The MDA study was designed to enroll 90 patients, but closed after it enrolled 58 because of safety signals (one arm looking convincingly superior to the other).  The study took 7 years to enroll.  It was closed early when there was worse neurocognitive decline (examining learning and memory at 4 months post treatment using a test to recall a list of 12 words) in patients receiving WBRT+SRS vs. SRS alone.  There was a 49% decrease in function with WBRT+SRS vs. 23% in SRS alone.  The patients in the WBRT arm received 30 Gy/12 fractions over 2 weeks, or 2.5 Gy/radiation treatment.  The in-brain control rate was better in the WBRT arm (no in-brain disease recurrence at 1 year out from treatment) vs SRS (1/3 of patients had further tumor in their brain, though over half of patients never got WBRT within their remaining lives).  Importantly, the overall survival of patients in the SRS arm was much better, a finding that is unexpected and unexplainable on the basis of the radiation treatment received for brain metastases. 

   So, the study adds more information to the debate on how to treat patients in this group.  For a single met, few people would recommend WBRT, and for 4 or more mets, WBRT remains the standard of care.  While this study appears internally consistent (following good statistical practices), the difference in survival based on brain radiation suggests some kind of imbalance of tumor burden between the two arms of the study, which may have just been a statistical fluke.  What about external validity – i.e., do we believe the results relate to patients overall?  Here several questions arise.

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   Therapeutic radiation beams given from outside the body (as opposed to brachytherapy –otherwise known as implanted radiation or “seed therapy” in prostate cancer, which will not be considered here at all) are like visible light waves, but much higher energy.  Like visible light, the physics of therapeutic radiation beams has the same wave/particle duality that make theoretical physicists lay awake at night.  From a therapeutic perspective, though, the fact that the beam “travels in a straight line” is useful for it allows us to point the radiation beam at the tumor and miss the adjacent normal tissue (like using a knife to cut a bruised part out of a piece of fruit).  However, like that bruised piece of fruit, the knife has to start on the outside of the fruit and cut deep enough to get out the bruise—if the bruise is deep, all of the fruit from the skin down to the bruise will also get cut away.  In cancer therapy, this means that all the tissue from the skin down to the tumor “sees” the radiation beam. 

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   To begin to answer this, we need to step back and consider what radiation therapy is, and what it is used for:  radiation therapy uses high energy photon beams (like supercharged light) to target cancer cells and kill them.  It is the true prototype of “targeted therapy”, which is now a phrase used a lot to discuss specific chemotherapy agents that “target” a specific molecule.  The absolute fundamental difference, however, is that a chemotherapy is inside the body when it targets a molecule, and thus the delivery (via a tablet or via the vein) doesn’t require people to take it exactly the same way every day.  You can stand and swallow the pill or you can sit.  You can sit in any of the infusion chairs at the chemotherapy suite, sitting still or wiggling around.  In contrast, targeting radiation therapy is like having to trace exactly the same line everyday, without changing it at all, for weeks.  The pencil cannot slip, cannot change direction or thickness, cannot merely be “close enough”.

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   Pneumonitis is one of the risk factors associated with radiation treatment to the lung.  Radiation pneumonitis is an inflammatory reaction that resembles a pneumonia that typically occurs in patients 6-24 weeks after they have completed radiation treatment.  The symptoms of radiation pneumonitis are often similar to the symptoms one experiences when one has a pneumonia or the bad flu.  Patients can complain of a cough, shortness of breath, or even chest fullness.  Most patients who develop these symptoms after radiation report that the symptoms resolve by themselves in 7-10 days.  A few of the patients have really severe symptoms and come in to be evaluated by a physician.  If the diagnosis of radiation pneumonitis is made, then patients can be treated quite effectively with a short course of steroids. 

   One of the important things to keep in mind is that radiation pneumonitis is a “diagnosis of exclusion.”  What this means is that a very thorough and careful evaluation must be undertaken to make sure that the symptoms the patient is experiencing is not caused by something else.  Only after the other possible explanations have been ruled out can one say that they have a diagnosis of radiation pneumonitis.  I have noticed that there has been increasing awareness of this complication more recently.  A really interesting analysis was recently reported in the literature.  The physicians went back through the charts of patients diagnosed with severe radiation pneumonitis to evaluate the outcomes of these patients.  They discovered to their surprise that many of the patients didn’t in fact have radiation pneumonitis but other serious conditions that had been initially “missed.”  For example, one of the patients was ultimately diagnosed with a heart attack.  Other patients were ultimately diagnosed with exacerbations of their COPD/emphysema.  And some of these patients had infections that were ultimately treated with appropriate antibiotics.  This report is a caution that should remind everyone to look elsewhere first before assuming that the symptoms are radiation pneunonitis. 

   Another thing to keep in mind is that some patients will have evidence of “radiation pneumonitis” on a CT scan but not have any symptoms.  I think that most of us agree that these patients don’t need any treatment as long as they remain asymptomatic.

   The causes of radiation pneunonitis are still being worked out.  There are a number of possible suspects.  The most obvious is the radiation dose, the daily fraction, and the amount of lung exposed to certain doses of radiation.  Certain chemotherapy or targeted agents may make the lung more sensitive to radiation pneumonitis or may actually cause it independently.  Although people with compromised lungs may do poorly if they develop radiation pneumonitis, I’m not sure that there is good evidence indicating that they are any more sensitive to this side effect than a person with healthy lungs.

   Patients who develop esophagitis will often complain of some heartburn like discomfort or pain with swallowing.  These symptoms come on gradually and get worse as they complete treatment.  They typically peak sometime after the radiation ends.  In the most severe form, an ulceration can form in the esophageal wall (this happens very rarely).

