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Lung cancer is the "number one killer" of cancer. Recently, I had the honor to invite Professor Zhong Wenzhao, director of the Guangdong Lung Cancer Research Institute, to do a live science broadcast on medium and advanced lung cancer (focusing on phase III), and today I shared a selection of content.
Preview: In May, six top oncologists will come to the "Pineapple Parlor" to share with you, please see the end of the article for the schedule
Professor Wenzhao Zhong
Chief Physician of Guangdong Provincial People's Hospital
Director of Guangdong Institute of Lung Cancer
Some of the highlights of this issue
The most important treatment for lung cancer is individualized treatment.
The staging of lung cancer, originally mainly pathological or anatomical staging, will gradually adopt molecular staging in the future.
Stage 2-4 non-small cell lung cancer should be considered for genetic testing, which will affect subsequent treatment options.
By detecting tiny residual lesions, it can help determine whether to add immunization or targeted therapy.
Pineapple: Let's talk about stage 3 lung cancer today. What kind of tumor is stage 3?
Professor Zhong Wenzhao: First of all, I would like to introduce the concept of staging. The same is lung cancer, some people can live for more than 20 years or even cure, some people may lose their lives in a year or two, the main problem is that the staging is different. Tumors are generally divided into four stages. Phases 1 and 2 belong to the early stage, phase 3 belongs to the middle stage, and phase 4 belongs to the late stage.
The concept of staging is conducive to domestic and foreign scholars to compare treatment effects and data, conduct scientific discussions and formulate reasonable treatment strategies.
How is the staging determined? Generally from the "TNM" three dimensions to evaluate, T is Tumor (primary lesion tumor nature), N is the lymph node (whether there is lymph node metastasis), M is distant metastasis. Each patient is staged according to the three numbers of T, N, M of their own tumor. As long as there is distant metastasis, it is stage 4 (such as bone metastasis or brain metastasis of lung cancer).
In stage 3 lung cancer, it is common to have mediastinal lymph node metastasis (numerical value N2-N3), as long as there is such metastasis, but there is no distant metastasis, no matter how large the tumor itself is, it can basically be determined as stage 3.
If the hilar lymph node metastases (numerical value is N1), in this case if the tumor is larger than 7 cm or invades the surrounding structures, this is also stage 3.
Stage 3 belongs to the middle stage, there is still a chance of cure, but has begun to appear local invasion or transfer, this time relying on a scalpel alone, may not be very good, need comprehensive treatment to achieve the best effect.
Pineapple: In China, what percentage of Phase 3 can be?
Professor Zhong: The previous data accounted for about 1/4. But now these situations are changing, because the country pays more and more attention to early cancer screening, the most important way is low-dose CT, many early patients are screened out, so we observe that the proportion of stages 1 and 2 is increasing, the proportion of stages 3 and 4 is relatively decreasing, and we also hope that in the future, the proportion of middle and late stages can be further reduced.
Tumor cells have a similarity with viruses: "two, two, three, three things in life", that is, they will continue to replicate and grow. At the beginning, the growth was relatively slow, and after a certain stage, it was a period of exponential growth, which was getting faster and faster. Therefore, the time window for lung cancer to stay in stage 3 is very short, and it will soon progress to stage 4.
The overall survival rate of lung cancer has improved significantly, mainly depending on three major aspects of progress. The first is early screening. The second is the advancement of drugs and technology, and the third is multidisciplinary integrated treatment, which combines the advantages of many different means.
For stage 4 lung cancer, many people only lived for half a year or even 4 months 20 years ago, and the 5-year survival rate was only 1%, but now the 5-year survival rate can reach 30%, or even higher.
Pineapple: What is the most critical part of successful lung cancer treatment?
Professor Zhong: The most important thing in lung cancer treatment is individualized treatment.
There are 4 major classifications of lung cancer, the first is staging, and the second is pathological classification. First of all, we must find out whether it is small cells or non-small cells, non-small cells have adenocarcinoma, squamous cell carcinoma, adenous squamous cell carcinoma, neuroendocrine tumors, etc., and there are typical carcinoid tumors, atypical carcinoid tumors, large cell neuroendocrine tumors, and other rare tumors in neuroendocrine tumors.
