It's been a few months since I sat down with my friend, Dr. Nasser Hanna, a great lung cancer expert from Indiana University, and also a friend in the field. Those of you who have been following GRACE content for a while may have come across his name: he's led a few of the more important trials that are part of our current core knowledge in lung cancer now, such as the trial that directly compared Alimta (pemetrexed) to Taxotere (docetaxel) as second line therapy for advanced NSCLC; the Hoosier Oncology Group (HOG) trial that showed no benefit to consolidation Taxotere after chemo/radiation for stage III NSCLC; a trial of maintenance therapy with oral etoposide after initial cisplatin/etoposide for extensive stage small cell lung cancer, as well as others.

Here's a transcript and a few key images from our discussion of a challenging case of an elderly woman considering the merits of post-operative chemotherapy for stage IB NSCLC. (I'll just note that this format of presenting a transcript and a few figures is a fast, cheaper way for us to present the content of conversations we've been turning into podcasts until this point. It may be easier to just have it here online, and cuts our costs. If you have a definite preference for the audio/visual format of a podcast vs. this, please voice that opinion).

====================================================

Dr. West: Hi, I'm Jack West, Medical Oncologist and President of GRACE, The Global Resource for Advancing Cancer Education. I'm here today with Dr. Nasser Hanna who is Associate Professor in the Department of Medicine, a Medical Oncologist at Indiana University and he was good enough to sit with me and talk about a few complex cases, so thanks for taking the time.

Dr. Hanna: Thanks for having me.

Dr. West: Let's start with a challenging type of situation that isn't rare in the adjuvant setting. I saw a 73 year old woman...use to smoke up to a couple of packs per day for fifty years and brought her self down to a few cigarettes per day. She has a good performance status and several months ago developed a worse cough, productive of some clear sputum, no hemoptysis and she was prescribed antibiotics but didn't get better.

She had a chest x-ray that showed a large right lower lobe mass, and that was followed by a chest CT that showed an approximately 5 centimeter mass in the right lower lobe, with no findings particularly suspicious for nodal involvement.

She had a CT guided biopsy that showed a moderately differentiated squamous cell carcinoma. Pulmonary function tests were adequate for resection an FEV1 of 1.25 liters. She'd had a head MRI that was negative. Her PET scan showed an SUV of 17 in the primary mass and mild uptake in a right hilar node SUV 3.5; negative everywhere else.

She saw our surgeon, had a mediastinoscopy that was negative, multiple more than 10 notes removed, and then had a lobectomy and the pathology showed a 6 x 6 x 4.5 centimeter moderately differentiated squamous cell carcinoma with no pleural invasion, negative margins and over all staging was T2, N0, N0 clinically.

So following surgery she's got a performance status of 1. She's recovering okay. She has a history of hypertension, coronary artery disease, and not too much more. She's reluctant about the concept of chemo. My question to you would be how would you approach this? You have somebody who's older than the age that was typical in the adjuvant trials, but she doesn't have any clear contraindications. How do you counsel somebody with Stage I or Stage II disease at this point?

Dr. Hanna: Well that is a difficult case, and I would say evidenced-based medicine would suggest that patients who have completely resected stage II and stage III non-small cell lung cancer should be offered adjuvant chemo therapy as a matter of standard of care.

The patient that you've described, who had stage I, really fall into what we consider kind of the clinically low risk versus clinically high risk patients. Now this patient has a few features that do concern you. Her tumor is a bit larger. You've described it as 6 centimeters or larger, and we know from several series that even though she has stage Ib disease, those patients with larger stage Ib tumors appear to have a higher risk for recurrence.

Secondly, you described her tumor as moderately to poorly differentiated, and those features appear to have a higher risk of reoccurrence of well-differentiated tumors. And thirdly, her preoperative PET scan suggested a very intense uptake on SUV, and there are institutional reports that would suggest that those patients with stage Ib disease that have higher SUVs preoperatively also have a higher risk for recurrence.

