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, Georgios Evangelou, MD, MSc spoke about his manuscript titled 

Neoadjuvant Capecitabine Plus Temozolomide in Atypical Lung NETs

, which he and his coauthors published in the July issue of 

Evangelou, a medical oncologist and consultant in the 3rd Department of Medicine at Sotiria General Hospital in Athens, Greece, reviewed the results of a case study involving the use of neoadjuvant capecitabine (Xeloda) plus temozolomide (Temodar; CAPTEM) for a 62-year-old woman with well-differentiated atypical carcinoid. The patient was asymptomatic at diagnosis, with imaging revealing an atypical bronchial neuroendocrine tumor (NET) as well as a pancreatic mass indicating another NET.

This patient subsequently underwent treatment with CAPTEM, which resulted in minor volume reductions of masses in the left lower lobe and subcarinal lymph node after 6 months of therapy. Although the pancreatic mass increased in size, Evangelou and colleagues excised it via central pancreatectomy, allowing the patient to resume treatment with CAPTEM for 6 additional months and undergo lobectomy with lymph node dissection. Further use of CAPTEM produced a partial response in the mediastinal lymph nodes and a 21% reduction in the size of the primary tumor.

Following treatment, the patient was able to recover without any significant complications. Additionally, follow-up scans revealed no avid lesions, and there were no signs of disease recurrence at 24 months after the lobectomy. Based on the results of this case study, the authors noted how neoadjuvant therapy may significantly impact the management of patients with atypical carcinoids, although larger clinical trials may be necessary to affirm the potential survival benefit of CAPTEM.

“I hope that others will recognize the potential value of CAPTEM as a neoadjuvant treatment in similar cases. Sometimes, these cases are very difficult to manage; you need the neoadjuvant treatment because it can offer tumor shrinkage. Eventually, it can lead to radical excision of the disease,” Evangelou said. “We need larger studies to better understand the effectiveness of the regimen as a neoadjuvant treatment.”

Georgios Evangelou, MD, MSc, speaks to the potential utility of neoadjuvant capecitabine/temozolomide in well-differentiated atypical carcinoids. 

Exploring the Value of Preoperative CAPTEM in Atypical Lung NETs

Rian M. Hasson Charles, MD, MPH, FACS, spoke about her career in thoracic surgery

 and her visions for increasing equitable care in the field as part of a new, first-of-its-kind role at Brigham and Women’s Hospital. She will serve as the inaugural vice chair for Diversity, Equity, and Inclusion (DEI) in the Department of Surgery as well as an associate surgeon in the Division of Thoracic Surgery.

Hasson contextualized the acceptance of her new role by highlighting her previous experiences in lung cancer surgery, which included pursuing a psychology major at University of California, Berkeley and working as an attending physician at Dartmouth Hitchcock Hospital. At Dartmouth, she formed a DEI program for the public health school and pursued initiatives designed to spread access to care for patients with lung cancer.

As part of her new role at Brigham and Women’s Hospital, Hasson aims to reduce significant disparities in care across areas surrounding the academic center, grow a diverse workforce, and form connections with members in the community.

Hasson also described some of the barriers she experienced and overcame as a woman in oncology. She offered advice to other aspiring surgeons in the field, emphasizing the importance of paying attention to the family, friends, and partners who can support them during their journey.

“The world is your oyster. This position is a dream position for me because it’s bringing together everything that I love to do,” Hasson said.

“I encourage people to find their focus, find their passion, find the thing that keeps them up at night or that wakes them up in the morning. You can do whatever you set your mind to. With today’s resources, there should be nothing that limits you. There may be things that seem like they’re discouraging, but you have the power to overcome those and collaborate with people that will help generate success,” she added.

Rian M. Hasson Charles, MD, MPH, FACS, discusses advances in equitable lung cancer screening and her experiences as a woman in thoracic oncology.

Achieving Health Equity in Lung Cancer Surgery

ONCOLOGY spoke with Eric Ko, MD, PhD, a radiation oncologist at New York–Presbyterian Weill Cornell Medical Center in New York City, who recently published a review article[1] with his colleagues on strategies for combining radiation therapy with immunotherapy for the treatment of non–small-cell lung cancer (NSCLC).