The third is molecular typing, which is the biggest progress in the era of precision medicine in the past 20 years, lung cancer can be divided into 8-9 or more subtypes according to the driving genes, including EGFR, ALK, ROS1, BRAF, cMET, KRAS, RET, NTRK and so on.
The fourth is the tumor microenvironment. For lung cancer with the same gene classification, the same stage, and the same pathology, sometimes the prognosis is also very different, I think it is the tumor microenvironment, including the difference in the immune system.
Pineapple: Do I need genetic testing for stage 3 lung cancer?
Professor Zhong: I think non-small cell lung cancer should usually be done, and more than 400 large panel genetic tests should be done, because genetic testing can further classify lung cancer and carry out more individualized treatment.
Do any test and consider whether it will change our treatment strategy. Some very early lung cancers, like ground glass, including carcinoma in situ and micro-invasive carcinoma, basically do not recur after surgical resection, and do not need to do any other treatment, then the significance of genetic testing is not so great.
However, genetic testing in Phase 2, Phase 3, And Phase 4 is very important and will determine subsequent treatment.
Pineapple: If it is small cell lung cancer, is genetic testing recommended?
Professor Zhong: Small cell lung cancer generally does not use targeted drug targets, and the significance of genetic testing is relatively weak. But we can't generalize, because we also see a lot of mixed small cell lung cancers in the clinic, that is, there are both small cell lung cancer and non-small cell lung cancer, and some of them will also have changes in driving genes.
By the way, in many other types of malignancies, there are fewer driver genes that can clearly have corresponding drugs than lung cancer, and genetic testing may not be so significant.
The biological behavior of small cell lung cancer is very fierce, staying in the early stage for a particularly short time, it is possible that last year's physical examination has not been, and now it has become advanced.
There is a popular saying that tumors are divided into "stupid tumors" and "smart tumors". Stupid tumor mutations are relatively simple, like chronic myelogenous leukemia, which has a very simple driver gene mutation that can be controlled with the targeted drug Gleevec.
While small cell lung cancer is a very intelligent, even very cunning type, there is no simple target. It has many genetic variants, but none of them have an exact driver gene.
The standard treatment for advanced small cell lung cancer is chemotherapy, as well as immunocommunotherapy, and local advanced stages require a combination of chemoradiotherapy.
Pineapple: EGFR-driven mutation-positive stage 3 lung cancer, adjuvant therapy after surgery, recommended targeted drugs or chemotherapy?
Professor Zhong: Opinions are constantly evolving. More than a decade ago, the idea supported chemotherapy, and in 1995, an article published in the British Medical Journal argued that postoperative chemotherapy was better than no chemotherapy, but only a little better. By 2005-2007, it had basically become the conclusion of the international lung cancer community, and postoperative chemotherapy was about 5% better than just surgery.
After the advent of EGFR targeted drugs, Canadian scientists began to explore whether postoperative targeted drugs would be better than chemotherapy, and this study was released around 2012, and the results were surprising: using targeted drugs was a little worse than not using them! Later, we learned that because the targeted drugs were not used on the right people, there was no genetic testing at that time, and all patients used targeted drugs, and the effect was definitely not good.
Beginning in 2011, Professor Wu Yilong's team and Japanese scholars, and multiple centers within the United Nations launched a study that slowly realized that in lung cancer with EGFR mutations and a high risk of recurrence, adding targeted drugs is better than not adding them, which can delay the time of recurrence.
However, after using a generation of targeted drugs, brain metastasis is still a lot, and recently there have been three generations of targeted drugs, because it has a high concentration in the brain, so it has overcome the problem of brain metastasis. Therefore, in 2015, Professor Wu and Japanese and European and American scholars changed the design of clinical trials, from one generation to three generations, and the effect may be better. It's a process that goes from negativity to affirmation to optimization.
So is it pure targeting or targeted + chemotherapy?
This is still being explored, and is likely to be related to tumor gene mutations. We found that in addition to the EGFR mutation, the presence of other gene mutations in tumors in the 2-3 categories can also affect the final results. Our study found that if the tumor has a deletion of the RB1 gene, it is optimal for these patients to complete chemotherapy after surgery.
