Martin Dietrich, MD, PhD

One of the biggest pieces of progress that oncology has made is in its handling of toxicity. The adverse effect profiles from the movies where patients are vomiting and hanging over a bucket, I think this has gotten a lot better. This is part of what instills a lot of fear in using chemotherapy. And the patients that have made up their mind about chemotherapy before they come to my clinic are oftentimes influenced by these images. I can tell you, there’s no other field that has gotten more attention in oncology than what we call supportive care. The first hour and a half of a treatment with chemotherapy is basically the infusion of medications that are preempting and the development of nausea and vomiting. And in fact, especially with these lung cancer regimens, I haven’t seen much nausea or vomiting at all. We’ve gotten very good; there are many different medications that can be utilized. And in fact, they probably use them in combination, or sometimes in all of them. And that’s a big part. In terms of concern for [side effects], the one that always scares us is the reduction in white blood cell counts and the development of fevers and infectious complications. That is something for which we have growth factors, that stimulate the bone marrow to produce white blood cells and can maintain the defenses. Low white blood cell counts are a medical emergency in setting of infection and should be prevented to the best extent possible. But now, when you have a patient only receiving, and this is the typical number of what we call a cycle or rounds of chemotherapy, of 4 cycles of chemotherapy, we can arrange a close watch to make sure that we can trend the numbers of white blood cells and treat either preemptively in patients at risk or in close, reactive nature if a patient’s white blood cell count is starting to drop. We have a clear signal that chemotherapy is indicated, the risk of recurrence is high, the survival is improved with adjuvant chemotherapy, and the toxicity profiles have gotten substantially better. In fact, this is one of the things that patients oftentimes come back to me and say, “Well, I didn’t expect this to be this manageable.” I’m not saying it is easy. I’m not saying it’s pleasant. Nobody would sign up for this voluntarily, but in the setting of high-risk disease, toxicity management has changed in our approach to how we can recommend therapy. Rest assured that what you are recommended when you’re getting adjuvant chemotherapy is based on data for almost all resected tumors, unless you’re looking at a stage 1a or a tumor that is in the lowest risk category of size and extent of spread.

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Martin Dietrich, MD, PhD, describes the toxicity profiles of chemotherapy agents used in the adjuvant setting in early non-small cell lung cancer.

Early Non-Small Cell Lung Cancer: Chemotherapy and Toxicity

: Dr. Dietrich brought in the concept of the adjuvant therapy. Adjuvant is sometimes added — meaning it’s the therapy we give for the disease we can’t see. And sometimes, that’s a hard concept for our patients to understand. Especially if the surgeon tells them, well, I went in and I got what I was looking for. I got the tumor out. It’s all out. But there are still a large number of my patients who I signed on to receive adjuvant therapy after resection. Most of my patients who have tumors greater than 4 cm [centimeters] or have any lymph node involvement or have tumors that extend to the lining of the lung, are recommended for adjuvant therapy. For my practice, I would love to tell you that 100% of the patients are recommended to go on to adjuvant therapy. But there are things in lung cancer patients that make that challenging. Sometimes patients don’t want it. Sometimes patients are sick. Sometimes if they’ve had complications from surgery, that’s not possible. And when we look at all patients in the United States who are, who qualify for adjuvant therapy, we think only about half of them get it. I’d love to say in my practice, it was 100% of those who qualify got it but it’s probably more than 50%. It’s closer to 90%. And I start the discussion of who needs adjuvant therapy in my preoperative visits. When I discuss what the resection looks like, I talk about taking the tumor and the piece of lung that surrounds the tumor and about taking the lymph node stations. Even if they’ve been biopsied by a pulmonologist before the operation, we take them at the operation, and we take them looking for tumor cells there. And I explain to my patients from the beginning that those lymph nodes are like the gatekeepers. And if tumor cells have reached those lymph nodes, we know that there are likely tumor cells which have escaped, and we can’t see them yet. There’s somewhere outside of the lung, in the bone, the liver, or something like that. And the idea of the adjuvant therapy, the added therapy is to kill the tumor cells we can’t see. I can only go after what we can see, I need Dr. Dietrich and medical oncologist to go over the cells we can’t see. And that’s why you need a therapy that goes everywhere in your body. And that’s the whole concept. And right now, adjuvant chemotherapy is very much the standard of care and all the other therapies that we recommend are in addition to adjuvant chemotherapy. And I send almost all my patients, with stage 1b, 2 or 3a disease that have been resected and are recovered to see a medical oncologist for a discussion of adjuvant chemotherapy. It is unfortunate and somewhat heartbreaking if we have someone who’s too sick to go on to that therapy, and we try to limit that happening as few times as possible. But complications related to surgery can make that more challenging. That’s another reason that it’s important to have small incisions so that patients have faster recovery and can be ready for that discussion and the therapy if needed. Dr. Dietrich, do you want to review some of the evidence supporting the use of systemic chemotherapy?