Could you give us an overview of how radiotherapy is generally used in treating NSCLC? Is radiotherapy used more predominantly in earlier-stage disease?

 Based on current practice guidelines, radiotherapy may be utilized across all stages of NSCLC, with different treatment intents. In early-stage disease, stereotactic body radiation therapy (SBRT) or stereotactic ablative radiation therapy allows the delivery of short-course, high-dose-per-fraction radiation treatments to lung cancer with curative intent. This is a very effective local treatment, often used for patients who are considered medically inoperable. It may also be used in patients who are surgical candidates.

In more advanced cases, such as large or central lesions not amenable to SBRT or any node-positive disease, conventionally fractionated radiation therapy is typically used, often with concurrent chemo, given the level 1 evidence to support this approach.

Patients with resectable, locally advanced disease may potentially receive radiation therapy along with chemotherapy in neoadjuvant or adjuvant settings.

Lastly, for metastatic disease, radiotherapy has traditionally been used in the palliative and sometimes consolidative settings, with the primary goals of addressing symptoms and stabilizing radiographically evident disease.

What is the accumulating preclinical evidence that there might be a synergistic systemic effect when local radiotherapy is combined with systemic immunotherapy?

 There is convincing preclinical evidence that combining local radiotherapy with systemic immunotherapy, such as immune checkpoint inhibitors, can result in significant tumor regression at sites not targeted with radiation. This effect has been shown to mostly depend on the generation of tumor-specific immune responses.

What’s important in many of these experiments is that you lose the ability to control tumor growth at distant nonirradiated sites if you test the same strategy in an immunodeficient mouse, or selectively deplete effector cells such as CD8+ T cells, or if you use a different tumor type, presumably one without significant shared antigens.

In addition, this effect is rarely observed in the absence of immune checkpoint inhibitors. It should be noted that this so-called abscopal effect is not a phenomenon that is necessarily restricted to NSCLC, but may be observed across other tumor types as well.

3. Is there clinical evidence accumulating for this combination approach in lung cancer?

: The strategy of combining SBRT or SBRT-like approaches with immunotherapy is still fairly new and has not made its way to broad clinical use yet. However, multiple early-phase trials have established a good safety record for this strategy, as well as displaying some promising signals in tumor control.

One good example is the PEMBRO-RT trial, which was presented at the ASCO [American Society of Clinical Oncology] Annual Meeting in June.[2] In this study, investigators from the Netherlands Cancer Institute showed that for metastatic NSCLC patients who have progressed past first-line therapy, a strategy that adds SBRT to one metastatic site, to a systemic regimen of the anti–programmed death 1 (anti–PD-1) antibody pembrolizumab, was effective in doubling the overall response rate-to greater than 40%. It should be noted that some of the observed differences could be due to differences in tumor programmed death ligand 1 (PD-L1) expression between groups. Regardless, these are exciting new data that will lead the way to additional strategies combining SBRT and immunotherapy.

We should also note the remarkably positive results of the PACIFIC trial in patients with unresectable stage III NSCLC,[3] in which there was a significant benefit in progression-free survival (PFS) when the anti–PD-L1 antibody durvalumab was given to patients who did not progress after definitive chemoradiation. However, this is utilizing conventionally fractionated radiation and also includes chemotherapy, so it is difficult to attribute the beneficial effects specifically to the combination of radiation with immunotherapy.

In addition, there was a recent post-hoc analysis of KEYNOTE-001[4] showing that patients who received radiation prior to pembrolizumab had increased PFS and overall survival. Although it is difficult to attribute the differences in survival outcomes specifically to the effects of radiation in this setting, these findings do provide supporting evidence for a beneficial effect in combining radiotherapy with immune checkpoint inhibitors.

4. So you are saying that patients are not yet being treated with this combination outside of a clinical trial?

 There are some uses of radiotherapy-immunotherapy combinations in standard practice as well as in clinical trials. However, the majority of the patients being treated with the combination are being treated in the setting of a clinical trial.