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   Whole brain radiation therapy (WBRT) is effective and the treatment of choice if there are many brain mets.  Using MRI to examine the brain, about 80% of patients have more than one lesion.  For patients with only a single brain lesion, SRS is a standard of care.  For WBRT, standard dose-fractionation in the US is 3000 cGy in 10 treatments over 2 weeks, with one fraction given each day, 5 days a week.  Multiple large studies have shown that this provides disease control in the brain for about half of people at 6 months (for many patients 6 months is longer than their survival, so in reality, more patients have disease control for their remaining lives). 

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   In its broadest sense, IGRT applies to any of a number of technologies that improve the ability of the radiation oncologist to validate the patient’s exact position prior to initiating radiotherapy.  For many of years, the standard approach was to apply tattoos (little dots, not the interesting kind) to the patient’s body and then line the patient up on the treatment table by using wall-mounted lasers to verify the patient’s position.  For some treatments, a customized mold or cradle is created for the patient to lie in for each and every treatment.  This customized mold conforms to the patient’s shape and position and then solidifies.  In this way, the patient is thought to be in the same position for each and every treatment.  Periodically during the treatment, the patient undergoes a “port film”.  This is a simple x-ray that is taken during the course of radiotherapy.  The radiation oncologist evaluates this x-ray to ensure that the patient is accurately positioned on the treatment table.

   More recently, IGRT has come to mean the use of a CT scan performed periodically prior to the initiation of radiotherapy.  There are several different equipment platforms that perform this function.  The Elekta Synergy and the Varian Trilogy are linear accelerators that have a built in imaging device that resembles a CT scan.  The Tomotherapy unit is a CT scanner that has a built in linear accelerator.  Although there are subtle differences between the different platforms, the purpose of each is to image the patient’s soft tissues and more accurately evaluate the patient’s position prior to treatment.  By obtaining images that are nearly CT quality, there is a wealth more information than what can be seen on a simple x-ray image.  In addition, the CT that is obtained prior to treatment can be analyzed by a computer to compare how closely the patient is positioned on the table at the exact time of current treatment to the position of the patient on the table at the time of previous treatment planning and simulation.  The computer will also specify how to adjust the table in terms of height (up or down), right or left, and front to back in order to more accurately align the patient in three dimensions.  The accuracy of this CT matching is thought to be less than 3 mm.  The additional CT scans that are obtained during the treatment course add to the radiation exposure, but this is thought to be only a small amount of additional exposure.

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   Radiation is a very effective treatment modality for patients with any type of cancer.  Most patients that have received treatment with radiotherapy in this situation receive conventionally fractionated radiotherapy.  Conventionally fractionated radiotherapy means that the radiotherapy is delivered daily Monday through Friday.  Most patients receive between 6.5 and 7.5 weeks of treatment.  It is usually between 33 and 37 fractions (individual treatments) of radiotherapy.  The outcomes with this type of treatment are generally pretty good.  The published outcomes from this type of treatment range from 30% to 81%, which is a large range.  Part of the explanation for this range is that there is such a tremendous variation in the patients included in the medically unresectable category.  Some of these patients are quite healthy with the exception of some reason that they can’t undergo surgery.  Other patients have really fragile lung function and oxygen dependent.  There is some suggestion that the control of the tumor is better with higher doses of radiotherapy.  There is also the suggestion that with improved technologies and newer treatment that the outcomes will continue to improve.

   It is quite common for surgeons to compare the surgical treatment of early stage lung cancer with radiotherapy alone and point to improved outcomes.  Unfortunately, this is not an accurate comparison.  The published surgical experience is based on an analysis of pathologically staged specimens.  This means that when a surgeon reports outcomes on the resection of a 2 cm tumor, the size of the tumor is based on the surgical specimen and the measurement by the pathologist.  Surgery also gives the chance to find lymph nodes that are involved microscopically but weren’t noted on scans.  Most of the time, the CT images (clinical staging) underestimate the size of the tumor that is measured by a pathologist after surgery, and it may understage nodal involvement.  This means that when you compare outcomes with radiation alone to the results with surgery for a similar stage, you’re likely actually including many higher stage patients on the radiation arm who are going to do less well.

    There is emerging interest in the role of stereotactic radiosurgery for the treatment of early stage lung cancer.  Stereotactic radiosurgery means the delivery of a very high dose of radiotherapy in just 1 to 5 treatments.  The dose of radiotherapy that is delivered is often biologically equivalent to 7 or more weeks of daily radiotherapy.  The early experience with this approach in Japan and the US suggest that control rates in excess of 90+% can readily be achieved.  The toxicity of this approach is reasonable in most instances. 

   In conventional radiotherapy treatment planning, patients are positioned in the CT simulator room in the position that they will be treated in.  The patients then actually undergo a CT scan.  The images are transferred to a treatment planning computer.  Specialized treatment planning software is used that processes the CT images for analysis.  A 3D image of the patients target region is created on the computer.  In patients with lung cancer, this region typically includes the lungs, spinal cord, heart, esophagus, ribs and other tissues.  The primary tumor and regional lymph nodes can often be identified on the CT scan and the 3D rendering.  The radiation oncologist and team will identify the targets that need to be treated and proceed to design fields that encompass the targets while minimizing exposure to the normal tissues.  This approach, however, doesn’t account for the motion of the tumor do to respiratory motion (from breathing). 

   The treatment planning CT scan represents a “snapshot” in time.  In essence, it lets the radiation oncologist and team identify the tumor’s location at that time and in that particular portion of the respiratory cycle.  In order to account for the tumor motion, most practicing radiation oncologists will add a “safety margin” around the target to account for this motion that is occurring while the patient is breathing.  In effect, a larger region is exposed to radiation to make sure that wherever the tumor might actually be it will still receive radiotherapy.  The size of the “safety margin” is typically about 1-2cm in every direction.  (more…)