Lung Cancer Progress: 2011
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 on currently available therapies. This talk discusses currently available therapies, including surgery, chemotherapy and radiation therapy. Newer, targeted therapies have 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 Medical Oncology Program in Thoracic Malignancies, Assistant Professor of Medicine, Division of Hematology/Oncology, at the David Geffen School of Medicine at UCLA. Dr. Garon has published both laboratory and clinical research. 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 research forward.
This is a summary of a lecture presented on November 15, 2011.
Lung cancer continues to be the leading cause of death from cancer, more so than breast, colon, prostate and pancreas cancers combined. Smoking has a strong relationship to lung cancer with 85% of the 200,000 cases per year being linked to a smoking history. The number of individuals being diagnosed with lung cancer, however, is declining. Approximately, 15% of individuals who develop lung cancer have no history of lung cancer 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 considered good screening techniques for the general public who have no other symptoms.
Types, Staging and 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 three primary types: squamous cell (25-30%), adenocarcinoma (35-40%) and large cell carcinoma (10-15%). Squamous cell carcinoma has declined. There are some questions being raised about whether these groupings make the most sense as there are newer ways of understanding tumors based on specific genetics of the tumor. For now, these subtypes are still used.
The stage of cancer is determined as part of the diagnosis. Unfortunately, many lung cancers have already advanced or spread at the time of diagnosis, which relates to the morbidity of this disease. Early stage NSCLC is treated most often with surgery, unless the individual is not a good candidate for surgery, in which case radiation or radiofrequency ablation might be considered to treat the disease. Staging is based on 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. In early stage disease where there are no nodes present, there is no data to support chemotherapy after surgery. In early stage disease with 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.
In stage III disease, some patients are able receive surgery, but they may receive chemotherapy prior to, and often again after surgery. When there are lung cancer cells in the pleura or a condition called pleural effusion (where there is increased fluid between the lining of the lung and the chest wall), this type of disease is considered stage IV disease and is treated as widespread. Stage IV disease is almost exclusively treated with chemotherapy, although some symptomatic areas may also receive more focused treatment such as surgery or radiation. It is often difficult for patients to understand why the primary lesion may not 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 treatments that are needed to get disease under better control.
Only 2% of patients with small cell cancer are eligible for surgery. This disease is treated as a systemic disease and treatment usually involves chemotherapy. In cases where the disease is limited and can be encompassed completely within the radiation port, radiotherapy may be used. Systemic treatment usually utilizes cisplatin or carboplatin and etoposide or irinotecan. If the disease is limited, chemotherapy is combined with radiation starting in cycle 1 or 2. There is evidence of prolonged survival with prophylactic whole brain radiotherapy 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.
In NSCLC, cisplatin-based chemotherapy has been combined with other chemotherapies. The survival curves with each of these treatments look exactly the same. Based on this study, the presumption has been that chemotherapy had reached a plateau in this disease. Research in the treatment of lung cancer, like many 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. These drugs target 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 the growth of the tumor and its ability to spread to other areas. In a trial in which paclitaxel and carboplatin were compared against 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. 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 histology did better, thus creating evidence for the importance of looking at the histology of tumors.
Other chemotherapies can be helpful after disease grows after the initial therapy. For example, docetaxel was given to patients who had been previously treated and it was found that tumor stability and survival were improved by this drug compared to best supportive care. However, the actual tumor did not shrink very often, but remained stable. These are examples of the some of the trials in the last decade that have changed how advanced NSCLC is treated.
Molecular Profiling of Lung Cancer Tumors
One of the exciting new areas of research in lung cancer involves molecular profiles of tumors in individual patients. The Lung Cancer Mutational Consortium came out of a grant that was funded through the Recovery Act. The goal of that grant was to molecularly profile 1000 different lung cancers. The objective was to test 100 tumor specimens from patients with lung adenocarcinoma for KRAS, EGFR, BRAF, HER2, PIK3CA, AKTI, NRAS, MEK1, EML4-ALK and MET amplification. Another goal was to use the information in real time to either select erlotinib with EGFR mutations or recommend a lung cancer consortium clinical trial of an agent targeting the specific mutation identified. The consortium was successful in this process and found mutations in 54% of the samples that were analyzed. In about half of the patients that were identified, there was a drug that could be tried as a targeted therapy. The largest numbers of mutations were EGFR (17%) and KRAS (22%). There is great value in identifying these targets and then putting people on trials with a specific target. This allows trials to have greater power with fewer numbers of patients, and increases the likelihood that an effect will be found for a particular drug with a particular group of individuals. One of the problems that arises when everyone is 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 of the initial trials that looked good, 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 and the only patients that take it are those that were in the initial trial and showed a response. 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. In this mutation there is a translocation on one chromosome involving the ALK gene. In the trials using crizotinib, patients with this particular mutation also had tumor shrinkage prolonged disease control. There are additional trials going on studying drugs for the RAS mutation such as selumetiniib. Preliminary research suggests that there may be improvement, but a larger trial is needed. At UCLA, we have been actively involved in these projects to target therapies to specific groups of patients.
Importance of Clinical Trials in Lung Cancer
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 no guarantee of this, however, if progress is to be made in this disease, 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.
Looking Ahead and Conclusions
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 this disease.
Over the last 10 years there have been significant improvements in the treatment of lung cancer, with more improvement for patients with tumors with some specific molecular changes than others. 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.
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