Based on the PACIFIC trial discussed earlier, patients are now able to receive durvalumab after chemoradiation for unresectable stage III NSCLC.

In the metastatic setting, patients are frequently receiving immunotherapy and occasionally radiotherapy as well. However, when both are used, it is typically the case that treatment decisions are based on clinical indications for each modality rather than an attempt to optimize the immunologic response. Most, if not all, of the other radiation and immunotherapy combinations are still being given in the setting of ongoing clinical trials, which we summarized in the table in our recent 

5. Of those trials, are there ongoing ones that you could highlight that combine radiation and chemotherapy?

 There are many interesting ongoing trials, the vast majority of which are still early-phase. Along the lines of SBRT or SBRT-like combinatorial approaches, there is still a lack of consensus within the field as to the optimal dose-fractionation schedule to use when combining with immune checkpoint inhibitors.

Other questions include: Who are the ideal patients for this strategy? Should we focus on early-stage disease, locally advanced but nonmetastatic disease, or metastatic disease? Now that immune checkpoint inhibitors have made their way to mainstream clinical use and are indicated for a significant number of metastatic NSCLC patients in the first-line setting, does this present more of an opportunity to offer targeted radiation in at least some of these patients?

A large proportion of the ongoing trials are looking into SBRT and immune checkpoint inhibitors in the metastatic NSCLC population. This is the basis of one of our institutional trials, which combines radiation to a metastatic lesion with dual immune checkpoint blockade utilizing ipilimumab and nivolumab.

There is also increased interest in combining SBRT and immune checkpoint inhibitors for early-stage NSCLC, in some cases even in those patients deemed to be surgically resectable. Neoadjuvant radiation and immunotherapy trials, such as PembroX at the University of California, San Francisco, and our institutional trial of neoadjuvant durvalumab and SBRT, have the distinct advantage of allowing pathologic tissue assessment to follow, which will provide correlative data to help us better understand the underlying immunologic mechanisms. These trial endpoints are very important, as they will provide a rational basis for the design of future clinical trials.

The author has no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

 Ko EC, Raben D, Formenti SC. The integration of radiotherapy with immunotherapy for the treatment of non-small cell lung cancer. Clin Cancer Res. 2018 Jun 26. [Epub ahead of print]

 Theelen W, Peulen H, Lalezari F, et al. Randomized phase II study of pembrolizumab after stereotactic body radiotherapy (SBRT) versus pembrolizumab alone in patients with advanced non-small cell lung cancer: the PEMBRO-RT study. J Clin Oncol. 2018;36(suppl):abstr 9023.

 Antonia SJ, Villegas A, Vicente D, et al. Durvalumab after chemoradiotherapy in stage III non–small-cell lung cancer. N Engl J Med. 2017;377:1919-29.

 Shaverdian N, Lisberg AE, Bornazyan K, et al. Previous radiotherapy and the clinical activity and toxicity of pembrolizumab in the treatment of non-small-cell lung cancer: a secondary analysis of the KEYNOTE-001 phase 1 trial. Lancet Oncol. 2017;18:895-903.

ONCOLOGY spoke with Eric Ko, MD, PhD, who recently published a review article with his colleagues on strategies for combining radiation therapy with immunotherapy for the treatment of non–small-cell lung cancer.

Eric Ko on Combining Radiation Therapy With Immunotherapy to Treat Non–Small-Cell Lung Cancer

To mark World Lung Cancer Day on August 1st, Cancer Network spoke with Dr. Alan Blum, Professor and Gerald Leon Wallace, MD, Endowed Chair of Family Medicine at the University of Alabama School of Medicine, where he also directs the University’s Center for the Study of Tobacco and Society, which he founded in 1999. Dr. Blum is an expert on the history of tobacco use, tobacco industry marketing, and the anti-smoking movement. He is a renowned pioneer in creative physician-led public advocacy initiatives to counter the promotion of unhealthy products and lethal lifestyles. 

You’ve studied the marketing tactics used by the tobacco industry to target consumers for a long time [over four decades]-and have organized clinicians to promote health among patients, to prevent [young people] from taking up smoking [and to help them] get off it. Can you talk about some of your recent efforts against smoking and the tobacco industry?