The image comes from the internet
Pineapple: Are there any similar studies now on targeted medications for ALK mutations?
Professor Zhong: Targeted drugs for stage 4 lung cancer with ALK fusion mutations have definitely become a standard, and the drugs have a generation of crizotinib, a second-generation aletinib, a third-generation loratinib, and so on.
This gene mutation is interesting, it is a golden target, and there are many young patients. When we encounter 20-30-year-old patients with advanced lung cancer, we will immediately think about whether there will be ALK mutations.
Before 2007, there was basically no effective treatment for such patients, but after the ALK targeted drugs came out, the survival time was greatly extended. Some of the stage 3 lung cancers with ALK fusion mutations are not suitable for surgery, but medication can make the tumor shrink, reduce the stage, and then perform surgery, or you can achieve a very good effect. Regarding this type of patient, there is currently an international multicentre clinical trial in which we are also involved, and enrollment has been closed and is now awaiting the final results.
Pineapple: If a patient with an EGFR mutation is already eating one generation of targeted drugs after surgery, do they need to be replaced by the latest three generations now?
Professor Zhong: This is also a very interesting question. There are two folk sayings, the first is to use one generation first, and then use two or three generations after drug resistance. The second is to use three generations directly.
Both statements make sense, for the former, there is still a chance to use three generations after a generation of resistance, and there are fewer choices after directly using three generations of resistance. For the latter, because tumor cells will continue to evolve, itself you can directly use three generations of effect can be very good, but after a generation of drug resistance, tumor cells become more complex, at this time the effect of using three generations is not as good as direct use.
However, from the existing research, in the clinic, I personally prefer to use three generations directly, first of all, the side effects of three generations of drugs are relatively small, and the prolongation of progression-free survival is also very significant, and the total survival is also prolonged. In addition, now that four generations of drugs and immunotherapy have begun to emerge, there will be more ways to resist drugs in the future.
Pineapple: For stage 3 non-small cell patients without sensitive mutations, is immunotherapy recommended after surgery?
Professor Zhong: Immunotherapy for stage 3 lung cancer has two major types of use: postoperative and preoperative.
Postoperative medication, called "adjuvant therapy", is after surgical cutting, and then use immunization or chemotherapy or targeted drugs to clear the micrometaltasis lesions.
Preoperative medication, called "neoadjuvant therapy" or "neoadjuvant induction", is not to do surgery first, for some patients with relatively large tumors or lymph node metastasis, first use drugs to shrink the tumor and then do surgery, the effect will be better.
In the past, both surgeons and patients preferred to do surgery directly first, but in the era of immunotherapy, this view is gradually changing. More and more surgeons are actively accepting immunization plus chemotherapy before surgery, especially for larger and more advanced tumors.
The first is that the scope of surgical resection has been reduced. Sometimes a total lung resection is done, and lobectomy is done at this time. And in the same range can be cut cleaner, in fact, some stage 3 lung cancer is already stage 4, the drug to clear these after surgery, may achieve a best effect.
This brings many patients the hope of reversing stage 3 lung cancer and achieving a cure. There are some patients who are tracheal tumors or tumors near the rumbriae, and they were going to have a big operation, so after using immunotherapy plus chemotherapy, they didn't have to cut so big.
Theoretically, immunotherapy may kill a part of the tumor cells at the same time, activate some tumor-specific antigens, activate immune T cells, act on micro-metastases in the blood and even distant metastases, so that the tumor-free survival is longer. A recent study code-named CheckMate816 is that immunization plus chemotherapy is followed by surgery, and as a result, nearly 1/4 of patients have completely disappeared before surgery, and about 40% of patients have tumors shrunk to only 10%.
Pineapple: Is it better to use immunity + chemotherapy before surgery, or is it better to use it after surgery?
Director Zhong: At present, whether it is a new assist or a postoperative assist, it is suggested that the addition of immunization is better than chemotherapy alone.
