Radiation Pneumonitis: A Radiation Oncologist’s Perspective

   Dr. West previously wrote an introductory post (here) about radiation pneumonitis, but this is a common enough problem that it merits further discussion, including input from a radiation oncologist.  The other issue is that Dr. West was using a review article of mine (abstract here) as a crib sheet, so now I can give you a bit of perspective directly from the source.

   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.

Radiation Esophagitis

   Esophagitis is a symptom that occurs in patients undergoing radiation for lung cancer.  It is not uncommon for patients to blame the radiation for this side effect.  Radiation esophagitis if often described as a “sunburn on the inside of the esophagus.”  The esophagus it the long swallowing tube that sits in the middle of the chest usually right next to the trachea (the windpipe).  The tube connects the mouth to the stomach.  Unfortunately, it is very difficult to avoid this structure when delivering radiation because it is intimately associated with the lung, central lymph nodes, and the trachea.  Avoiding the esophagus would mean undertreating the tumor in many instances.

   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

   A diagnosis of brain metastases has to be one of the most scary and disappointing of all potholes on the cancer journey.  It is unfortunately common, happening to about 170,000 new patients each year in the US alone, about half of whom have lung cancer.  Radiation therapy is the standard treatment and it is very effective.  Until recently, radiation therapy was delivered to the whole brain, but now stereotactic radiation therapy, or radiosurgery is often used.  Radiosurgery (SRS) is often known by the trade names of the machines used to deliver it:  gammaknife or cyberknife.  While these names sound really high tech and Star Trek-like, both machines are delivering radiation therapy of the same type (photons) as a regular radiation machine (linear accelerator), just in an incredibly precise and focused manner.

   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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Treatment Interruptions or Delays with Radiation

   Despite the acute side effects, it is important to try and deliver the radiation treatment without any interruptions or delays in treatment.  Experiments in the laboratory with cancer cell lines demonstrate quite convincingly that interrupting the radiation treatment even for a few days allows the cancer cells to grow back.  A large retrospective study has demonstrated that the survival is significantly worse if patients had an interruption in their treatment of longer than 5 days.  These results have also demonstrated that patients that go through the treatment without an interruption have a statistically higher chance of beating the disease than patients that experience an interruption in their treatment.  Sometimes the interruption in treatment is simply unavoidable (i.e., because a patient is simply too sick), but treatment interruptions scheduled out of convenience should be avoided if at all possible.

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An Introduction to Image-Guided Radiation Therapy

   Image Guided Radiotherapy, which his also known as IGRT, is a new and emerging technology in radiotherapy.

   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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Radiotherapy for Medically Unresectable NSCLC

   Some patients with small and early stage lung cancer are not able to undergo a surgical resection because of other medical conditions that might make an operation too risky.  In this patient population, radiotherapy alone has often been the primary treatment.

   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. 

Radiation Therapy and 4-Dimensional (4D) Planning

   The treatment of lung cancer with radiotherapy is rapidly changing as new technologies make the treatment safer and more effective.  One of the more recent developments has been the development of tools that allow for designing radiation fields that account for a tumor’s specific motion, or it’s change in position over time, the fourth dimension.

   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.  Read the rest of this entry »

Stereotactic Body Radiation Therapy (SBRT) for NSCLC

One emerging alternative to standard radiation therapy for medically inoperable patients with early stage NSCLC is stereotactic body radiation therapy (SBRT). This technique requires fixation and very precise treatment planning for a brief course of radiation that targets a more limited radiation field. One key issue with SBRT is that it presumes you don’t need to do extensive radiation to lymph node areas around the primary tumor — this is a big topic, but the evidence generally suggests this to be true, that we really need to focus more on treating the disease we see with stronger and more precise radiation, rather than get too distracted by the potential presence of microscopic regional disease in lymph nodes that appear normal on scans (abstract here, for example).

Our standard radiation dose of 60-66 Gray (the unit of radiation administration) for NSCLC is based on remarkably little evidence and goes back several decades. In fact, we know that similar or lower doses of RT are very effective in eradicating microscopic disease and laryngeal cancers that measure just a few millimeters, but radiation that is routinely administered in the 70 Gray and higher range are fair to good at treating smaller tumors like prostate and cervical cancers, both of which generally falling in the range of a few cm. In contrast, radiation for NSCLC lung lesions are often in the 5-10 cm range, and radiation in the 60 Gy range just isn’t that effective for such large and not especially radiosensitive tumors.

