Lung cancer causes 160,000 deaths each year – more than the next four cancers combined. Diagnostic and treatment options have improved greatly in the past decade and continue to advance at a rapid rate. Among the most important advances have been: Learning that chemotherapy combinations of a platinum-containing drug produce substantial improvements in tumor shrinkage, quality of life and extension of life. Second, these combinations, when added to surgery and/ or radiation for early stage disease, improve survival and increase cure rates. Third, the introduction of “Targeted” drug therapies have led to often dramatic tumor shrinkage and increased disease free survival. Patients who develop lung cancer which has spread still generally die within a year of diagnosis but progress is apparent and improvements are developing quickly.
Drug therapy for lung cancer had been disappointing until recent years. The combination of platinum containing compounds such as cisplatin or carboplatin with drugs like premetrexed, docetaxel, paclitaxel or gemcitabine have substantially improved the response rates, progression-free survival and the overall duration of survival as well as reduce symptoms from lung cancer. Most patients will have substantially less pain, less difficulty breathing, and reduced cough, among relief of other symptoms as well. Whereas only 10% of patients with advanced non-small cell lung cancer (NSCLC) will live for one year with “supportive care” alone, approximately 50% will survive one year with current chemotherapy. However, virtually all patients with advanced lung cancer still die within 3 years of diagnosis. So a major advance but still a long ways to go.
For patients with limited small cell lung cancer (SCLC) or those with localized or locally advanced NSCLC, chemotherapy has a vital and potentially curative role. In combination with radiation therapy, approximately 25-30% of patients with localized SCLC or NSCLC can be cured. In selected patients with localized NSCLC, surgery may incrementally improve outcome, though this is controversial. The use of multimodality therapy in these diseases has been one of the major advances in oncology in the past 25 years.
Another major advance in drug therapy of lung cancer today is the development of so called “targeted” drugs. Many cancers have mutations or rearrangements in their DNA that in turn produce an abnormal protein – a protein that can initiate cancer, lead to its proliferation or its metastatic potential. These are changes in the DNA of the tumor itself that are critical to the initiation and progression of the cancer, hence the term “driver” mutations. A targeted drug is one that attacks or binds these abnormal proteins that are directly causing or encouraging the growth of the tumor. Among patients with lung adenocarcinoma (which represent about 40% of lung cancers), about 17 percent have a mutation of a tyrosine kinase receptor gene called EGFR (epidermal growth factor receptor), about 22 percent have KRAS (Kirsten rat sarcoma viral oncogene ) mutations and perhaps 5 percent have an EML4 (echinoderm microtubule-associated proteinlike4) rearrangement with the ALK (anaplastic lymphoma kinase) gene. There are at least seven other of these mutations or rearrangements, each occurring uncommonly and it is likely that many more will be detected in the years to come. These three mutations/rearrangements appear to be mutually exclusive and occur very rarely in the other forms of non-small cell lung cancer (NSCLC), i.e., squamous cell and large cell tumors. Since these DNA gene changes direct the formation of abnormal proteins, inhibiting the protein action by a targeted drug can lead to shrinkage of the cancer or slowing of its progression, often with rather dramatic success.
These driver mutations make it possible to categorize many adenocarcinomas based on molecular variations. It is instructive to appreciate that although a group of tumors may appear identical by histology under the microscope, they are actually distinct subtypes of lung cancer with different responses to the available therapies. This helps to explain why patients with equivalent staged and histologic tumors may respond much differently to the same treatment. It is clear that at least adenocarcinoma (and presumably squamous and large cell will follow suit shortly) should be molecularly typed before undertaking treatment.
Patients whose tumors have one of these mutations have a greater likelihood of responding to the corresponding targeted receptor inhibitor. Among the EGFR tyrosine kinase inhibitors are the new drugs erlotinib (Tarceva), gefitinib (Iressa) and afatinib (Tomtovok). Though these drugs may be dramatically effective in reducing disease burden, it is important to note that drug resistance will develop over time in virtually all patients. The average patient experiences about one year of benefit for erlotinib and similar agents. There are some patients (about 5-10%) who may benefit for several years. Newer drugs are under development that can be used once resistance develops. A recent trial compared erlotinib to the current standard chemotherapy of platinum-based therapy for initial treatment of EGRF positive adenocarcinoma patients. The median progression-free survival was 10.4 versus 5.1 months.