So is it better to use it preoperatively or postoperatively? Several recent studies have found that postoperative immunity improves progression-free survival, but I've spoken to many surgeons and may still be more sympathetic to the neoadjuvant model.
In animal experiments, it has also been found that it may be better to use immune drugs and then operate on them than to do surgery first and then use drugs. This problem, the results of clinical trials have not yet come out, you need to wait for the results of head-to-head.
Clinically, many times we are still exploring the sandwich cookie model, that is, "new assist - surgery - postoperative assistance", that is, immunization is used before and after surgery.
However, the treatment can not be blindly added, but also depends on the patient's side effects, but also depends on how the postoperative recovery, whether there are complications and so on to consider comprehensively.
Pineapple: It's really important to avoid overtreatment. So how to judge whether to add treatment after surgery? Not only Phase 3, but possibly Phase 1 and Phase 2 also face this problem.
Professor Zhong: Now everyone is very concerned about a concept: MRD (Minimal Residual Disease), that is, a tiny residual lesion in the blood, through which to help determine whether to add immunization or targeted therapy.
If mrd is negative, which means that the blood is clean, treatment may not be needed. On the contrary, if the tumor is cut off, the MRD is positive, that is, the mutant genes of cancer cells are constantly detected in the blood, and the significance of medication is even greater at this time.
The previous concept of staging was actually based on anatomy and imaging. But now there is a saying called molecular staging, which binds to MRD/ctDNA in the blood.
For example, some patients who appear to be stage 1 still relapse after surgery. These people can often test positive for MRD in the blood, indicating that tumor cells are more aggressive, so its prognosis is the same as many stage 3 and stage 4. The reason why some stage 3 patients can not recur for so many years after surgery may be that the tumor cells have not yet entered the blood, or have entered the blood but have not had a suitable implantation organ.
Therefore, the understanding of staging, the original is mainly pathological or anatomical staging, and will gradually apply molecular staging in the future.
Pineapple: What stage is MRD in clinical use now?
Professor Zhong: It's still in the clinical research phase. At present, according to the previous data, MRD is generally considered to be a prognostic factor, and the recurrence rate of MRD positive is higher than that of MRD negative. However, for MRD-positive patients, the difference between the effect of treatment and non-treatment is still being carried out in clinical trials.
Pineapple: Now if patients want to test MRD, can they find a place to test it?
Professor Zhong: Now many places can be measured, but the quality is uneven. The challenge now is to achieve standardization and harmonization. And the technology in this area has also advanced rapidly, and it may be iterated once every two or three years. I believe that it will become more and more reasonable and unified.
Pineapple: How often should I follow up after treatment?
Professor Zhong: Generally speaking, for people with low risk of recurrence, the follow-up time is relatively long, and it is possible to review half a year, one year or even two years later.
However, stage 3 is at higher risk of recurrence and basically requires a three-month checkup.
Pineapple: What are the special features of stage 3 lung cancer that you would love to tell you?
Professor Zhong: The first feature of stage 3 lung cancer is that it is very "heterogeneous" and varies greatly from patient to patient. Therefore, it is of great significance to subdivide stage 3 lung cancer again.
For example, there is a type called "accidental stage 3", that is, it was initially thought to be stage 1 and stage 2, but after the operation, it was found that there was lymph node metastasis. Such patients must be treated with adjuvant therapy after surgery, otherwise it is easy to turn the brain or bone.
The second is called "potential resectable", that is, imaging can see lymph node metastasis, the surgeon thinks he can be removed, but the radiotherapy doctor feels that it should be mainly based on radiotherapy, and the internalist feels that it is necessary to do neoadjuvant therapy first. This type of patient is the most complex and problematic, and requires multidisciplinary consultation to give these patients a more reasonable treatment plan.
The third is inoperable. In some cases, the benefits of surgery are not great, and topical treatment is the mainstay. Of course, the situation is also constantly changing, some tumors used to feel incisive, but now with targeted drugs, after immune drugs, some patients can shrink and reverse the tumor to cutable or even curable after using drugs.
The second feature of stage 3 lung cancer is "outcome". That is, stage 3 is actually a transit state, if the treatment effect is good, after neoadjuvant therapy, it may be reversed to stage 1 and stage 2, but if the treatment is not good, it may also quickly develop into stage four.