Newer techniques allow us to potentially deliver one or just a few fractions of very high dose radiation to a precisely limited area, thus reducing the risk of damage to surrounding areas and the need to administer radiation over many fractions over several weeks (radiation at low doses over many weeks takes advantages of the fact that normal non-cancer cells can recover better from radiation-induced DNA damage, leading to our routines of small doses accumulating over many weeks). By giving very high doses to a very defined area, stereotactic radiation becomes similar to a non-invasive form of surgery, leading to it being marketed as “gamma knife” or “cyber knife” (if you actually see any knives during these procedures, you should be concerned). This line of study was pioneered in the field of treating brain lesions, where the skull can serve as a reference system and the entire area can be immobilized with a fixed frame screwed into the skull (temporarily). These strategies are now very widely used for primary brain tumors or metastases to the brain from other sites.

But there are new techniques that allow introduction of the previously brain-based approach to body lesions as well. One of the less technical ones is to have a device that compresses the abdomen to minimize the ability of the diaphragm to move up and down and change the shape of the lungs:

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That white arc is where a patient’s abdomen is, and the vertical screw clamps down on the abdomen to limit motion. You may also note the presence of a metal frame on either side of the chest to hold it in place as well. It may seem medieval, but this is a potential step forward in treating cancer. Read the rest of this entry »

Radiation Therapy for “Medically Inoperable” Patients with Early Stage NSCLC

Many patients with early stage NSCLC but marginal or just plain poor pulmonary function tests and/or significant comorbidities pursue non-surgical therapy options rather than resection of the cancer. This primarily entails definitive radiation therapy (RT), stereotactic body radiation therapy (SBRT), or radiofrequency ablation (RFA) of these lung tumors. There is far more experience with definitive RT than with the other options, but I’ve never covered it. I’ve really only covered the newcomer RFA (prior post here), which was recently the subject of an FDA announcement of a number of patient deaths following RFA to lung tumors (post here). So now I need to rectify that. The most common primary treatment modality for “medically unresectable” patients with early stage NSCLC has been definitive RT alone. There has been a wide range in the reasons for patients to be ineligible for surgery, and many of these patients have other serious medical problems. A meta-analysis of multiple trials that enrolled medically inoperable patients with stage I or II NSCLC who received definitive RT (abstract here) reviewed results of a total of approximately 2000 patients in 26 non-randomized trials. This analysis demonstrated that overall survival at two, three, and five years ranged from 22-72%, 17-55%, and 0-42%, respectively. Cancer-specific survival was 54-93%, 22-56%, and 13-39% for those time intervals, respectively. Notably, 11-43% of the patients enrolled died from non-cancer-related causes, highlighting the real competing risks of these patients. Results with surgically treated patients are clearly better, but it’s not possible to separate how much of this is from the benefit of surgery over RT vs. how much is due to the difference in general level of health in the surgical vs. non-surgical early stage NSCLC populations. Another central problem with interpreting non-surgical data is the fact that the latter are derived from clinical staging, which consistently understages patients compared with pathologic staging in surgical trials. Approximately 40% of patients with clinical stage I NSCLC are subsequently found to have higher stage disease on surgical staging (abstract here), so surgical series reflect a higher stage, while non-surgical studies report an inferior survival at a lower clinical stage.

In addition to RFA as an alternative local therapy, stereotactic body radiation therapy (SBRT) has emerged as a novel technique, and one that hasn’t been the subject of a recent FDA warning. I’ll cover that work soon.

Stereotactic Radiosurgery for Brain Metastases

We’ve previously discussed whole brain radiation therapy (WBRT) has been the historical cornerstone of treatment for brain metastases, and how surgery is sometimes employed in certain cases, but stereotactic radiosurgery (SRS) has dramatically changed the treatment of brain metastases. SRS involves using a high dose of extremely focused radiation to a small area, most commonly in the brain tissue. Several machines can be used for this approach, most commonly Gamma Knife, potentially Cyber Knife, but sometimes other machines.

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It has been best studied in the setting of just 1-3 brain metastases, but it’s being used increasingly in patients with many brain metastases, a setting in which we have no real data, and there’s a good deal of controversy around whether patients are better served by whole brain radiation in that setting. Read the rest of this entry »