Absolutely. We’ve had a very consistent signal since the early 2000s, in fact, that would support the use of adjuvant or added chemotherapy and follow-up to surgery. What’s been clear and that’s been learned from the metastatic space, and the regimens repeat themselves whether it is immunotherapy, targeted therapy or systemic therapy. What works in the metastatic space typically works in their early space, and typically better. Think of a tumor as a fortified infrastructure that has support connective tissue blood vessels, its own oxygen and nutrients supply, much more difficult to attack with chemotherapy than isolated microscopic cells that have no support structure. Additionally, if a body is not encumbered by a significant tumor burden, it’s typically stronger with therapy. What works in the metastatic setting typically works better in the early-stage setting. The two-drug combinations that we’re using are typically based on a medication called cisplatin. This is the precious metal platinum that is utilized as the core of this treatment. And then we have a variety of binding partners that are tailored to the individual patient’s [side] effect tolerance, kidney and liver function, and also to their histology. We know that this hasn’t changed much over the last 10 to 15 years and the data has been very consistent. Now, what we know is the higher the stage, the higher the risk, the higher the benefit for adjuvant chemotherapy. And to Dr Donington’s point, the higher the stage, the higher the frequency of being offered chemotherapy for the setting. The first data pieces are from the early 2000s. We’ve had multiple confirmatory study trials that showed this in what we call meta-analysis, or basically review of multiple trials in one setting. And even though this is not a perfect way of doing it, what we’re seeing is a consistent benefit of chemotherapy. We don’t have a question of whether chemotherapy works. And we certainly know that chemotherapy is not perfect in preventing the recurrence of cancer, but it certainly reduces the risk. Depending on the setting, it’s somewhere between 5% to 20% in a good case scenario for the reduction of therapy. We don’t know who those patients are, and there’s not a good predictive marker that would tell us this is the patient that would respond to this therapy, and we have to lean on these studies. But for your reassurance, those studies have been very consistent in their messaging that they’re helpful. The improvement in survival here, so that’s a clear cut, we still must look for a recurrence, getting scans, especially in the first couple of years, to ensure that disease doesn’t come back. Sometimes, there are opportunities for treating, again, with a localized form of therapy. Quite frequently, we have a patient that had a part of the lung removed or a lobectomy had a lymph node evaluation, maybe had chemotherapy, and then has a recurrence in the mediastinum or the center of the chest, and where lymph node recurrences may be occurring. And many people would consider localized approaches for those kind of recurrences as well followed, again, by systemic therapy in the same setting.

Two experts detail the use of adjuvant therapy, including chemotherapy, in treating early non-small cell lung cancer.

Early Non-Small Cell Lung Cancer and Adjuvant Therapy

There’s one more factor that in 2021 plays a huge role in how we determine upfront treatment and treatment plans altogether and that’s something called molecular testing. And that means taking the tumor and looking inside the tumor for what’s going on in the DNA of the tumor. And that’s because now, we have lots of molecularly-targeted medications, medications that were designed just for some of the mutations. And we also have cancer immunotherapies. But we need to know about the DNA of the tumor to appropriately pick those treatments. And that is important, even for early-stage patients, as we design a treatment that’s specific for each patient.