In short, for the treatment of stage 3 lung cancer, it is necessary to combine staging, pathology and molecular typing to give a personalized plan.
Pineapple: Audience Question: If you want to participate in your multidisciplinary consultation for stage 3 lung cancer, how do you do it?
Professor Zhong: We arranged for a multidisciplinary outpatient clinic at the Dongchuan Clinic of Guangdong Provincial People's Hospital on Thursday afternoon, and also had an outpatient clinic at Huifu Road Branch on Friday morning.
In the past, it was generally necessary to have a complex case and then call a doctor to consult, which was very inefficient, so we fixed a time and place and provided a multidisciplinary diagnosis and treatment plan in the outpatient clinic.
The doctor's assistant will contact the patient in advance and prepare the imaging data, genetic testing data, and pathological data, so that he can provide a more reasonable and one-stop diagnosis and treatment plan more efficiently.
The image comes from the internet
Pineapple: Audience question: After stage 3 lung cancer surgery, do you want radiation treatment?
Professor Zhong: This is a very interesting question, and it was very controversial until the first two years.
First, a 1998 study found that postoperative radiotherapy was worse than no radiotherapy prognosis. However, retrospective studies have all concluded that plus radiation therapy is a little better, especially in stage 3 patients.
Later, International designed a prospective study of LUNGart, in which patients with lymph node metastases were enrolled after complete surgery and standard treatment, a group of simple surgeries, and some postoperative radiation therapy.
The final study found that patients receiving radiation therapy had a slightly longer tumor-free survival, but the difference was not significant, and the overall survival was exactly the same. Therefore, the conclusion is that there is little benefit from radiation therapy.
At present, postoperative radiotherapy for stage 3 lung cancer is more inclined to be done. But it also requires personalized consideration, I think it needs to be discussed with the surgeon who operates on you, if the surgeon feels that the surgery is cut clean, he may not need to receive radiation therapy, of course, if he feels that there is a residual risk, it is still a reference to his opinion.
Pineapple: Audience Question: Does Stage 1 EGFR-sensitive mutant lung cancer require targeted drug adjuvant therapy?
Professor Zhong: This is also very controversial. It turns out that in order to be as precise as possible, we thought that stage 2 or 3 patients with lymph node metastases should consider using adjuvant therapy.
Later, some foreign scholars believe that the 1b period should also be added, according to the recently published data, it can be seen that patients with EGFR mutations in the 1b stage with three years of adjuvant targeted therapy with osimertinib reduces the risk of recurrence by 61%. Patients with stages 2 and 3 are even larger, reducing the risk of recurrence by 83%. But the benefits of total survival will depend on the outcome.
In the guidelines of the NCCN, phase 1b also believes that postoperative adjuvant targeted therapy is needed, but clinically this issue is still very controversial.
Clinically, we will consider whether the tumor has some high-risk factors, such as whether the tumor is fully solid and dense, or if the MRD in the blood is positive, indicating that the recurrence probability of these tumors is very high. In these cases, we would recommend adjuvant therapy.
Pineapple: One last question, can lung cancer patients get the COVID-19 vaccine?
Professor Zhong: This is also a very common problem, and my own views are changing. 1 year ago, I was still conservative and only suggested that patients who were particularly early and did not need any adjuvant therapy could go to the fight.
But now from the data of Hong Kong and foreign countries, the elderly and tumor patients, who are in poor physical condition, have a significantly higher fatality rate and severe disease rate without vaccination. Therefore, for patients who have completed neo-assisted and postoperative adjuvant therapy, if the side effects are not large and the physical conditions permit, my current opinion is inclined to play.
As for whether patients who are still undergoing immunization and targeted drug therapy in the middle and late stages should be hit, whether there is a mutual influence between drugs, and how beneficial they are, there is still no conclusion.
*Due to space limitations, only a selection of Q&A has been selected. This article aims to popularize the science behind cancer, not drug promotional materials, let alone treatment options recommendation. For guidance on treatment options, visit a regular hospital.
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