On the other hand, she is 73 years old, and she is reluctant to take adjuvant chemotherapy. And I would certainly suggest even those patients of high risk stage Ib disease should only be counseled to consider adjuvant chemo if they are highly motivated themselves, have recovered well from surgery, and understand the lack of overwhelming data to support the use of adjuvant therapy in her case.

What I would recommend for her is to consider the CALGB trial. This is a very important trial that is led by David Harpole and Anil Potti from CALGB and Duke University: the group at Duke has reported on a "metagene" that is able to identify high risk and low risk genes within tumor specimens. And they have reported on several series that they're able to identify a population of patients with pathologic stage I disease who have a very high risk of recurrence based on biologic features alone and a separate group that had very low risk for recurrence.

(click on image to enlarge)

That observation has led to a CALGB trial, in which patients with stage I disease who recover well from surgery have their tumor tested by metagene analysis, and if they fit the low risk profile, they're simply observed. If they fit the high risk profile, they're randomized to observation versus adjuvant chemotherapy.

So I would encourage her to participate in that trial if we were to consider chemotherapy.

Dr. West: How do you feel about particular regimens, and particularly cisplatin versus carboplatin, in somebody who is either wary about toxicity or older, may have a creatinine of 1.4 - 1.5? Are you most committed to the idea if you're giving adjuvant chemotherapy, it should be cisplatin-based, or would you be inclined to make a substitution?

Dr. Hanna: I would use cisplatin, assuming there are not contraindications to cisplatin. There are no statistically positive trials for carboplatin either in the neo-adjuvant or adjuvant setting, and there are several trials now with carboplatin-based regimens that have been reported, and while there are small trends suggesting some benefit, they are statistically negative trials.

In the metastatic setting, comparisons of cis versus carbo, at least in a meta-analysis, has suggested that cisplatin is a slightly superior drug -- not dramatically so in the metastatic setting -- but any advantage you can get in the curative setting is very important.

So as long as they're no contraindications, cisplatin is the platinum of choice. Today, there's really no reason not to safely give patients cisplatin. It is rarely nephrotoxic if you adequately hydrate the patient and make sure that they don't suffer from volume depletion with nausea and vomiting. And most of our anti-emetics can prophylactically prevent significant nausea.

Dr. West: There has been additional work done from one of the larger adjuvant trials, the IALT trial, that looked at ERCC-1 expression, the molecular variable that seemed predictive of whether patients would get a benefit from adjuvant chemo or not. Do you use that in the adjuvant setting to help with decisions in a case like this; either regardless of a patient's stage or in a more marginal patient who's dubious about getting chemo?

Dr. Hanna: I think that's a very good question. So, in the International Adjuvant Lung Trial (IALT), ERCC-1 levels were assessed in a subgroup of those patients, suggesting that if you had high levels of expression of the excision repair enzyme, that you had a better prognosis, but that you may not benefit from this platinum-based adjuvant therapy.

That was a subset analysis; I think at this time I'm not ready to utilize that in my everyday practice, particularly if you have conflicting information. If you have an ERCC-1 level that's high, suggesting the patient has a favorable prognosis, yet the patient had a poorly differentiated tumor with an SUV of 17, and the tumor was six and a half centimeters in size, that would not be enough reason for me not to offer the management therapy.

Secondly, sometimes it's difficult to interpret the ERCC-1 levels. How do you define high versus low? The labs that draw these levels give you a number; they don't tell you if it's high or low, and where's the cut off? I think it's a very important area of study; ERCC-1 is one of a handful of enzymes that are involved in DNA repair. It may or it may not be the most important of the enzymes, and so at this point I would still consider that investigational.

Are you using it?

Dr. West: It is still retrospective and subset analysis, and your issue with methodology is well taken. For me, I'm swayed by the fact that the data thus far have all pointed in the same direction, and the data suggest that if you guess wrong, you could harm a patient. So it's not just an issue of, it's neutral or it's helpful. If you give someone, particularly someone with comorbidities, platinum-based chemo and they are resistant, you may just be giving them both short term and potentially longer term adverse effects.

