single liver metastases is the same as a patient having a single adrenal metastases.”

Many thanks,
-Roger

Mr. Racer,

Thanks for your comment. I should have clarified my point 2 better.

I believe the data suggests that doing local treatment for adrenal metastases or brain metastases can provide long term control. However if somebody has a single liver lesion then expecting similar benefits may not be reasonable. This is because somebody who has liver metastases is much more like to have other areas of involvement and these areas are likely to show up on scans in a relatively short period of time. Thus making local treatment less meaningful. While patients who have only adrenal or brain metastases are less likely to have other areas involved or it may take some time for the other areas to show up on scans.

What I wanted to emphasize was that the consideration for local therapy is influenced by the site of metastases and not just the number of metastases.

Dr. Gadgeel

It’s true that the data and reports of patients who have done well after tretment for a “precocious metastasis” have primarily been patients with an isolated brain metastasis or an isolated adrenal metastasis. In my training and over the last few years I have sometimes extended the principal to an isolated bone metastasis or lung metastasis, and perhaps a rare isolated liver metastasis (though I’m having trouble recalling a case definitively). I don’t think I’ve had a really great response from any of these latter cases, and there are not nearly as many cases of as favorable long-term results as for brain or adrenal metastases.

There certainly haven’t been any comparative studies of these very individualized treatment courses, and my experience that amounts to fewer than 10 patients over the last few years doesn’t provide any firm answers, but I believe that Dr. Gadgeel’s assessment reflects the impression of many other experts, based on the very limited evidence as well as clinical experience.

That said, one real advantage of actually studying the practice of administering radiation for a focal residual lesion in the setting of established metastatic disease is that in addition to clarifying how probable it really is or isn’t to obtain excellent results with local therapy, we can also get a better sense of which patients are best served by this approach and which are not.

-Dr. West

What this says to me is that these studies are incredibly valuable, albeit not for the majprity of patients. Results of the studies could change some of the one-size-fits-all thinking about metastatic disease. And enough of these cases could produce a critical mass of long-survivors that could refine the perception of insurance companies when it comes to approving more of these procedures.

This is precisely the point at which my wife and I find ourselves now. The device treating her will be a tip-of-the-arrow radiation delivery system, of which there are only a few in the country. That, coupled with using it in the setting of a Stage IV metastatic tumor says to me that getting this approved by our insurance might not necessarily be the slam-dunk we’d like it to be.

We are cautiously optimistic about it all, but also recognize that our situation is more the exception than the rule.

Roger

Why is it possible to obtain access to this novel technique without first waiting the requisite seven years for clinical testing and FDA approval? What makes this different from a new drug?

The FDA has different and more lenient rules about medical devices and procedures than for new agents. These techniques are approved for particular indications — for instance, stereotactic radiation is indicated for re-irradiating a local recurrence within a radiated field — but they’re often pursued far outside of those indications. This is akin to using chemo agents approved for one thing in another setting — such as Abraxane in lung cancer (approved in breast cancer).

Practically speaking, it’s easier to get access to treatments that are already commercially available in some setting and where the barrier is whether the rationale is strong enough (considering benefit and risk) and whether it will be reimbursed. I can assure you that these interventions, whether the intervention is a procedure or a drug, wouldn’t be pursued outside of a clinical trial if the health care facility wasn’t getting reimbursed for it. Many oncologists have learned what treatments will or won’t be covered by insurers in their area, and unless a patient will pay for the ones that aren’t reimbursed, they aren’t given. I know that insurers also have input about techniques like stereotactic radiation, and they aren’t always covered, particularly in cases in which the value is unclear.

Clinical trials of new drugs and new techniques can not only provide a mechanism for patients to have access to these approaches, but if the results look favorable, they can provide the rationale for offering them to other people later on.

Dr. Gadgeel,
I would like to understand the rationale of the localized treatment of chemo or Tarceva responding patients. After radiating or rescting the lesion(s), the possible microsatellites that are left in the body will not have their biological clocks reset to zero, is that right? In other words, if a remaining particular microsatellite is on course to develop Tarceva resistance, the localized treatment, say administered one year into the scenario, will not ‘reset’ the clock of the microsatellite. So it will mutate in just one more year but not two. So the benefit of localized treatment is more of wiping out sites that produce seeding of potential microsatellites, but not ‘resetting’ the clock of microsatellites already in the body. Does this lining of thinking make sense?
Also, in localized treatment, would you be treating just the metastasis, or would you go after the primary tumor as well?
Thanks,
ctrider

The rationale for considering local therapy in stage IV patients after the disease has shown a response to systemic therapy is the hope that even if the micrometastatic sites have not been wiped out, it would be some time before these sites became big enough to be detected or become an issue. So if the cancer that can be seen on the scans responded then the micrometastatic sites also should have responded, may be not wiped out but shrank with treatment. So in a sense the hope is that the systemic therapy did ‘reset the clock’ of the micrometastatic sites.

Since the hope is that with systemic therapy we have ‘reset the clock’ the local treatment of the ‘limited’ sites that can be seen on the scans can be helpful to the patient.

As far as addressing the primary site as well. I only consider local treatment if I can treat all the sites we can see on the scans. In general if we cannot treat all the sites we can see then just doing local treatment to one site or some of the sites is not useful. Of course we do give local treatment to single sites to comfort symptoms, such as radiation of bone metastases.

I am currently 11-months into 2nd line Tarceva. My primary was removed. The only remaining evidence of disease is some shadowy mets in the lower soine and pelvis. I had pain from two places last August and had 10 radiation treatments which have worked marvelously to erradicate the pain. Most recent C-T scan was “mighty good” in the words of my oncologist. All of this makes me think I could hold the line here indefintely with radiation in one form or another.

Just checking in with a bump on this. Any relevance for me that I should be considering? Stable on Tarceva for 15 months, except for a single new 6 cm lesion (tumor?) in my liver. Previous liver lesion is reduced and stable at 5mm or so.
Thank you.

I think it’s reasonable to consider local therapy if there’s only a single lesion that is growing against a background of stability everywhere else, especially if a person has been followed a long time and has had the chance to demonstrate that this is truly a situation of “unifocal” progression. I can’t speak to how challenging it might be to do radiation for a 6 cm liver lesion. Though I think radiofrequency ablation (RFA) to liver lesions has almost no relevance for NSCLC in general, this might be a situation in which it would be worth consideration (though I think RFA is far more feasible for smaller vs. larger tumors).

Dr. West - -

Is surgery totally out of the question in the type of situation discussed by ts?

Laya

Nothing’s totally out of the question, but it’s a very significant, morbid intervention for a situation that would still represent a long shot. Because the concept of local therapy for this situation is essentially ignoring the probability that there are other areas with viable cancer cells, it’s important to not undertake a treatment that is considerably more likely to harm than to help a patient.

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