GRACE :: Lung Cancer

Targeted Therapies in a Post-Operative/Adjuvant Setting

GRACE Cancer Video Library - Lung

GCVL_LU-D21_Targeted_Therapies_Post-Operative_Adjuvant_Setting

 

Dr. Nathan Pennell, Cleveland Clinic, reviews the available trial evidence for the use of targeted therapies in the post-operative/adjuvant setting.

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I’d like to talk to you now about adjuvant treatment with molecularly targeted therapies for non-small call lung cancer. We know that early stage patients, so patients with stage I, II, or III non-small cell lung cancer — many patients are cured with surgery, but unfortunately, many patients go on to recur with metastatic disease. The reason this happens is that some of the cancer cells have escaped from the tumor before surgery and spread elsewhere in the body. This is called microscopic metastatic disease, and for this reason, we offer patients at high risk of occurrence adjuvant therapy. Adjuvant just means that we give four cycles of chemotherapy after surgery, and we know that this provides a modest, but significant improvement in cure rates after surgery alone.

Well, what about for patients who have molecularly defined subgroups of cancer, like EGFR mutation-positive cancer, or ALK-positive cancer? We know that, in the advanced setting, targeted therapies like Tarceva or Gilotrif for EGFR-positive cancer, or crizotinib or Xalkori for ALK-positive lung cancer, are better than chemotherapy in terms of inducing tumor responses, delaying the progression of cancer, and potentially even improving overall survival.

Since they work in the advanced setting, wouldn’t it make sense that they might work better in the adjuvant setting as well? Well, it’s not quite that simple. For one thing, we don’t have any evidence for any type of molecular subgroup, other than EGFR mutation-positive patients, but even in that setting, we really don’t have good evidence that adjuvant therapy improves cure rates after surgery alone. We have a little bit of evidence, so we know that the doctors at Memorial Sloan Kettering Cancer Institute in New York have treated several hundred patients with adjuvant Tarceva after surgery and they’ve reported that the patients have probably a lower than expected recurrence rate compared to what we might expect for that risk of patients, and they’ve suggested that maybe even they’re improving cure rates with adjuvant Tarceva.

Unfortunately, you can’t draw conclusions from a retrospective series and not a prospective trial. There have been at least two prospective trials that have been done, including one phase II trial that treated patients with two years of adjuvant Tarceva after surgery and then a subgroup of patients from a phase III trial called the RADIANT trial — so these were not EGFR mutation-positive patients in the overall trial, but there were 160 mutation-positive patients on the trial who were treated with two years of Tarceva, or two years of a placebo. All of these put together have suggested that adjuvant Tarceva does potentially delay the recurrence of cancers, but once the adjuvant treatment stopped, many patients went on to recur at a later time. None of the trials have suggested that patients lived longer or were cured at a higher rate than patients who were treated with standard treatment, including adjuvant chemotherapy.

What we really need is a randomized prospective phase III trial. Luckily, there is one that’s open and enrolling called the ALCHEMIST trial. Patients with stage IB, II, or III non-small cell lung cancer are tested for EGFR mutations or ALK gene fusions, and if those are found, they’re randomly assigned to two years of Tarceva for EGFR, or Xalkori for ALK-positive lung cancer patients, or two years of a placebo. Hopefully, at the end of this trial we’ll know whether patients are cured at a higher rate when treated with these adjuvant target therapies, versus just delaying the recurrence of the cancer.

For now, in 2015, I would not routinely recommend adjuvant therapy with a targeted drug like Tarceva or Xalkori outside of a clinical trial, but would strongly encourage patients to enroll in the ALCHEMIST trial.


Induction Chemotherapy Followed by Chemo/Radiation for Stage III NSCLC

GRACE Cancer Video Library - Lung

GCVL_LU-E10b_Induction_Chemo_Radiation_Stage_III_NSCLC

 

Dr. Mark Socinski, University of Pittsburgh Medical Center, discusses the benefits of giving two additional cycles of chemotherapy in combination with radiotherapy for stage III NSCLC.

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One of the areas of controversy is with regard to induction chemotherapy, followed by chemoradiotherapy in stage III disease. I mentioned before that systemic micrometastatic disease is a huge problem in these patients, and one has to give adequate, effective chemotherapy in this setting. We typically give chemotherapy with radiation, but radiotherapy strategies typically last six to seven weeks, and therefore, that would really account for essentially two cycles of chemotherapy. Now, in stage II or III when we are giving adjuvant therapy, or in the metastatic stage IV setting, our current standard is to give four cycles of chemotherapy in that setting, maybe sometimes six in the stage IV setting, so I’ve always wondered why would we just give two cycles concurrent with chemoradiotherapy in the stage III setting?

