Lung Cancer 2012: Traditional and Novel Approaches
About the Lecture
Lung cancer is a very common malignancy. Treatments are currently available for patients with all stages of disease, and much research is also being conducted to improve currently available therapies. This talk discusses currently available therapies, including surgery, chemotherapy and radiation therapy. The role of surgical treatment and non-surgical interventional procedures for early and late stage lung cancer are covered. Targeted therapy has recently entered clinical practice. These advances are discussed, as well as clinical trials available at UCLA applying these types of approaches. Clinical trials often provide opportunities for patients to advance the science of lung cancer and to participate in trials of medications at an early stage of development.
Edward Garon, MD, is the Director of the Thoracic Oncology Program Malignancies, Assistant Professor of Medicine, Division of Hematology/Oncology, at the David Geffen School of Medicine at UCLA. Dr. Garon has published extensively in both laboratory and clinical research in the area of lung cancer. Dr. Garon focuses on translating developments in the laboratory into clinical studies, and eventually clinical practice. He is conducting several clinical studies. He actively sees patients with lung cancer, thus he understands the importance of quickly moving new therapies from research to bedside.
This is a summary of a lecture presented on September 11, 2012.
Lung cancer continues to be the leading cause of death from cancer, causing approximately the same number of deaths as breast, colon, prostate and pancreas cancers combined. Smoking has a strong relationship to lung cancer—approximately 85% of the 200,000 cases per year are linked to a smoking history—but this does not tell the whole story. Approximately 15% of individuals who develop lung cancer have no history of smoking and approximately 10% of smokers develop lung cancer. Lung cancer is typically first diagnosed when patients have a cough. Sometimes it is detected on a routine chest x-ray, but routine x-rays are generally not helpful for screening the general public if there are no other symptoms. Most patients are diagnosed with advanced stage disease, which is, of course, harder to treat.
Lung Cancer – Types, Staging and Traditional Treatment Approaches
Lung cancers are typically divided into two categories: (1) small cell lung cancer, which accounts for about 15% of diagnoses OR (2) non-small cell lung cancer (NSCLC), which includes about 85% of the diagnoses. Within NSCLC there are three primary types: squamous cell (25-30%), adenocarcinoma (35-40%) and large cell carcinoma (10-15%).
When you are diagnosed with lung cancer, the first thing that needs to be done is to determine the stage of your tumor. Treatment decisions are based on the stage. Staging is based on the size and characteristics of the tumor, the presence or absence of lymph node involvement and their location in the chest, and whether disease has spread to distant sites. Early stage NSCLC is treated most often with surgery. If the patient is not a good candidate for surgery, we will treat with radiation or we might consider radiofrequency ablation. In early stage disease where there are no nodes present, there is no data to support chemotherapy after surgery. In early stage disease where there is lymph node involvement, the risk of recurrence can be decreased with cisplatin-based chemotherapy. Unfortunately, cisplatin-based chemotherapy can be difficult for patients to tolerate and we do not really know which patients will benefit most from this treatment. From a statistical standpoint, 15-20 patients must be treated in order to prevent recurrence in one patient with chemotherapy treatment after surgery. As a physician, having this conversation with patients is very difficult; we know the side effects are great and the likelihood of benefit can be small—unless you happen to be one of the ones that will respond to this type of treatment. In stage III disease, some patients are able receive surgery, but many are not. There are some benefits to receiving chemotherapy prior to surgery to shrink the tumor. There are also benefits to receiving cisplatin-based chemotherapy after the disease has been surgically removed. In patients for whom surgery is not an option, chemotherapy and radiotherapy are the optimal choices.
Stage IV disease is any lung cancer that has spread to other organs, such as to bones or the brain. In addition, when there are lung cancer cells in the pleura (lining of the lung) or a condition called pleural effusion (increased fluid between the lung and the chest wall) or pericardial effusion (cells found in fluid around the heart) these findings are considered Stage IV disease and thus lung cancer must be treated systemically. Stage IV disease is almost exclusively treated with chemotherapy, although some symptomatic areas may also receive more focused treatment such as surgery or radiation. This might occur in situations where it has spread in an isolated way to the brain or bone and focal treatment may help with control. It is often difficult for patients to understand why the primary lesion cannot be removed from the lung when it is widespread, since they often see it as isolated masses of the disease. For the physician, it is seen as a systemic disease, such as diabetes, needing treatment that will encompass the entire body. Once lung cancer has spread to other organs, surgery may compromise or delay the necessary systemic treatments needed to get the disease under better control because time is needed for healing after the surgery. If there are surgical complications, it can further delay chemotherapy. All of these issues need to be considered and your doctor will make a decision based on what will lead to the best outcome for the patient.
