Well, knock me over with a photon: Curative SBRT for metastatic disease?

I recently heard a fascinating presentation by Dr. Paul Okunieff, a leader in radiation oncology.  Dr. Okunieff recently relocated to my home state to become the director of the University of Florida Shands Cancer Center.   He discussed his pioneering work on treating patients with just a few sites of metastatic cancer (a condition known as oligometastatic disease, oligo meaning “few”) with stereotactic body radiotherapy (SBRT).   I will admit that I have never been a fan of chasing after metastatic disease with radiation.   After hearing Dr. Okunieff’s presentation, though, I definitely felt that his approach was worth pursuing in larger clinical trials.

Prior to the 1970s, with very limited chemotherapy options, local therapies (such as surgery or radiation) were pursued more frequently for metastatic cancers.   Even today, for metastatic tumors with few effective chemotherapies (such as melanomas and sarcomas), removal of multiple metastases may be performed.   For colon cancer, resection of liver or lung metastases can lead to long-term survival in some patients.   Resections of solitary brain metastases have long been undertaken, including for patients with lung cancers.   However, most oncologists would understandably object to local therapy (either surgery or radiation) in a patient with lung cancer and 2 metastatic deposits in the contralateral lung and 2 in the liver.   The argument is that metastatic cancer is a systemic disease: if we can see 2 metastases, there are probably hundreds of micrometastases that we cannot see on scans.   If we use local therapy, it’s like playing whack-a-mole: as soon as one metastasis is destroyed, another will pop up and so on and so on…

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Amifostine (Ethyol) as a Potential Radioprotectant

   Amifostine is the generic name for a drug that is marketed using the name Ethyol. This medicine is supposed to protect against the damaging effects of radiation. The medicine was originally developed by the military that was working on a medicine that would protect soldiers from exposure from a radioactive “dirty” bomb. It was ultimately licensed by the pharmaceutical industry for medical uses.

   The drug is supposed to be a free radical scavenger.  Since radiation creates free radicals that subsequently damage DNA, a free radical scavenger would theorectically mitigate some of this effect.  The drug is believed to be preferentially taken up by normal tissues instead of the tumor, which is why amifostine shouldn’t protect the tumor.

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Interview Podcast with Dr. Mehta on Novel Techniques in Radiation for Lung Cancer

In this audio interview with Dr. Vivek Mehta, Radiation Oncologist and Director of the Center for Advanced Targeted Radiotherapy at Swedish Cancer Institute, Dr. Mehta explains current and emerging new radiation techniques, as well as the current state of radiation therapy to treat patients with “medically unresectable” early stage NSCLC, or patients who decline the option of surgery for resectable disease.  He also covers side effect challenges with radiation and particularly when chest radiation is combined with chemotherapy.  In addition to the audio portion, there are a few figures synchronized with the discussion in the video version, or you can just download the figures as a separate pdf file.  The transcript is also provided below.

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Interview with Dr. Vivek Mehta: Radiation for Early Stage and Locally Advanced NSCLC

Vivek Mehta, Radiation Oncologist, on radiation approaches for early stage and locally advanced NSCLC.

Transcript: V Mehta Interview I Transcript

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High Dose Rate (HDR) Endobronchial Brachytherapy

   In some instances, patients present with growth of lung cancer on the inside of the airways (endobronchial).  For example, a tumor is growing inside the wall of the trachea or the bronchi.  When this occurs, patients often have symptoms like shortness of breath or persistent cough.  This situation can occur when patients have disease in their lung or even when this is the only site of disease.  The diagnosis is usually made by a pulmonologist who performs a direct visualization of the airways by bronchoscopy.  These nodules are missed on CT scans frequently because even when the block most of the airway –they are actually still quite small.  Here’s a representative view of an endobronchial lesion:

 (Click to enlarge)

   This type of tumor position is perfectly suited for a treatment approach called endobronchial high dose rate (HDR) brachytherapy.     This treatment approach utilizes a radioactive seed that is placed directly in contact with the tumor.  The length of contact and time of contact are determined by the size of the tumor and its location.  High dose rate refers to the use of a very hot radioactive seed that is usually made out of iridium.  The seed is attached to the end of a wire.  A very specialized machine houses the radioactive seed and wire.  It can then be programmed to feed the wire out of the machine and into the catheter for a predetermined length and time.  High dose rate procedures have basically replaced low dose rate procedures because the radiation dose can be delivered in a period of minutes rather than days if one used low dose radioactive sources. 