However, I will tell you that all the level one evidence does not routinely support the use of more chemotherapy, other than during the radiotherapy. Obviously, it could be given before, as so-called induction, or it could be given after chemoradiation, so-called consolidation therapy. Many investigators have pursued giving two cycles prior to initiation of chemoradiation — that’s a strategy that I like personally, and frequently do in my practice. I don’t have level one evidence to suggest that it’s a strategy that has, in clinical trials, which in my opinion have been limited and relatively small in number, so relatively underpowered in this setting — but the advantage of induction therapy is, often patients are symptomatic, the response rates tend to be in the 40-60%, depending upon which study you look at — a response makes the patient feel better because their symptoms may get better, but the other thing it does is that it may allow a smaller field of radiation, if you believe that it’s okay to treat the volume of cancer that is present after chemotherapy, which is what we do at our particular center. So it may allow a smaller field of radiation be using induction therapy, that may then reduce the toxicities you may see during chemoradiation.

Again, this strategy has not been proven at the phase III level one evidence. However, it’s very commonly used and I will also note that it’s very common for a practicing oncologist to recommend two cycles of consolidation chemotherapy if the initial treatment is concurrent chemoradiotherapy. So rather than give chemotherapy before, it’s given afterwards. Again, not a proven strategy at the phase III level one evidence point of view, however, many of our major clinical trials done in cooperative groups allow two cycles as consolidation therapy, which is typically what is commonly done in practice.

My personal bias is that you should think about giving four cycles in this particular setting. I think two cycles are inadequate to control micrometastatic disease, particularly if during radiation, the chemotherapy strategy that is pursued is low-dose weekly approaches, which may not be the optimal way to control systemic disease.


Management of Locally Advanced NSCLC in the Elderly and Frail

GRACE Cancer Video Library - Lung

GCVL_LU-EA02_Mark_Socinski_WCLC_6

 

Dr. Mark Socinski, University of Pittsburgh Medical Center, describes strategies for treatment of the elderly and frail patient with locally advanced NSCLC.

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A substantial portion of our patients are over the age of 70, and this disease is still often associated with smoking, so the older patients tend to have more comorbidities, and often may have a frailness to them at the time of diagnosis. All the paradigms that we’ve been talking about — chemoradiation, surgical excision, certainly have a toxicity associated with them, and surgery has a risk of morbidity and mortality associated with it. So I think special consideration needs to be made to those elderly, frail patients which have been largely underrepresented in many clinical trials because they would have been excluded based on comorbidities or performance status, and therefore you can’t necessarily apply the paradigms defined in published clinical trials to this population.

It is very clear that, for instance, in the chemoradiation world, the standard of care is concurrent use of chemoradiation. This substantially increases the risk of certain toxicities such as esophagitis, myelosuppression, and fatigue, and may be very debilitating in an elderly, frail patient. So one must consider: is this the best treatment for that particular patient? In many patients, we may give a brief course, two to three cycles, of chemotherapy to see how they tolerate it, and then consider following it if they tolerate it well, and if they have a response, particularly with radiotherapy. Often we give that radiotherapy alone, or sometimes we give it with a low dose of chemotherapy during the radiation with a regimen such as carboplatinum and paclitaxel.

So that’s a very common approach at our institution. Alternatively, patients may start with concurrent radiotherapy, or we may start some frail patients who may have very symptomatic disease, who may have impending obstruction of a bronchus or something like that in the medial part of the chest — often we may start them with radiotherapy alone with the intent to palliate their symptoms, to relieve the obstruction as best we can, and then again, if patents do well with initial radiotherapy, follow it up with systemic therapy following this — assuming that the patient’s condition improves as a result of the initial radiotherapy.

So, I don’t know in this population of elderly, frail patients that there’s a one size that fits all. I think one has to review the CT scans, examine the patient, get an idea of how symptomatic the patient is and what the symptoms are. I do think the strategy of chemotherapy alone, followed by radiation, or sequential strategy is something that we do quite often in this population. I think that concurrent chemoradiotherapy can be done with low dose strategies in an eldery, frail population, and actually may be a reasonable strategy if you have local/regional issues that need attention, such as impending bronchial obstruction would be the best example there. We do know that adding chemotherapy to radiation does lead to better regional control in the area, or the field of radiation. So again, I think one has to personalize and customize the treatment for this elderly, frail population.


Defining Resectability in Stage IIIA Lung Cancer

GRACE Cancer Video Library - Lung

GCVL_LU-E05_Mark_Socinski_WCLC_5

 

Dr. Mark Socinski, University of Pittsburgh Medical Center, discusses the factors to consider in defining resectability in stage IIIa lung cancer.