Small Cell Lung Cancer Treatment
Only 2% of patients with small cell lung cancer are eligible for surgery since this disease is generally found after more extensive spread. This disease is treated as a systemic disease and treatment usually involves chemotherapy. It is staged in the same way that non-small cell lung cancer is staged, but it is further categorized as limited or extensive. The disease is “limited” when all of the disease can be encompassed completely within one radiation port and in these circumstances radiotherapy may be used. All other disease is thought of as “extensive” and, thus, must be treated with chemotherapy as a systemic treatment. The best most effective treatment is cisplatin or carboplatin and etoposide, although some oncologists substitute irinotecan for etoposide. If the disease is limited, chemotherapy is still combined with radiation starting in cycle 1 or 2. Some patients also receive prophylactic whole brain radiotherapy, which has been demonstrated to increase survival in patients who respond to chemotherapy. Unfortunately, there have not been many advances in the treatment of this disease, most likely because so few patients go through surgery and there are very limited tissue samples to research and better understand the molecular nature of this disease. As a result, no targeted therapies have been developed for small cell lung cancer to date.
Non-Small Cell Lung Cancer Treatment
In NSCLC, cisplatin-based chemotherapy has been combined with other chemotherapies. The survival curves with each of these treatments look exactly the same. Research in the treatment of lung cancer, as with other cancers, has been oriented toward understanding more about the molecular structure of the tumor itself and then searching for specific treatments. These treatments hopefully target some aspect of the tumor that promotes its growth or inhibits its demise. One of the first targeted treatments was an anti-angiogenesis drug. This class of drugs targets the tumors ability to generate blood vessels to help feed the cancer. As a tumor grows, it needs its own supply of blood and as a result must send signals to the body to create more blood vessels that directly support the tumor. An anti-angiogenesis drug stops the tumor from creating this blood supply. As a result, it limits tumor growth and its ability to spread to other areas. In a trial in which paclitaxel and carboplatin were compared to paclitaxel, carboplatin and bevacizumab (Avastin), significant improvement was found when the anti-angiogenesis drug bevacizumab was added to the 6 cycles of chemotherapy.
One big question has been whether we should continue therapy after four to six cycles of initial chemotherapy. This practice is called “maintenance therapy.” In one trial, Erlotinib (Tarceva) was used as a maintenance treatment after 4 cycles of chemotherapy in Stage IIIB or Stage IV patients. This trial showed that the disease could be stabilized and was less likely to progress after response to the chemotherapy. In a study looking at pemetrexed (Alimta) and best supportive care versus best supportive care and a placebo after initial chemotherapy, pemetrexed and best supportive care was found to improve overall survival and progression free survival in patients with advanced disease. In addition, patients with a non-squamous tumor did better, thus confirming the importance of looking at the histology or type of tumor.
Other chemotherapies can be helpful if the disease progresses after the initial treatment. For example, we have found that when docetaxel was given to patients who had been previously treated, their tumor stability and survival rate were improved. However, the actual tumor did not shrink very often, but at least it remained stable and stable is good.
Molecular Profiling of Lung Cancer Tumors and Novel Treatments
One of the exciting new areas of research in lung cancer involves molecular profiles of tumors in individual patients. The Lung Cancer Mutational Consortium was started by a grant that was funded through the 2009 Recovery Act. The goal of that grant was to molecularly profile 1000 different lung cancers. The objective was to test 1000 tumor specimens from patients with lung adenocarcinoma for KRAS, EGFR, BRAF, HER2, PIK3CA, AKTI, NRAS, MEK1, EML4-ALK and MET amplification. These mutations exist in the DNA of the tumor; they are not in the genes that a person is given from birth. Further, part of the goal is to try to identify which are driver mutations, meaning the mutations drive the growth of the tumor. Some of these may be bystander genes, meaning that they may promote or help with growth, but may not be the primary driver of the cancer. We are still working to identify which elements of the tumor are true driver mutations.
Another goal was to use the information in real time to either select erlotinib for patients who had tumors with EGFR mutations or recommend a lung cancer consortium clinical trial for patients who had a specific mutation identified. The consortium was successful in this process and found mutations in 54% of the samples that were analyzed. Since the start of this study, additional mutations have been identified and researchers hope to have a Lung Cancer Mutational Consortium II in the near future. For nearly half of the patients who were found to have a specific mutation in their tumor, there was a drug that could be tried as a targeted therapy. The largest numbers of mutations were EGFR (17%) and KRAS (22%).
