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

Transcript: V Mehta Interview I Transcript

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   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. 

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:

(Click on image to enlarge)

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 »

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.

While PCI is a recommended component of aggressive multimodality treatment for LD-SCLC, PCI does not at this time have any clear role in the treatment of NSCLC. To be potentially valuable, the risk of brain metastases needs to be high enough to justify to potential side effects, time, and expense of PCI, and is likely to be of value only if the risk of cancer recurrence elsewhere is low enough to make risk of brain recurrence a limiting factor in survival. With stage I and II disease, the risk of brain recurrence is not especially high compared with the risk of disease in the rest of the body, and in stage IV disease, control outside of the brain is usually a more pressing issue. But in stage III, or locally advanced NSCLC, as we have gotten better at controlling cancer in the chest, dealing with the potential for cancer in the brain has become enough of a problem that PCI for stage III disease is now a very timely question. Read the rest of this entry »