Lung Cancer Part 5 - Multi-disciplinary Team Care

Lung cancer causes 160,000 deaths each year. Diagnostic and treatment options have improved greatly in the past decade and continue to advance at a rapid rate. Someone seeking diagnostic assistance or seeking a venue for treatment should find an institution that has the full gamut of staff that has the experience and expertise and which uses the multi-disciplinary approach to care. Meeting with the surgeon, radiation oncologist and medical oncologist together and regularly to receive a single, unified approach is an important and critical element to receiving the best possible outcomes as is working with a palliative care team beginning shortly after diagnosis.

Most patients are found to have lung cancer only after symptoms such as cough or shortness of breath develop. At this point, the cancer has usually progressed and spread to the regional lymph nodes or to organs outside of the lung. But recently it has been demonstrated that lung cancer can be detected with low dose CT scanning such that over 50% can be found while still stage IA or IB. This greatly improves the opportunity for curative treatment which might be by either surgery or radiation therapy. Further, it has now been amply proven that the addition of combination chemotherapy with a platinum-based compound and another drug given as adjuvant therapy with surgical resection or radiation therapy substantially improves the cure rate.  These dame drugs can be used with good effect for those with advanced cancer, leading to lessened symptoms, better quality of life and lengthened survival. And there are now a series of recently introduced drugs that are targeted at the abnormal proteins produced by mutations or rearrangements of the tumor cells’ DNA. These abnormal proteins created by the DNA “driver mutations” can be inhibited leading to marked regression of the tumor until such time as the tumor develops resistance. The question than is who and where should one go to for the best possible care?

Most patients are not cured at this time although certainly more than previously. For those with advanced disease and who respond to treatment, relapses occur usually within a few months or a year so that only about 50% live more than a year and very few exceed the three year mark. But this is a great improvement over just a few years ago and it is clear that the combination of discovering this cancer earlier and being able to treat it with more effective means is making a substantive difference in not only survival but in quality of life. As a result, these are exciting days for those that treat patients with lung cancer.

The questions for the person who is at risk for lung cancer and wants to consider screening options or for the person who has been found to have lung cancer are the following. Where do I go to get screened? Or, where do I go to obtain the most advanced treatment in a setting that will be as comforting as possible?

The basic answer is to go to an institution that has the staff who are both expert and experienced. The stakes are high; there is little opportunity to reconsider and start again. Let’s consider this in some detail.

Treatment for lung cancer, as with most cancers, is best done in a multimodality or multidisciplinary fashion, i.e. with evaluation by medical oncology, thoracic surgery and radiation oncology at the time of diagnosis. At a minimum, this should be done in a tumor conference. Ideally, patients should be seen in a multidisciplinary clinic by the members of the three disciplines all at one time who then together, in appreciation of the patient’s desires and needs, recommend a joint plan of approach to treatment. This is particularly important for patients with localized or locally advanced NSCLC and those with localized (limited) small cell lung cancer, for which curative therapies are available. But it is relevant for all lung cancer patients as it improves patient and family understanding, prevents misunderstanding, assures that all providers are “on the same page” and that the patient has now met each of the physicians who will be involved in his or her care. Another team member is usually a the nurse practitioner, who will likely be the glue and the connection between the patient and the treatment team over time and who will help the patients “navigate” the medical care delivery system. Further it is always best to have the providers each come to the same clinic location rather than have the patient travel to different doctors’ offices as he or she migrates from treatment with surgery to radiation to drug therapy. This allows the patient the comfort of a familiar location and a well-known and compassionate clinic staff.

Why is this so important? First, it means that the various physicians, each with a different background and perspective, will discuss the various approaches to treatment among themselves and then with the patient. This brings out the best of all parties. But it also means that they come to a unified approach to treatment which can then be presented to the patient. This is much superior to having the patient, over time, visit each of the physicians only to learn that the course of therapy is now to be unilaterally modified. This is very upsetting to the patient and serves to tell the patient that the team is not marching “to the same drummer.” Ideally, the physicians involved will take the time to understand the patient’s and the patient’s family’s needs, concerns and issues. This must be incorporated into the plan of treatment if it is to be met with the patient’s full acceptance and enthusiasm. 

This quote from the University of Maryland Greenebaum Cancer Center Thoracic Oncology Program is a good summary of the some of the key elements of multi-disciplinary care. “The team meets twice a week to evaluate patient profiles, review and discuss treatment plans and examine new innovative treatments that could be beneficial to patients. They work together throughout the treatment process to ensure that care is coordinated and duplication of services is eliminated. Patients receive the highly individualized program of care they need while undergoing complex, aggressive therapies.”

Most of the highly experienced, expert institutions also have an active palliative care team. Made up of physicians with expertise in pain management and symptom support, plus nurses, pharmacists, social workers, chaplains and others, this team greatly enhances the work of the treatment team. It has been amply demonstrated that palliative care providers, when their services are offered beginning with diagnosis, result in greater patient comfort, less anxiety and depression, less pain, greater support overall and an improved quality of life and often lengthened survival.

Lung cancer is devastating yet the chance for a cure today is much greater than in the past especially if the disease is detected early. When detected later with spread of disease, it can still be treated with good success although not cure. But the treatment options are complicated and oft times confusing making care in a setting with high levels of expertise essential. The multi-disciplinary approach is far superior and results in a higher level of quality. When combined with an expert palliative care team, the patient will be well served throughout the course of care. With the advent of early diagnosis with CT screening, more effective yet less damaging approaches to radiation therapy and now targeted drug therapy for those with driver mutations, perhaps the light is now actually to be seen at the end of the tunnel for lung cancer patients and their families.