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“Brachytherapy” for Lung Cancer

   There some patients with early stage lung cancer that are not good candidates for standard lung surgery because of their underlying poor lung function.  A standard lung surgery typically involves removing the entire lobe of the lung that contains the cancer.  Unfortunately, for some patients with underlying COPD or emphysema – they can’t afford to lose a complete lobe of the their lung.  In this situation, some surgeons have performed more limited surgery including doing a “sub-lobar” resection.  The results for patients who have this limited surgical resection are not nearly as good as patients that have a complete lobectomy.  In some series, the incidence of local recurrence can be as high as 20-40% if only a limited surgery is performed.  The problem with these limited surgeries is that the surgeon often leaves microscopic disease behind along the edges of the surgical specimen.  In other tumor types, the surgical margins are evaluated carefully and more tissue is often resected if the margins are involved.  In lung cancer, evaluation the margins from the surgery specimen is more difficult, and the incidence of additional microscopic cells left in the area around the resection is probably quite high.  This probably explains while the recurrence rate for small tumors is quite low with a conventional lobectomy, and much higher when less tissue is removed in a sub-lobar resection.

   Brachytherapy means the use of locally placed radiation.  In this case, radioactive seeds are placed in and around the surgical suture line after the surgery is complete.  These seeds are sewed into the lung tissue or sewed into a mesh fabric that is then placed on the lung in the area that is at highest risk. 

   (Click to enlarge)

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Long-Term Results with SBRT

   As I described in my last post, stereotactic body radiotherapy (SBRT) is a technique of treating lesions in the lung with a high dose of radiotherapy.  Usually the treatment is administered in 3-5 fractions.  Several institutions have reported very good results using this technique.

   Recently, some centers have started reporting the long term follow up of these patients.  As an example, Usematsu and colleagues from Japan reported at this year’s ASTRO that 131 patients with biopsy proven stage I NSCLC were treated with SBRT using between 5-10 fractions.  Only 5 of the 131 patients demonstrated local progression.  The 5 and 10 year overall survival rate was 54% and 48%., with a 5 and 10 year cancer-specific survival rate was 78% of 74%, respectively.  Remember, the significant difference between the overall survival and cancer-specific survival in this setting is because many patients treated with SBRT are medially inoperable because of competing medical problems.  Illustrating this factor, the 5 and 10 year overall survival rate of medically operable patients (who had refused surgery) was 72% and 65%, respectively.

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Spinal Cord Compression: Pain that is an Oncologic Emergency

   Pain is one of the most awful symptoms of cancer, and the one that most people talk about when discussing the value  of physician assisted suicide.  While I (thankfully) have never had a patient directly ask me for such aid, I have had many conversations with patients and their families about pain management and how we can do a better job.

   This post cannot possibly tackle the entire field of pain syndromes and pain management.  Instead, here I want to emphasize a specific area, that of tumor impinging on the spinal cord.  Lung cancer frequently metastasizes to bone, and the bones of the spine are a prime target.  Those metastases can be directly painful, but even more worrisome from an oncologist’s perspective, the tumor can impinge on the nerves leaving the spine (by growing into the foramina, or holes by which nerves branch off from the spine and go out through the body to all muscles, organs etc) or compressing the spinal cord itself.

Spinal Anatomy (spinal cord in yellow):

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   Symptoms of spinal cord compression depend on the level of tumor pressure.  Usually, the first thing that patients notice is change in sensation—things feel funny, like a foot that has fallen asleep.  Later, muscle weakness comes and often change in the ability to control urine or bowel function.  Once it reaches that level, making the diagnosis is straightforward and a CT or MRI of the spine will be ordered by your treating doctor.  Treatment is typically radiation, as soon as feasible, but sometimes surgery first is needed for rapid relief of the pressure on the spinal cord.

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Complications Associated with Stereotactic Body Radiation Therapy

   Stereotactic Body Radiation Therapy is a technique designed to deliver a very high dose of radiation to a target lesion in the lung.  There are a variety of platforms that are used to deliver this type of treatment including Imaged Guided Linear Accelerators and the Cyberknife.

   Increasing evidence suggests that this technique might be very effective at eradicating the disease in the areas treated.

   Recently, however, there have been reports of complications associated with this treatment approach.  Unfortunately, complications associated with treatment are often underreported because it is more interesting to report positive data then negative data.