These targeted clinical trials have been exciting, informative and in many cases successful. We were able to have trials with fewer patients but had an increased likelihood of success because their treatment was specifically targeted to their tumor’s specific mutation. One problem that arises when unselected patients are placed on a targeted therapy is that all the patients that one would not expect to benefit are included in the analysis of the data. This can dilute the findings such that a drug may not appear to be effective when it is in fact effective but only for a particular population. This occurred with a drug called gefitinib (Iressa), where many patients were put on the drug because the initial trials looked promising, but the actual trial did not have a way to target those who might be most likely to respond. As a result, this drug did not receive FDA approval. Erlotinib (Tarceva), which has similarities to gefitinib (Iressa) in that it also targets the EGFR mutations, has been found to be helpful in most patients with this gene mutation. Characteristics of the best responders include women, individuals of Asian backgrounds and those that have no smoking history. Patients who did not have the mutation generally do not respond as well with Tarceva as patients who do have the mutation. There are clear benefits to identifying the mutation and having a drug that targets the mutation.
Crizotinib (xalkori) is a recently approved drug that targets the ALK translocation, one of these genetic mutations found in tumors. Keep in mind these are not inherited mutations; these are mutations in the tumors themselves. In this mutation there is a translocation on one chromosome involving the ALK gene. In the trials using crizotinib, patients with this particular mutation had tumor shrinkage and prolonged disease control. The studies with crizotinib are an example of how much faster drugs can be moved to market. This was a 4 year process which, in reality, is a very short period of time. There are additional trials going on studying drugs for the RAS mutation such as selumetinib. In one study, in which selumetinib was combined with docetaxel compared to docetaxel alone, the overall survival appeared to improve but did not reach statistical significance. However, the secondary endpoints of progression-free survival, objective response rate and alive and progression-free at six months all demonstrated a statistically significant improvement in favor of selumetinib in combination with docetaxel versus docetaxel alone.
EGFR mutations have been responsive to Tarceva, yet that drug sometimes does not work or stops working for some patients. One key is to figure out the next drug that may be able to target that same mutation in a different way. AUY922 is an example of some of that work.
A significant shift is occurring in research and in the scientific paradigms for understanding cancer and clinical trials. For example, new studies are being done where a group of patients with a particular mutation is tried on a targeted therapy that may already be approved. The goal is to try it in a small number of patients, a Phase I trial, to see if there is any benefit. If there appears to be none, then research dollars are saved because a huge randomized trial can be avoided. In addition, by trying to develop therapies for the known mutations, progress can be made in subsets of lung cancer as research continues on understanding the mutations that are not currently known. There are old drugs that were shelved because they showed some promise in a few patients, but when tested more globally, did not work. The hypothesis is that previously, we lacked the ability to identify who would benefit from the drug and thus washed out the advantage of the drug by using it on people that it would never work on. This is a significantly different way of approaching lung cancer and, in fact, many cancers.
Clinical Trials in Lung Cancer – Altruism and Hope
Many patients wonder when they are offered a clinical trial if this is an indication of how bad their disease is, however, this is a misunderstanding. Clinical trials are the pathway to new medications and potential improvement in quantity and quality of life. Participating in a clinical trial might be participating in the next medication revolution in your disease. There is never any guarantee; however, if progress is to be made in improving outcomes in lung cancer, clinical trials must take place and patients need to participate. Even Phase I clinical trials, in which the primary goal might be to simply find the dose that patients can tolerate, may have benefits in a drug that fits their cancer.
In the best case scenarios, clinical trials are not giving just “yes” and “no” answers about whether a drug works or not, they are also giving more information and clues that lead to the next approach to the disease, the design of treatments or a better understanding of the molecular underpinnings. Ultimately, having tissue samples has become a key area for gathering this information. Some patients do not want to undergo a second biopsy, which is understandable, but there are many altruists who will do it because they become part of the process of advancing the science, treatment and care for the next group of patients with lung cancer. There is much optimism, enthusiasm and hope that science is advancing and at a more rapid rate than ever before.
One area of research is looking at which genes are turned on, and which are not, in particular cancers. While this research used to be done in a painstaking manner with one gene at a time evaluated, researchers can now look at 20,000 genes all at once. The goals now are for researchers to figure out how to make meaning out of all the data that can be generated and translate that from the laboratory to the clinical care of patients. These efforts, combined with investigations into targeted approaches, are likely to add to the knowledge and care of patients diagnosed with lung cancer.
Over the last 10 years there have been significant improvements in the treatment of lung cancer, with more improvement for patients with tumors having some specific molecular changes. One of the biggest limiting factors is the amount of funding available for this disease. Even with this limitation, researchers here at UCLA and around the world are making significant strides forward. The goal at UCLA is to look at the evidence, pick the best trials that have supporting theory and data and to bring these to the clinic for patient participation. While chemotherapy will likely play a significant role for some time, newer treatments are adding benefit and changing care. For now, a goal in metastatic disease might be to have treatments that evolve such that as one treatment reaches its limit, there is another treatment that extends that limit. In so doing, patients are able to live for longer period of time and, hopefully, enjoy a life with meaning.