Here we are on World Lung Cancer Day, and it is sort of a bittersweet moment in that we have to have a day like this. In fact, I don't understand why we don’t have 364 days for this and maybe give the tobacco industry 1 day a year to blow smoke. It is truly astounding that we need a day to raise awareness of the leading cause of cancer deaths.

I don’t know what to say more than that our medical profession, our oncology societies, our pharmaceutical companies, our insurance companies, [and] our hospitals have not [done] a sufficient job in ending this terrible pandemic. We have pretty much ceded the battlefield to the tobacco industry.

Cigarette advertising has been out of sight for really the past 20 years, since a master settlement agreement in the United States was signed to end cigarette billboards and, for all practical purposes, to remove tobacco advertising from television and from the sponsorship of sports [events].

However, the industry has maintained its grasp on the next generation: There is still internet [-based] promotion, supposedly to those over 21 years old, and there are bar nights and all sorts of clever gimmicks in the Far East and in Central and Eastern Europe, where lung cancer is still extremely prevalent.

Our complacency in the United States is the most important concern that I have. We have Stand Up 2 Cancer, which purports to be working toward a cure for everything, but some of its leading sponsors include those that are still part of the cigarette fuel chain, or the cigarette supply chain, you might say.

Siemens, for example, makes a great deal of the laboratory equipment that we use, but still makes the fastest cigarette-making machines in the world. Then there is CondÃ© Nast (the publisher of 

), which still has cigarette advertisements in 

 and other [of its] magazines. There are [also] examples [of companies] like Safeway supermarkets, which still sells cigarettes [and] are sponsors of Stand Up 2 Cancer.

We need to stop the hypocrisy, at the very least. Our own pension funds (such as TIAA) are investing in tobacco stocks. Every university I know has an endowment that is still invested in tobacco stocks. So, you could say that we have met the enemy and he is us; it’s not just the tobacco industry.

As a clinician, what techniques have you found to be particularly effective in helping your patients stop smoking and preventing them from relapsing? I imagine that the process is very individualized.

The issue of smoking cessation has not greatly advanced. We’ve known for a long time that the best way [to stop-I don’t use the negative word ”quit”] is to go cold turkey. In the 1970s, we knew that even a few extra words and personal attention on the part of a physician meant more than just about anything; it improved the cessation rate by 5% [per year] just by saying, “[I care about you and really want you to please] consider this.”

[It would be helpful] if every oncologist who works with a lung cancer patient can also look around and talk to family members and say, “Although we don’t have a foolproof cure for lung cancer yet, we can prevent this, as upwards of 90% of lung cancer is entirely preventable-so I am sure that your dad or your mom would want you to stop smoking and never have any of your children smoke.”

Those are the things that are probably going to do more to immunize the next generation than all of the “Opdivos” and “Keytrudas” that we have [that claim in ubiquitous TV ads to] extend the life of a patient with lung cancer.

If you break down smoking cessation, one of the problems is that medical schools do not teach this. They talk about asking patients [about “quitting”] and “assisting” them and “arranging for follow-up,” but they don’t really look at the words and don’t even ask what brand of cigarettes their patients buy.

I think every physician needs to know what brand of cigarettes their patient buys, because that tells you a lot-if they are buying a budget brand, or whether they think they are getting a benefit from menthol, which is just an anesthetic that deadens the throat. Or whether the patient is buying a cigarette with a filter. No physician asks, “Why do you buy cigarettes with a filter?” Patients assume that since 99% of cigarettes have filters, those must be safer, but that is just not true.

The filter is probably the leading myth that physicians can explode. Filters actually make you inhale more deeply and probably more frequently, to compensate for having to get the nicotine through that filter. That is quite a striking myth that physicians can debunk for their patients.

The filter is essentially a fraud-and the early cigarette filters were made out of asbestos! I think that “low tar” is another example of this; this just means “low poison,” and there is no safe level of it. If [physicians] switch gears from finger-wagging [and preaching about] how dangerous smoking is, to making it a consumer product that is a “rip-off”-that is roughly $5 to $7 a pack in the US, except in New York City, where it’s upwards of $14 or $15 a pack.

