From the Grace Archives--Originally Published December 6, 2009 | By Dr. Pinder
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…
For this reason, we generally use radiation only with palliative intent in patients with metastatic cancers. If a metastasis isn’t causing pain or other symptoms, we do not radiate it. But not so fast, argues Dr. Okunieff. We are now picking up more patients with oligometastatic disease than ever before, due to improvements in our imaging. Let me use one of my patients as an example:
A 50 year old man initially came to me for consideration of definitive chemo/radiation for a stage IIIA adenocarcinoma with bulky mediastinal lymph nodes. He had undergone CTs of the chest, abdomen and pelvis and brain MRI but no bone scan or PET. I performed a PET scan and found 2 tiny areas of increased activity, one in the femur and another in a thoracic vertebra. He had a biopsy of the femur and sure enough, it was metastatic adenocarcinoma. This patient had an excellent response to chemotherapy, with a 50% reduction in the tumor in his lung and the lymph nodes in the mediastinum. Even off chemotherapy, he has not developed any new sites of metastasis.
If this patient had presented 20 years ago, these metastases probably would not have been discovered and he would have proceeded on to definitive treatment. Presumably, they would have eventually blossomed and would have been detected clinically. There is a large gap in survival between patients who underwent resection of liver metastases in the pre-PET era compared to post-PET. One explanation is that PET may select for patients who truly have oligometastatic disease while patients who were thought to have metastases limited to the liver with older imaging modalities likely had more widely metastatic disease. So we may be picking up a different breed of stage IV patients now and may need a new paradigm for approaching these patients. An alternative explanation is that these are simply patients with a very indolent metastatic cancer and might do well whether we treat with chemotherapy or with local therapy.
We typically assume that metastases originate from the primary tumor but Dr. Okunieff suggests that perhaps metastases can generate more metastases and so just leaving oligometastatic disease alone when it appears stable may mean that we miss a window of opportunity for cure.
It should be noted that Dr. Okunieff’s work has focused on SBRT rather than convention radiation. While conventional radiation involves spreading the total dose of radiation out over many days, SBRT involves delivering high-doses of very focal radiation over a short period of time. When conventional radiotherapy is given as a palliative rather than a curative treatment, the total dose delivered is typically much lower. Several groups, including Dr. Okunieff’s, have demonstrated that these high doses of radiation may result in immune-stimulation against the cancer. In this way, SBRT to metastases may actually be a systemic therapy as well. Several researchers are looking at combining SBRT with drugs that stimulate the immune system to see if it is possible to strengthen this effect. Only certain tumors can be treated with SBRT – it doesn’t tend to work as well on larger tumors and can be dangerous if vital structures are nearby.
Survival results from Dr. Okunieff’s work with patients treated with SBRT for lung metastases are shown below. While the majority of patients eventually progressed and died of metastatic disease, a subset of patients demonstrated long term survival. As the graph indicates, these patients were mainly those with primary breast or lung cancers. Although a 20% long-term survival rate in patients with metastatic lung cancer is not something to ignore, it is difficult to know if this is a subset of patients with more indolent disease who would have done just as well (or better) with just systemic therapy.
Okunieff et al. Acta Oncologica (2006)
Although this work is exciting, the studies of SBRT for metastatic disease have included only small numbers of patients – they show promise and are a launching point for larger studies but cannot be used yet to guide patient care. Dr. Weiss recently wrote an excellent post on how new treatments become standard of care and we are definitely not there yet on SBRT for metastatic disease. Furthermore, the majority of patients are not demonstrating prolonged control of their cancer with SBRT, even in this carefully selected population. Several researchers, including Dr. Okunieff, are trying to discover how to predict which patients would benefit most from treatment with SBRT.
Studies to validate this concept are planned through SWOG, and I am looking forward to seeing more.