This five part series first appeared in Medical News Today at http://bit.ly/12bCUqD   

Lung Cancer Part 4 - Drug Therapy

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.

Lung Cancer Part 3 – Rx with Surgery and/or Radiation

Surgery has long been the only way to cure lung cancer. If the tumor was discovered early – a rare occurrence in the past – then resection could remove it totally. Recently it has been shown that radiation can be used successfully for early stage disease. And new approaches to radiation therapy result in the ability to give higher doses to the tumor, limit damage to surrounding normal lung and do so with relatively few sessions under the machine.

Thus far in this five part series has been a general discussion of lung cancer facts and figures followed by controlled enthusiasm about early diagnosis using CT scanning. The treatment of lung cancer has also progressed dramatically and with early diagnosis as a result of CT scanning high risk individuals, it is now possible to cure a larger proportion of patients.

Today an increasing number of individuals are having their cancer detected early so curative approaches will become more common. But many if not most lung cancer patients are older and have either chronic lung disease, heart disease or both, rendering them at higher risk for surgery. At a minimum the surgeon wants to do as limited a procedure as possible, using the least invasive approach. Still, not all patients are good surgical risks.

Despite finding the cancer when it is still small and with no apparent evidence of spread, many patients still relapse in a few months or years after surgery. The addition of chemotherapy to treat microscopic but undetected disease has a resulted in improved cure rates. The same approach is being used for those treated with radiation of early stage lung cancer.

Until recently, it was assumed that only surgical resection could cure small early stage lung cancer. But many patients are poor surgical candidates due to age, chronic lung disease, heart disease or other concomitant conditions. The question thus arises, could these newer approaches to radiation therapy be as effective.  Multicenter trials have now demonstrated that stereotactic body radiation treatment (SBRT) appears equivalent to surgery in terms of the local control of the tumor in small (<3cm p="" tumors.="">

It is important to understand that radiation can destroy any cancer if sufficient radiation can be applied. For many cancers, however, the risk of damage to adjacent normal tissues that are essential for life (e.g., normal lung) makes it impossible to give the desired dose. That said, radiation oncology has advanced dramatically in the past decade and the rate of progress is increasing rapidly. Innovations as a result of engineering and computer advances along with conceptual advances are making a dramatic difference. Major advances in radiation therapy mean greater effectiveness, fewer side effects and less time in treatment.

Newer devices allow stereotactic treatment not only for stationary tumors but also lung cancers– overcoming the problem of motion caused by breathing or even heartbeat and blood flow. The combination of continuous imaging, motion detection and robotic guidance combine to allow much more effective treatment than in just the very recent past.

Stereotactic body radiation treatment appears to be a very useful new approach to many otherwise difficult to treat cancers such as in the lung. It begins with the use of earlier techniques where the cancer is treated from multiple angles such that the tumor receives a large dose but the adjacent normal tissues receive much less. Stereotactic means that the tumor is imaged and the radiation adjusted to directly attack the cancer and not the normal tissue. A related innovation is to link actual delivery of radiation with the patient’s breathing parameters (gating). This is done with an infrared device that observes motion and turns the radiation beam on and off during the breathing cycle. This can be of great value in lung cancer because the target is constantly moving. This greatly reduces normal tissue damage occurring as the lungs move with respiration. It also means that the cancer gets a higher dose because the physician is less encumbered by a concern for damaging adjacent normal lung. This is a real improvement as in the past it was necessary to curtail the ideal dose with the realization that that dose would cause unacceptable side effects on adjacent normal tissue.

Hypofractionation, that is giving a much higher dose of radiation per session, with the much greater accuracy of the stereotaxic approach, means many fewer sessions yet with high effectiveness. Much SBRT is now done in 3-5 fractions rather than the more typical approach of multiple, perhaps as many as 45, fractions over as many days or more. Add robotic guidance based on motion detection and the combination becomes very powerful. With robotic control of the equipment from outside the treatment room, this means less time is wasted by the staff moving back and forth to make adjustments and less time on the table for the patient. 

Most radiation today is delivered by X-rays or electrons (photons). Another approach is to use protons. Proton beam therapy has the advantage that the proton gives up its energy only when it hits its intended target – in this case the tumor. It does not continue through the tumor and damage normal cells on the far side. So it allows for the delivery of very high doses of radiation to the tumor with minimal side effects. It follows that proton beam might prove very useful because one can give a much higher dose without as much fear of adjacent normal tissue damage. But it is critical to keep in mind that there are no controlled studies showing superiority of protons over photons and certainly none in lung cancer as of yet. As a result it is important that the clinical value of proton beam therapy not be over inflated. The cost of one center runs into the hundreds of millions of dollars -- which would purchase 20 or more photon linear accelerators.

What is clear is there is a steady and rapid, advance in the ability to deliver radiation therapy to those with lung cancers in a more effective and more safe manner, often in much less time than in the past. The realization that radiation can actually be used to cure early stage lung cancer is a stunning advance, allowing effective treatment for those not able to undergo surgery.

In the next of this series will be a discussion of the dramatic advances in lung cancer treatment with drug therapy.