There are no targeted drugs for KRAS at this time however there is one for those with ALK rearrangements. Crizotinib (Xalkori) was approved by the FDA based on results among patients with EML4-ALK fusions who had a better than 50 percent response rate that persisted for nearly a year despite this being second line treatment (i.e., the patient had already received prior therapy and had had their disease progress before trying this drug). Compared to standard combination chemotherapy, the response rate was 65 percent compared to 20 percent and side effects were generally modest. Only 3 -5 percent of lung cancer patients have the ALK+ gene rearrangement so that equates to maybe 50,000 patients worldwide per year. But for these relatively few patients, crizotinib has become the new standard for first line therapy. There are also some additional new drugs in the pipeline that are ALK+ inhibitors. These may prove effective for those that develop resistance to crizotinib as essentially all of these tumors eventually will do.
A separate approach is to target the growth of blood vessels since the tumor needs a steady supply of nutrients to persist and progress. Affecting such “angiogenesis” might prove of value. Bevacizumab (Avastin) is a monoclonal antibody that attacks vascular endothelial growth factor (VEGF), a molecule that encourages the growth of small vessels. It has been found to add a few months to progression free survival when used with cisplatin and paclitaxel for non-squamous NSCLC. Overall survival was increased from 10.3 months with cisplatin and paclitaxel alone to 12.3 months with the three drug combination. Avastin has not demonstrated any advantage when added to other chemotherapy regimens. The current approach is to use it as first line therapy with a platinum based combination of drugs and after maximum response to continue it until relapse or progression of disease. Avastin costs about $100,000 per year.
There are multiple messages here.
· First, the combination of platinum-based combinations has markedly improved the treatment of late stage lung cancer.
· Second, chemotherapy combined with radiation for early stage disease offers an increased opportunity for cure.
· Third, certain patients, principally those with adenocarcinoma, will have one of these “driver” mutations in their tumor DNA. Knowing what is driving the cancer may be the most important development of recent years.
· Fourth, new drugs have and continue to become available that inhibit these abnormal proteins resulting in meaningful shrinkage and occasional complete responses.
· Firth, the responses, although heartening, can be but are usually not long lasting and come with various toxicities that can be quite serious.
· Equally important, sixth, knowing that a specific mutation exists – or does not exist – can save a patient time, the expense and the toxicities of receiving a drug that is destined to be inactive.
· Seventh, and quite important, the technologies to test for these mutations are new and not fully understood as yet. It is clear that it is not a matter of pushing a simple “on/off” switch. But it is a definite start with improvements of a degree and duration not seen previously in this disease.
· Eighth, it may well be, just as with cancer chemotherapy, that combinations of targeted drugs or targeted compounds plus standard chemotherapy will be found to be more effective and lead to more long lasting responses.
· Finally is the issue of cost. Combinations such as platinum/paclitaxel or platinum/gemcitabine are inexpensive as the drugs are off patent. But the new targeted drugs are each highly expensive. This raises the question of whether and when this level of expense is justified for a relatively short period of time without the cancer progressing or with such limited added survival. Some countries such as the British have refused to cover the expense of Avastin for lung cancer citing that it does not cure but is highly expensive. In the USA, some commercial insurance likewise will not pay for some of these highly expensive drugs. The pharmaceutical companies maintain however that the response rates justify the costs and that the prices are appropriate given the expense of developing these new compounds.
Although there is obviously room for improvement, it is clear that there has been major progress in the drug treatment of lung cancer. The rate of development of new approaches has been rapid and can be expected to continue.
The next and last of this series will discuss the importance of multi-disciplinary care, palliative care and seeking high levels of expertise combined with compassion and caring.
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