Unresectable locally advanced NSCLC
Options and controversy around management options for unresectable stage IIIA and IIIB NSCLC
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Treatment of Locally-Advanced NSCLC in the Elderly: As Individualized as Medicine Gets
“Locally-advanced NSCLC” is a term generally applied to lung cancers with tumors that have either grown into major structures (such as vertebrae or spine bones, the central airways, or involve the main blood vessels supplying the lung or central chest) or those cancers that have spread to lymph nodes in the central chest (the mediastinum). In the case of many of these cancers, removing them with surgery is not possible, but treatment with the combination of chemotherapy and radiation given at the same time may be used with the goal of curing the cancer.
While administering chemotherapy and radiation at the same time (termed “concurrent therapy”) is more effective at killing cancer cells than when the treatments are given separately, this approach also causes increased side effects for the patient. Side effects may include nausea, vomiting, neutropenia (decreased levels of white blood cells which can lead to increased risk of infection) with or without infections, anemia, fatigue, and pain with swallowing (from radiation “sunburn” to the esophagus). In order for a patient to tolerate this rather stout combination, they need to be fairly healthy and active, and to have a strong physical reserve (measured with a term “performance status”).
Most studies of the combination of chemotherapy and radiation, although not excluding older patients, have enrolled younger patients. Typically, the average age of patients enrolled on trials like these is 64 or 65. This allows for decent conclusions to be drawn for patients of this age group and younger, but how do these studies apply to the elderly; patients 75, 80, older?
Prophylactic Cranial Irradiation for Stage III NSCLC: Some Answers, Some Open Questions
In my last few weeks as a GRACE guest faculty, I have been struck by the number of forum discussions that deal with brain metastases. Brain metastases are a growing problem in non-small cell lung cancer (NSCLC), as well as in multiple other cancers. Why is this? Twenty years ago, patients who developed brain metastases were usually at the end-stage of their cancer, with widely metastatic disease and few systemic treatment options. The prognosis for these patients was very poor, but not really because of the brain metastases. Brain metastases were simply a marker that the cancer was taking over and patients often were on hospice care at that point. Some of the fatalism of those days still holds over to today, but the clinical picture of a patient with brain metastases has changed dramatically.
Now, we have many more effective systemic therapies. Unfortunately, most of those therapies do not penetrate the blood-brain barrier (BBB) very well. The brain thus becomes a “sanctuary site” for cancer cells, where they can hide out and start to grow while the cancer cells in the rest of the body are susceptible to chemotherapy or targeted therapies. I am increasingly seeing brain metastases in stage IV patients with good control of cancer in the rest of their body. I am also seeing more patients with earlier stage lung cancer where the brain is the only place that the cancer has relapsed. This is particularly true of patients with locally advanced (stage III) NSCLC. And this was the motivation behind a rather disappointing trial that was presented at ASCO recently.
Patients with stage III lung cancer have very high rates of brain metastases. Published studies show rates of brain metastases of 30-55%. More importantly, up to 30% of patients have brain metastases as the first site of recurrence. Even though many patients do well with treatment for brain metastases, it would certainly be desirable to prevent this from happening. In small cell lung cancer (SCLC), for instance, prophylactic cranial irradiation (PCI) is now standard practice for both limited-stage and extensive stage patients. Not only does PCI decrease the incidence of brain metastases but it improves survival in SCLC, another disease where the brain is a common site of relapse.
The investigators of tthe trial by the Radiation Therapy Oncology Group (RTOG 0214) hoped that similar results would emerge for patients with locally advanced NSCLC. The trial included patients with stage IIIA and IIIB NSCLC who had undergone treatment and had not progressed with their initial treatment (chemoradiation for most, with 1/3 of patients having undergone surgery). The primary endpoint of the trial was overall survival. Secondary endpoints included disease-free survival, incidence of CNS metastases, neurocognitive function, and quality of life. The trial was designed with a target accrual of 1058. This target accrual for a clinical trial is calculated by statisticians as the number needed to accurately access your hypothesis. Unfortunately, accrual of patients was VERY slow, and though the trial was open for six years, only 356 patients were enrolled. For this reason, the trial closed early.
Interview with Dr. Suresh Ramalingam: Current Standards and Controversies in Locally Advanced NSCLC
Dr. Suresh Ramalingam is a longtime friend of mine and a national leader in the field of lung cancer. He is the Director of the Lung Cancer Program at the Winship Cancer Institute at Emory University in Atlanta, and he was kind enough to sit down with me to talk about his perspective on the current optimal treatment for patients with stage III, or locally advanced, NSCLC. We also spoke about managing metastatic disease, which will be covered in a separate podcast. It’s an audio interview, but if people watch the video version, there are some figures synchronized with the discussion.