Going back into how treatment is going to look like and how it’s going to impact the quality of life and treatment options, in general terms, the early detection of lung cancer is often a coincidence. We are aiming at increasing the rate of lung cancer screening similar like we would encourage breast and colorectal cancer screening. We know especially for certain high-risk patients, there is a role for lung cancer screening with an annual low-dose CT [computed tomography]. There are pros and cons that should be discussed. But in general terms, it is a reasonable intervention that helps us catch a cancer early. If we find a cancer early in lung cancer, again, there goes a big deal of discussion and planning, testing ahead of time into finalizing the disease treatment plan. Obviously, surgery is always on the table. Radiation and systemic therapy options that would entail chemotherapy, targeted therapy, and immunotherapy — all of them are now combined. What you’ll ideally find is a table of experts for their respective specialties that are reviewing images, pathology, and the patient’s clinical status at the same time and come up with a joint treatment plan. Early-stage lung cancer doesn’t necessarily mean it’s easier treatment. And oftentimes, the short-term investment is quite significant. We made quite a bit of progress for treating early-stage lung cancer, the surgical techniques have been clearly more refined, and the endobronchial diagnostic approaches have been substantially better. I always tell my patients when you have a smaller robotic surgery, it doesn’t mean that it is a small surgery because you’re operating on a very large organ and you want to be sure that you have a clear understanding of the anatomic extend that certainly guides the treatment options and radiation therapy as part of this consideration. And radiation’s impact on treatment is mainly guided to what organ structures are in the vicinity. The radiation therapists and radiation oncologists have gotten a lot better at delivering radiation in that precise fashion. But when you have spread into areas of lymph nodes, for example, you do want to have a mix of precision by avoiding unnecessary tissues. And when I say dispersion or more broad distribution — because you’re covering not one spot but an entire field. Then the main concern here is typically the irritation and inflammation of the food pipe or the esophagus, and swallowing concerns are an issue. Other than that, it’s very well-tolerated. It’s the localized collateral impact that makes the decision-making process for the surgery and radiation. I have to say that even though most patients have a challenging time at some point for their early-stage treatment, this is typically short-lived and can be recovered from well. And it’s worthwhile to early discovery. That’s a fair statement. When it comes to systemic therapy, as Dr Donington already pointed out, the molecular testing just decides, in 2021, how your treatment is going to look like. At this point, we are basically looking at first a genetic marker called EGFR [epidermal growth factor receptor]. If this is present, we would always consider chemotherapy, especially for high-risk patients. But if a patient is not eligible for chemotherapy and chooses not to pursue chemotherapy for personal reasons, then targeted therapy remains an option. We’ve always known this in breast cancer for estrogen receptor-positive disease that we would give an estrogen blocker for treatment after surgical resection, and we knew that patients would do better, and their cancer would either not come back or at least come back later. For EGFR, we have a similar EGFR blocker or inhibitor that can do similar things. Now, not everybody has EGFR. It’s about 15% to 20%, depending on geography. We have many cancers that respond very well to immunotherapy. This was just approved by the FDA [Food and Drug Administration] last month, options to introduce immunotherapy that was available for now for many years in stage 4 disease in the early stage 1, 2, and 3 disease post-surgery. There is plenty of opportunity for treatment that may be improving outcomes and that’s well-tolerated. It’s a little bit of a mix, where you go from a very high-intensity pace in the beginning where you control all the visible disease to then a more long-term, I call it the sprint and the marathon sequence from our patients, into disease control systemically afterwards. The prognosis for patients with early-stage lung cancer, unfortunately, tells you that the systemic component is always of concern. It doesn’t mean that you don’t want to take out the primary tumor, but you do have to account that even in a stage 2 setting, you’re looking at, depending on the studies, you’re looking at 30%, 40% disease recurrence. And if you go into stage 3 disease, you can certainly see up to 70%, 80% of patients recurring. This is a very high rate of concern for patients that have been treated. And if you have a chance after surgery to experience disease recurrence that high, systemic therapy should be on the table for discussion and obviously should be tailored to your individual needs. We have a lot of interest in immunotherapy but again, not everybody does qualify for it. And those are risk factors. There’s some risk factors on the pathological level that the size and lymph node involvement, and then some more refined histological features of pleural involvement and other microsatellites within the lungs. Those are things that your healthcare provider will discuss with you at the time of decision-making for a follow-up systemic therapy. We have a pretty good handle and understanding how high-risk disease is and what should be offered. In general terms, with the exception of very early-stage disease, and Dr Donington mentioned the 4 cm [centimeter] tumors as kind of the cutoff, unless you have a very small, isolated tumor, systemic therapy is on the table for discussion for virtually all early-stage lung cancers at this point.

Dr. Martin Dietrich explains the role of molecular testing in early non-small cell lung cancer.