   At the recent meeting at the American Society for Therapeutic Radiation and Oncology (ASTRO, the main US-based radiation oncology professional society), the incidence of severe pain and rib fracture were reported in a combined series from the University of Virginia and the University of Colorado.  Dunlap and colleagues (abstract here) reported that 13 of the 31 patients with lesions that were with 1.5 cm of the chest wall underwent high dose stereotactic radiotherapy either experienced chest wall pain or rib fracture.  Most patients who experienced rib fracture or chest wall pain experienced it around 7 months.  When they evaluated the plans after the fact, they identified the risk of rib fracture or chest wall pain to be associated with high dose radiation in the region of the rib.  This series suggested that if the volume of the chest wall that received over 30 Gy was greater than 40 cc the risk of complications approached 50%.  Although this series is somewhat small, there is the suggestion that if one can use techniques to limit the high dose region that overlaps the rib/chest wall region the risk of rib fracture or chest wall pain will be less.

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Re-Irradiation of Brain Metastases

   Re-treatment of brain metastases is one of the most difficult of cancer treatment problems.  It is also an area where the art of medicine supersedes the science by a long way.  The good news is that it is likely easier and safer as we shift from whole brain radiation therapy (WBRT) as standard for the first line treatment of brain metastases to stereotactic treatment (SRS).  The bad news is that our ability to look to the medical literature for guidance of risks and benefits is less.

   There are some studies looking at re-irradiation of the whole brain using altered radiation fractionation schedules (abstract here) after patients received standard WBRT.  The rationale for that is that the brain is an example of a tissue that is very sensitive to the size of the radiation treatment fraction.  So, giving smaller doses (fewer centiGray or rads) with each treatment and then treating twice a day to get the necessary total dose in a reasonable time, is an approach with solid theoretical rationale.  The study linked above treated 15 patients and none had significant side effects while on treatment, but median survival was 3.2 months, with 2 longer term survivors, out past 9 months.  Sixty percent (9 patients) had improvement from the re-irradiation. 

   A larger, though older, study (abstract here) looked at re-irradiation using standard fraction size after WBRT first line.  Median survival was 4 months, though the longest survival was 72 months.  Of the 86 patients reported on in this study, twenty-three patients (27%) had resolution of neurologic symptoms, 37 patients (43%) had partial improvement of neurologic symptoms, and 25 patients (29%) had either no change or worsened after re-irradiation.  Another retrospective study, this one from Princess Margaret Hospital in Toronto, Canada (abstract here) of 72 patients showed similar outcomes, with median survival of 4.1 months after re-irradiation.  Thirty-one percent responded, 27% were stable and 32% deteriorated post re-irradiation (though it is not stated if this is likely radiation or disease related, but clearly the re-irradiation provided no benefit).  The similarity of the results is noteworthy given that in Canada it is more common to use larger doses per fraction of radiation and shorter courses of treatment than in the US.  Therefore, it confirms for us that the effects from two courses of whole brain radiation are that roughly 1/3-2/3 of patients will benefit.

   What about re-treatment after stereotactic treatment front line?  If the tumors are distant from each other, there is no difficulty or concern on treating the new brain mets with radiosurgery, as that area of the brain hasn’t received much or potentially any radiation dose so far.  What if the tumors are close together or recurrent in the same area?  Here the data are thin soup- ie, sketchy.  Data from the group at the  University of Pittsburgh group (abstract here), which is one of the best and most experienced in the world, shows that it can be safe even if in the same area, depending upon dose used and volume treated, but keep in mind, most places do not have the expertise that U. Pitt does.  Also, as the volume of retreatment increased, so did the neurologic decline of the patient.

   More difficult still is the question of when to move from repeated stereotactic treatments to whole brain radiation therapy.  For that, there is no clear answer and falls very much under the rubric of “clinical judgment”.  In the ASTRO (American Society for Therapeutic Radiation and Oncology) abstract discussed in a previous posting, there are many patients who now never move from stereotactic to whole brain treatment, despite repeated intracranial metastases.  Factors to consider when deciding on whole brain vs. stereotactic re-treatment are how many metastases, the overall functioning of the patient and the status of disease outside the skull. 

   Having been involved in this forum with patients and their families, I would add that side effects from whole brain radiation therapy can be more disabling than is often reported in the medical literature, and so it seems that we will likely continue to see a clinical practice shift away from this option as SRS permeates more of the local cancer treatment centers.  In my opinion, WBRT continues to have a valuable role in cancer treatment, but at this point, in the situation of recurrent brain metastases it is probably best suited for patients with many (>4) brain mets, and/or limited survival, though, in the interest of full disclosure, many of my colleagues would disagree.  There is little consensus about “how many brain metastases are too many” for SRS in actual clinical practice.