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Video Podcast Presentation on Locally Advanced NSCLC
Ask and ye shall receive! The leading requiest for a video podcast presentation was for a summary of the subject of locally advanced, unresectable stage III NSCLC. Here you go:
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Sorry it’s a little rushed, but it’s a struggle to do a topic justice with a 10 minute limit (the most YouTube accepts). In the future, we’ll try to divide bigger topics into two podcasts if it’s going to require cramming into a 10 minute interval. It may help for you to have the images and transcript available, so here they are:
Locally Advanced NSCLC vodcast images
Interview with Dr. Vivek Mehta, Radiation Oncologist: Early Stage and Locally Advanced NSCLC
As we move forward in our audio/visual odyssey, we’re going to add audio interviews with experts in various aspects of cancer care. The first of these is from our own Vivek Mehta, who sat down with me to go over current radiation approaches for patients with early stage NSCLC, as well as management locally advanced NSCLC.
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And along with that is the transcript for this interview, here. Dr. Vivek Mehta Interview I Transcript
We’re still trying to get the optimal setup, which this isn’t. There’s some background noise, but it’s all audible. And things will only get better. There are a few more in the works.
What I Really Do: Locally Advanced, Unresectable NSCLC
The setting of unresectable, stage IIIA or IIIB NSCLC (without a malignant pleural effusion) is currently one for which what we feel is best for the patient isn’t necessarily something for which we have good evidence. For fit patients, there is a strong consensus that giving concurrent chemo with radiation provides a modestly but consistently higher cure rate than giving chemo and radiation sequentially. But that concurrent chemoradiation plan lasts for only 6-8 weeks, but whether there’s more we should be doing, or what we should do, is entirely unclear.
As described in a prior post, several studies in the last decade have shown that about two cycles or 6-8 weeks of weekly chemotherapy along with about 60-66 Gray of radiation over 6-8 weeks is associated with the best survival results we’ve seen in unresectable, locally advanced NSCLC (somewhere in the 20% range long-term, and a median of about 16-18 months). There are two main approaches in North America for the chemotherapy. Some use the SWOG approach that showed very promising early results (prior post here), giving cisplatin and etoposide. The other very common alternative that is widely used in a community setting is weekly carboplatin/taxol. Until very recently had relatively little published experience to support it, but in the last few years now has been included in a few trials that demonstrate survival in the same ballpark as what we routinely see with cisplatin-based chemo: examples include RTOG trials such as described in a prior post and another abstract.
Erbitux with Radiation in More Marginal Patients with Locally Advanced NSCLC
One of the core ideas in the management of stage III, or locally advanced, NSCLC is that unresectable disease that is being treated with curative intent is most effectively treated with a combination of concurrent systemic (“whole body”) therapy and chest radiation to all of the visible cancer. The systemic therapy, which has been conventional chemotherapy, is given to both make the radiation work better and to treat potential micrometastatic disease, cancer cells in the bloodstream that can’t be reached by radiation but could potentially be killed off by a treatment that goes throughout the bloodstream.
The challenge, though, is that concurrent chemo and radiation is hard on people, with a rate of treatment-related deaths of about 5-7% of people even on clinical trials (which often select for a fitter population than are seen in the “real world” of many ineligible patients). So we reach a point where the aggressiveness of the treatment can be associated with problems that are as threatening or worse than the underlying disease. And this is a particular problem for older and/or frailer patients, which happens to cover a significant proportion of people with lung cancer.
Part of the promise of targeted therapies all along has been that they could potentially substitute for standard chemotherapy as a systemic therapy that is perhaps as effective as chemo but with fewer side effects. Most of our work with these agents has been to just add them to our current standards, but it still makes sense to consider using them as a substitute in patients for whom conventional chemo is really at the upper limits of what is tolerable. And it’s clear that doing chemo concurrent with radiation is overall more effective than doing them sequentially, but perhaps we could get the tolerability of a sequential approach with the efficacy of concurrent therapy by doing a program of targeted therapy (and no chemo) concurrent with chest radiation.