Buying cigarettes is like spending $100 for a pack of hot dogs. It is a total rip-off. After all, it’s just dead leaves that you are inhaling the burning product of, and that has upwards of several thousand chemicals that nobody would want to take in if they knew about [].          

You’ve constantly been vocal about some of the overlooked aspects of smoking, like the filter that you mentioned, and many [factors] that many [people], including oncologists, don’t know about. Could you highlight some more of these?

I think the key thing is that there are many ways to go about appealing to the individualized preferences of someone who smokes. First of all, I don’t call anyone a “smoker.” I don’t use the term “alcoholic,” just as I don’t say a person with the flu is a “flu-ic.”

If we personalize to the point where here is 

 and you are a physician who wants to help that person, it automatically becomes a partnership, as opposed to a kind of lording over someone and finger-wagging. Developing that personal tie, and touching that person and saying “I care” is probably the best thing that one can do. Then, shifting the focus away from the guilt and the anxiety of having a physician talk at you, to [a frank discussion about] the “rip-off” nature of the product itself.

Why does a cigarette burn in a 50-mile-per hour wind? Because there are chemicals in there to keep it burning, so that you keep buying more and more because they keep burning up. Why are 20 cigarettes in a pack? It has to do with taxes. Most patients don’t know that.

We really don’t need to be talking on rounds about the number of cigarettes or the number of packs per day. Med students like to say “Oh, he has a 50-pack-year history,” but [that] is a totally meaningless term. Instead, why not talk about the number of inhalations? It’s about 10 inhalations per cigarette, and there are 20 cigarettes per pack; that is 200 inhalations per day, which is more than 70,000 inhalations per year.

It’s like going up to a bus in Manhattan and breathing in from the exhaust pipe. You would never do that, but that is exactly what you are doing when you are taking a hit from a cigarette. It’s a combination of terrible poisons that add up.

I had a patient who was a Marine, and we counted how much money he had spent, and he said, “Gee, I smoked a Porsche!” He could have bought himself a luxury automobile with the money he spent on smoking.

Anything to shift the focus from the guilt and anxiety [toward] getting people angry about the product and the manufacturer and all of those organizations that haven’t helped them stop smoking.

You've been a major advocate of lung cancer prevention through education of consumers so that they never take up smoking, and helping patients quit smoking as soon as possible. Pharmaceutical companies are obviously developing therapies to treat lung cancer; you mentioned Opdivo and Keytruda. Do you think [these companies] should have a more active role in prevention of this disease rather than its treatment?

I am ambivalent about the pharmaceutical industry. They missed their chance. They could have helped many, many decades ago in preventing lung cancer. The Metropolitan Life Insurance Company had advertisements on preventing illnesses. I’ve never seen the pharmaceutical industry do anything that is not in its self-interest.

That is not to say that the industry has not made some great advances. I prescribe pharmaceutical products every day. I think that some of these humanized monoclonal antibodies that are now being used to treat patients are incredible. But when we talk about commercials that are incessant, even on televised baseball and football games-and everywhere you look “For a chance at extra life,” I think it is a cynical gambit.

These drugs are absurdly expensive, and the return is whatever the patient’s family wants to make of it. I am sure that the valued extra time these products promise is good. I haven’t seen that enormous benefit, but I am not an oncologist and can’t judge what would be best for a patient. If you want to look at a cost factor, however, a better investment would be in primary prevention.

Lastly, on lung cancer screening, guidelines generally recommend low-dose CT scans for individuals at a higher risk for lung cancer. What is your perspective on the effectiveness of lung cancer screening? Should there be more of an effort to make such screening more widespread?

Lung cancer screening has been a major controversy. The United States Preventive Task Force [USPSTF] recommends low-dose CT screening.

I guess I am really unhappy that [in 2018] we are in the 100th anniversary of World War I, where many men got their start smoking cigarettes-and they got their start smoking cigarettes because the Red Cross and the women’s auxiliaries of medical societies passed the can around in movie theaters to raise money to send cigarettes to the boys overseas.