I am not using it to override standard of care in somebody who I think the available data suggests they should get it, but if somebody's 76, marginal performance status, poor renal function; or in somebody who has, say, a stage Ib tumor around 4 centimeters, I would use that to help clarify what my recommendation might be. Or at least inform the decision.

Another question I would ask is if it's the same patient, but her tumor is 3.9 centimeters: how important is the size of the tumor, and what are your recommendations if someone has a poorly differentiated tumor and it's 3.9 versus 4.4 centimeters?

Dr. Hanna: Well, I think it's all relative. I don't think there's a magical cut-off at 4 centimeters. Certainly there's a risk spectrum. And at this point, there is insufficient data to routinely justify the use of adjuvant chemotherapy for patients who have anything other than stage II or stage III disease.

I think those patients should be encouraged to participate in clinical trials. If there's a patient in whom I think they have very worrisome features clinically, I would at least discuss the role of adjuvant chemo therapy with them. They would have to understand that, at this point, this is theoretical and that we don't have hard randomized trials that would suggest that the risk/benefit ratio would favor benefit.

This is all the reason why it's imperative to enroll patients on clinical trials. The CALGB trial is a really, really important trial. One would argue it's amongst the most important trials we've ever done in lung cancer, because it's first deciding on whether you're going to treat somebody or not, based upon the biology of the disease and not what it looks like under a microscope. And secondly, if they have bad risk features, can we do anything about it with our current therapies?

Dr. West: It's interesting to ask, if you can identify that someone has a poor prognosis, can we change that with our treatments?

Dr. Hanna: We can identify they have a bad prognosis, but the question is can we do anything about it? I suspect yes, but we'll see.

Dr. West: What would your approach be for a 73 year old never-smoker who has a moderately differentiated adenocarcinoma and you see post operatively, and EGFR mutation testing has been sent and is positive, and she's reluctant about chemotherapy? Would you make the same recommendation for chemo, or how would the EGFR status affect your decision?

Dr. Hanna: That's a very important and interesting question. We don't really know the answer to that. It appears the patients who have EGFR mutations have a better prognosis, at least in the metastatic setting -- they just do better. They live longer and the respond better not only to EGFR inhibitors, but they respond a little bit better to chemotherapy than if they were EGFR wild type.

We really don't know in the post operative setting what that means. Maybe it means that they're going to well if you just leave them alone. Maybe it means that an adjuvant treatment with erlotinib (Tarceva) would improve not only their disease free survival but maybe improve the cure rate.

There was some interesting data from Memorial Sloan-Kettering that was presented at ASCO 2009. The group at Memorial had been genotyping EGFR status on their post-operative patients for many years, and they had a cohort of patients in whom they treated in the usual manner, either no therapy or adjuvant chemo, even if they had EGFR mutations and they weren't receiving erlotinib. But in the last couple of years they had routinely been giving these patients erlotinib in the adjuvant setting if they had mutations.

They presented the disease-free survival between these two cohorts and this was not a randomized trial, but just consecutive patients who had that that same profile. There was a substantial difference in the disease free survival between those two, suggesting that adjuvant Erlotinib could not only prevent recurrences but maybe improve the cure rate.

Right now there is a trial called the RADIANT trial that randomizes patients to either erlotinib or placebo in the adjuvant setting. Some have received chemo and haven't received chemo, and that trial hopefully will address that specific question.

What do I do today if that comes up? I talk to the patient. I think that there may be some merits in giving Erlotinib. I'm always hesitant to do things in which we don't have a lot of data because there's always a potential for harm.

So far the data from Memorial Sloan-Kettering look very promising, and I think it merits a discussion with your patients. I haven't yet done that, but I have to say that there have been a couple of opinion calls that I've gotten in which I've suggested that they consider that for their patients.

Dr. West: Great, thanks.

[NOTE: Though I haven't talked with Dr. Hanna about this last question since the presentation of the BR.19 trial at ASCO 2010, I strongly suspect that based on the negative results with Iressa vs. placebo in that trial, with even a strong trend of detrimental effect from post-operative Iressa, that he would now be much more inclined to advise against it outside of a clinical trial.]