Integrating Alimta and Cetuximab in Locally Advanced NSCLC
As a follow-up to my last post on the appeal of developing new regimens for combining with radiation in treatment of locally advanced unresectable NSCLC, I wanted to highlight work being done by the Cancer and Leukemia Group B (CALBG), one of the major cancer cooperative research groups in the US. As I mentioned previously, we’ve had difficulty developing widely accepted alternatives for the few chemo regimens commonly used in combination with concurrent radiation — primarily cisplatin/etoposide or weekly carbo/taxol. Some experts feel that weekly carbo/taxol has a shortcoming in that it is given at a more frequent but lower dose than the “full dose” every three week regimen, and the lower dose may have very little activity against micrometastatic cancer cells traveling throughout the bloodstream. For that reason, it may be preferable to give full, “systemic dose” chemo at least at some point during treatment for locally advanced NSCLC, and giving it during radiation could allow you to treat a person for both local cancer in the chest(disease you can see and treat directly, with radiation, while chemo bolsters the radiation — called chemosensitization) and distant disease outside of the radiation field. But there are relatively few chemo regimens that can be given safely at full “systemic” doses with radiation concurrently. The CALGB lung cancer committee has been working on a new regimen that incorporates a regimen of carboplatin and alimta one day every three weeks at full dose, with radiation, an approach that could potnetially be enthusiastically adopted in the lung cancer community as a newer and more convenient alternative if it looks as good or better than our older standards.
Now that there is evidence from early safety/feasibility studies that chest radiation can be given along with full dose alimta every three weeks along with carboplatin (abstract here) or cisplatin (abstracts here and here), CALGB developed a trial to test the activity and safety of carbo/alimta/RT followed by alimta “consolidation”, or the same strategy with erbitux added throughout, both during the radiation and afterward, with the alimta consolidation (abstract here). The trial design is as shown here:
Introducing Erbitux and Other Agents into Treatment of Locally Advanced NSCLC: RTOG Experience
While there have been new agents introduced and rapidly changing standards in advanced NSCLC, another 40% of patients with NSCLC have locally advanced (stage III) NSCLC, many of whom with disease that is not resectable but is potentially curable with agressive chemo and radiation. Last year’s ASCO meeting included results that strongly suggested that consolidation taxotere after 6-7 weeks of concurrent chemo and radiation may not add a benefit, and in an important trial by the Hoosier Oncology Group (affectionately known as the HOG), the best treatment was with just two cycles of cisplatin/etoposide chemotherapy along with radiation (as detailed in a prior post).
Many oncologists, myself included, have been reluctant to accept that just two cycles of chemo and seven weeks radiation are really enough to treat stage IIIB disease, which is clearly more of a threat than stage II NSCLC, for instance, and for which we standardly give four cycles of platinum-based chemo. Most US-based oncologists give either two cycles of cisplatin/etoposide with concurrent chest radiation, or weekly low-dose carboplatin/taxol for about 7 weeks while a patient is getting radiation, and it’s a bit unsettling to think that either there aren’t potential improvements to be made by adding new agents, either to replace some of our older standards or to add along with the chemo/radiation concurrently or as a different consolidation therapy. Cisplatin/etoposide/RT has been used now for both limited SCLC and locally advanced NSCLC for 20 years, so we’re all impatient to see new agents take their place and define some new standards.
Surgery for T4 Tumors: The Importance of Local vs. Distant Failure Risk
People who have been following my comments know that I am often questioning the wisdom of surgery in patients who don’t fit the usual criteria for resection, which is most commonly pursued in stage I and II NSCLC and is often considered an option for some patients with stage IIIA NSCLC. To provide a very quick review of NSCLC staging, it’s a combination of three factors:
1) Tumor (T) stage — from 1 to 4, going from smallest and easiest to remove to hardest or largest to remove
2) Node (N) stage — from 0 to 3, going from none to further distances from the main tumor
3) Metastasis (M) stage — just a 0 or 1, to reflect whether there has been distant spread outside of the tumor’s lobe of origin
Here is the more detailed staging system, for T stage on one figure, and then for N and M stage in the other.
(Click on image to enlarge)
At the bottom of the second figure are the “Stage Groupings” that define our current (although increasingly refined over time) staging system. You can see that stage, which correlates with prognosis overall, is a product of a combination of how advanced the tumor itself is and measures of likelihood of distant spread, which is nodal stage (correlates with increasing risk of micrometastatic disease and distant spread) and M stage (M1 defining metastatic spread).
A key point is that there are related but distinct risks from a lung cancer. While we are generally most worried about distant spread of SCLC, which is why surgery has no established place in SCLC management, NSCLC can have very differing degrees of local or distant risk. We need to weigh these, potentially also along with the third variable of risk in the brain, as we develop treatment plans:
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