The origin of this epidemic is ourselves; we have helped promote this. Here we are, 100 years later, [with an advance] of maybe diagnosing something a little bit earlier. I think that it is certainly a proven technique when it works. But you have to screen, as I understand it, upwards of 300 individuals to diagnose a [single patient with] cancer. Then you have false-positives and the invasive testing that goes along with that. And I am told that, for every 900 patients, you give 1 [patient] cancer because of the dosage of radiation. So, I personally don’t recommend low-dose CT screening for the indications that [USPSTF] recommends. I recently ordered one on an otherwise healthy individual that I thought would possibly benefit were cancer detected. But I really think that we are in this technological age where we have abandoned our own words and our own confidence in prevention for the lure of technology and pharmaceutical products.

Anything else you would like to add on these topics?

It’s funny, because I happened to [come across] a copy of the Osler textbook. Sir William Osler wrote this great textbook in the golden age of medicine (from 1890s to the 1920s), and there was one mention of tobacco in the book; it was called “tobacco heart.”

I fear that the focus on lung cancer solely when it comes to smoking and the supposed cures that we are coming across with newer therapies are overlooking the fact that the leading cause of smoking-related diseases is heart disease. So, we can’t forget that even if we had a foolproof immunization for lung cancer, this wouldn’t necessarily result in any decrease of heart disease-and it might even increase heart disease and emphysema because people might gain a false sense of security.

There was also one page on lung cancer in Osler’s textbook [including] a comment that the causes are entirely unknown. We’ve come a long way to understanding that upwards of 90% of lung cancers are due to cigarette smoking. Lung cancer is a man-made epidemic, and we really need to do a better job [of preventing it]. I hope that we can do a better job in the future, using lung cancer as the example of the modern day Black Plague that never had to happen.

Smoking cessation and relapse prevention expert Alan Blum, MD, discusses how oncologists and other clinicians can and should play a larger role in tobacco control.

We Have Not ‘Come a Long Way, Baby’: Dr. Alan Blum on Smoking Cessation and Prevention

In conjunction with the 2018 American Society of Clinical Oncology Annual Meeting, Cancer Network had the opportunity to speak with Dr. Luis G. Paz-Ares, to discuss the results of a phase I trial with a novel, first-in-class fusion immunotherapy protein called M7824, in patients with advanced non

; ClinicalTrials.gov identifier: NCT02517398). Dr. Paz-Ares is an associate professor at the Universidad Complutense, and is head of the Lung Cancer Unit at the CNIO (National Oncology Research Center) both in Madrid, Spain. He specializes in the care of patients with lung cancer, including those participating in clinical trials. 

First, can you describe M7824, the agent that was tested in this phase I trial? What’s unique about this novel drug, and what does it target?

M7824 is a first-in-class, innovative bifunctional fusion protein

composed of an IgG1 monoclonal antibody against the PD-L1 [programmed death ligand 1] protein fused with the extracellular domain of human transforming growth factor–Î² (TGF-Î²) receptor II. It functions as a “trap” for all three TGF-Î² isoforms. In brief, the bifunctional protein works by inhibiting the PD-L1 protein ligand on the one hand; and [inhibiting] TGF-Î² signaling on the other hand. By these two functions, you are able to activate the immune system against the tumor. That is the idea behind this molecule.

You presented results of an expansion cohort part of a 

. Can you tell us the details? How many patients were involved, what kind of patient population was this, and what was the goal?

This cohort specifically enrolled non–small-cell lung cancer patients, and we had 80 patients on the trial. We previously treated patients with stage IV non–small-cell lung cancer with at least one platinum-based chemotherapy, and the design for this cohort was a randomized design. Half of the patients were treated at a 500-mg every 2 weeks dose, and the other 40 patients were treated at a higher dose of 1,200 mg every 2 weeks. The main endpoints were to see the activity at these two different doses in non–small-cell lung cancer, [and] to describe the toxicity profile of the drug in this patient setting.

What were the most important efficacy results in this cohort?

In a phase I trial, this first-in-class novel drug yielded a 71% response rate in very high expressers of PD-L1 treated at 1,200 mg every 2 weeks.

Lung Cancer

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