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Defining resectability in stage III lung cancer really needs to be under the supervision of a qualified thoracic surgeon. Ultimately, I say that no one but a surgeon should make the distinction of whether a patient is resectable or unresectable. Medical oncologists shouldn’t do it, pulmonologists shouldn’t do it, and radiation oncologists shouldn’t do it. These are specialties that are often involved, but really, the surgeon is the ultimate decision maker.  Now, obviously we can collaborate and discuss issues with regard to resectability with the surgeon, but I think ultimately, it comes down to that decision making process.

Now, obviously, resectability has to focus around two things — can you remove the primary tumor, and as we previously mentioned, T3 lesions that involve the pericardium, the diaphragm, the chest wall — these can typically be resected en bloc, taking part of the chest wall or part of the pericardium. I think that for experienced thoracic surgeons, that is not a difficult procedure. I think there are many questions when you start to have T4 lesions that involve vital structures such as the esophagus, the trachea, the great vessels, perhaps the spinal column, bony disease in that area — there are highly selected situations in which one may consider that with obviously, reconstruction of the vital structures. But, these are very few and far between, they need to be done by very experienced surgeons and a team of medical oncology and radiation oncology before I would embark on that sort of decision. T3 is a little bit easier than T4.

The second issue, and more common issue, is with regard to the mediastinal lymph nodes. Now obviously, if you have bilateral mediastinal involvement, and this would be both N2 and N3 — N2 being in the same side as the cancer, N3 being on the opposite side of the cancer, then we would say that patient is not resectable. N3, by definition, should preclude surgery and really is treated optimally with chemoradiation. The real issue centers down to those patients who have isolated N2 disease.

Now, there’s not universal agreement about what’s resectable and what’s not resectable. Certainly, if you have small lymph nodes measuring less than 2cm, and particularly if it’s only in one site, I think most people would consider those patients potentially resectable. The question starts to evolve when one gets into a situation of what we refer to as bulky lymph node involvement. Bulky is a bit of a random definition, most of us use over 2-3cm, and if you have that bulk, as particularly in multiple nodal stations, besides the trachea or the subcarinal area. I think with most of those patients, the likelihood that surgery is going to be able to completely sterilize the mediastinum is quite low, and I would consider that those patients would not be resectable, in that they should be best served by the combination of chemoradiotherapy, which still offers patients a chance at being cured, and as I have previously mentioned, it’s not clear in this population that surgery improves the overall cure rate of this subset of patients.

So I think, really in the non-bulky, particularly isolated, one-site lymph node involvement — that would be a patient that we may consider for preoperative treatment, either chemotherapy or chemoradiation as we talked about before; those would be considered potentially resectable patients.


Neoadjuvant Chemotherapy vs. Chemo/Radiation for Stage IIIA NSCLC

GRACE Cancer Video Library - Lung

GCVL_LU-E04_Mark_Socinski_WCLC_4

 

Dr. Mark Socinski, University of Pittsburgh Medical Center, compares the use of chemotherapy to chemo/radiation in the preoperative setting in stage IIIA lung cancer.

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As I previously mentioned, the role of surgery in stage IIIA disease remains controversial, although there are many patents who are suitable candidates for this, and for whom this approach is a very reasonable approach. One of the questions that is often raised in this situation is: what type of treatment should the patient receive prior to going into the operating room? As I previously mentioned, if you document N2 disease, and in this case IIIA disease, going to the operating room should not be the initial therapeutic approach in these patients, and we generally believe that they need preoperative therapy. The two choices are chemotherapy alone, versus chemoradiation.

We actually have no good data to guide us in this way — both approaches seem to be reasonable, both approaches are backed by previous trials addressing these sorts of things. One of the issues with regard to chemoradiation is that one has to be careful about the dose in the field of radiation, as well as the timing of surgery, following this to avoid postoperative complications that can be difficult to manage in the postoperative setting.

Obviously with chemotherapy alone, you don’t have the risks of radiotherapy. There is some evidence to suggest that, perhaps, chemoradiation may improve local/regional control relative to chemotherapy; it may increase the rate of what we call downstaging, which we think is a positive prognostic thing. What I mean by downstaging is, if you know the lymph nodes are positive at the time of initial diagnosis, if you employ chemotherapy or chemoradiation at the time of surgical resection, those lymph nodes that were positive pretreatment are now negative, so the chemotherapy and chemoradiation had an effect. We tend to see higher downstaging rates with chemoradiation, and downstaging has been associated with improved survival in this population, so that might argue for preoperative chemoradiation as a more reasonable strategy, but the data is not entirely clear in this regard.

One thing I will say is that, whether it’s preoperative chemotherapy, or preoperative chemo/radiotherapy, the surgeon involved should be involved right from the beginning. He or she should be an experienced surgeon that does this quite often, so they know how to manage patients both prior to the operation, intraoperatively, as well as postoperatively to minimize the risk of some of the complications such as ARDS, volume overload, postoperative infections and arrhythmias, and those sorts of things really should be managed in experienced hands from the thoracic surgeon point of view.


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