Molecular Testing for Early Non-Small Cell Lung Cancer

 Expert Connections. I’m Jessica Donington, professor of surgery and chief of the section of thoracic surgery at the University of Chicago in Chicago, Illinois. I would like to welcome my fellow expert panelist, Dr. Dietrich, to introduce himself.

Hello, I’m Martin Dietrich, a medical oncologist at Florida Cancer Specialists at the University of Central Florida in Orlando [Florida]. Thank you for having me today.

Today we’re going to discuss management of early-stage non-small cell lung cancer [eNSCLC]. We’ll address the treatment options for patients with early-stage non-small cell lung cancer, the role of adjuvant therapy in early-stage disease, and the role of the multidisciplinary care team in treating patients with early-stage non-small cell lung cancer. Let’s get started. Dr Dietrich, I’ll let you start.

I want to talk about early-stage non-small cell lung cancer. We typically define early-stage as patients with disease that is either surgically resectable or accessible by radiation in the earlier stages. Stage 1, stage 2, and stage 3, considered early; stage 4 then the late-stage disease. I have to say this is obviously a spectrum of different challenges from going from stage 1 to stage 3 and obviously, from surgery to more radiation approaches the higher the stage goes. It’s important to understand what your stage is and what the individual opportunities are for treatment. And there has been for patients that have had difficulties undergoing surgery either because of medical comorbidities or lung function problems, the introduction of targeted therapy, targeted radiation therapy in the early-stage setting. And then looking at lung cancer as a systemic disease, there's clearly a component of treatment that requires local approaches either by surgery or by radiation. But then there is a component that may not be able to see on the original imaging. But that certainly does require attention as well, because that microscopic or invisible disease is the part of the disease that eventually drives disease recurrence, metastatic manifestation, and eventually, death. Those are two different components of lung cancer that we’d like to discuss today.

When we talk about treatment for lung cancer, it usually starts by figuring out the stage because the stage help drive treatment decisions. As we talked about, we can go from early-stage disease all the way to metastatic. When we talk about the earliest stage of disease, stage 1, and especially those tumors in stage 1 that are less than 4 cm [centimeters], the recommended treatment tends to be surgery — removing the portion of the lung that contains the tumor of interest in those patients who have enough lung to tolerate surgery. For some patients who have significant medical comorbidities, lung disease, COPD, [chronic obstructive pulmonary disease] and things like that, sometimes we trade surgery out for radiation. In patients with tumors that are starting to get bigger, like tumors that are maybe 4 cm or more, maybe the size of about a peach or so, or those that have started to involve some of the lymph nodes in the lung, surgery is still the initial treatment of choice. But those patients have a pretty high risk of having their tumors come back. And therefore, we now recommend that those patients also get what we call systemic therapy, after their resection. Finally, once the tumor has spread to the lymph nodes in the center part of the chest, or called the mediastinum, that’s a big cross of the line for our patients. Once that is involved, then the treatments get more complicated. I would say they get pretty messy with lots of options and everybody getting different tailored treatment for not only themselves but for their disease. The rule for those patients, who have what we call stage 3 or locally advanced disease is that everyone needs a local therapy, and everybody needs a systemic therapy. And trying to put that puzzle together in 2021 is complicated. But we use things like how big the lymph nodes are, whether the lymph nodes are on the same side as the tumor or on the other side to help us make those decisions. Typically, if we are going to operate, surgery is not the first treatment. We start with some type of systemic therapy. When we’re choosing which patients can or cannot undergo an operation for the lung cancer, we use both the stage that we just talked about, how extensive is the tumor, how far has it spread within the chest or outside of the chest, and then we use the patient’s overall health. Ideally, removing a fairly big portion of the lung, maybe a third of the lung is a typical lung cancer operation, which does mean patients have to have good lung function because we would never want to leave someone short of breath or on oxygen after an operation. When we’re talking about those stage 3 patients, the ones who have lymph nodes involved, the discussion gets even more complicated — how much good lung is left, and again, how much can a patient tolerate?

Martin Dietrich, MD, PhD, and Jessica Donington, MD, MSCR, provide an overview on early non-small cell lung cancer and the available treatment options.

Martin Dietrich, MD, PhD

Early Non-Small Cell Lung Cancer: Chemotherapy and Toxicity

Early Non-Small Cell Lung Cancer and Adjuvant Therapy

Molecular Testing for Early Non-Small Cell Lung Cancer

An Overview of Early Non-Small Cell Lung Cancer

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