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Dorchester Center, MA 02124
The following is an article I wrote for a newsletter in 2002 when I was a surgical oncology fellow. The names have been changed to protect the privacy of those involved.
MRS. SMITH’S ABDOMINAL SARCOMA AND THE PROMISE OF ANTI-ANGIOGENIC THERAPIES
Mrs. Smith’s primary physician told her that her CT scans showed a huge mass inside her abdomen and some early lung metastases. She had developed increasing fatigue and inability to eat over that past month, and her doctor had ordered the appropriate tests. She was referred to Memorial Sloan Kettering Cancer Center in early May, and Dr. Archibald Thornton III, her surgeon, told her she would require an operation to try and remove this tumor and alleviate her symptoms. A cure was unlikely, but the options were limited. A biopsy had shown this tumor to likely be a sarcoma. The tumor was too large to be effectively treated with radiation therapy, and chemotherapeutic agents shrink sarcomas in a minority of patients.
As is usually the case, this sudden interruption in Mrs. Smith’s life came at an inopportune time; her daughter was getting married later that month. Mrs. Smith put off the operation so that she could see her daughter get married. She collapsed a few days after the wedding and was transferred to Memorial from another hospital. I was the surgical oncology fellow on Dr. Thornton’s service, and first met Mrs. Smith in the hospital shortly after she was admitted. After taking her medical history, examining her, and reviewing the labs and films, I was amazed that she had kept herself out of the hospital for so long. She had severe metabolic derangements from her tumor including a very low glucose level and one of the highest white blood cell counts that I’d ever seen in someone without leukemia, and the repeat CT scan showed the tumor had grown. Despite this, she was quite cheerful and talked mostly of her daughter’s wedding.
Dr. Thornton and I operated on her 3 days later. She had a basketball-sized, aggressive tumor that invaded many of her abdominal organs, and we took out as much tumor as we could along with parts of her stomach, small bowel, pancreas, and spleen. The pathologist reported her tumor to be a rare subtype of high-grade sarcoma. She made a slow but steady recovery over two weeks during which time we got to know her family including her recently married daughter. I talked with Mrs. Smith every morning and evening during her time in our hospital. She worked as a nurse in a doctor’s office, and she had many friends and family members constantly at her bedside. A framed picture stood on the nightstand by her hospital bed of her and her daughter at the wedding that she was somehow able to attend.
Late one night, Mrs. Covell had an increasingly difficult time catching her breath and subsequently began dropping her blood pressure. She failed to get better with additional oxygen and fluid administration, and she was transferred to the Intensive Care Unit. Her condition rapidly deteriorated and she died a few hours later. Her family had gathered in the waiting area by that time, and I said what I could. The autopsy showed she had died of an overwhelming infection originating from her residual tumor. I remember mostly a feeling of helplessness at that time. Helpless to get the entire tumor out. Helpless to offer other treatments. And helpless to enable Mrs. Smith to complete her life.
I am now in my second and final year as a surgical oncology fellow at Memorial Sloan Kettering Cancer Center, and there are many success stories that I could relate of patients surviving sarcomas and other cancers. However, Mrs. Smith’s story seemed most appropriate as a prelude to discussing new research into sarcoma treatment since she and patients like her are the impetus for cancer researchers to develop better treatments. Fortunately, periods of helplessness have not led to loss of hope.
There is reason for optimism. We are approaching the fifty-year anniversary of the discovery of the DNA double helix by Drs. Watson and Crick, and during this time an explosion has occurred in our understanding of the molecular mechanisms by which tumors grow. This has led to unique strategies in combating cancers, one of which has been termed anti-angiogenic therapy. Tumors must induce nearby blood vessels to proliferate and form new blood vessels to supply nutrients for growth. This process has been termed angiogenesis, and there are several theoretical advantages to blocking angiogenesis. First, anti-angiogenic therapies target endothelial cells (the building blocks of blood vessels) rather than cancer cells. Endothelial cells are in closer proximity to blood-borne drugs, which often never reach some regions of a tumor. Second, endothelial cells are genetically stable while cancer cells acquire thousands of genetic mutations. Genetically stable cells are much less likely to develop resistance to drugs as opposed to genetically unstable cells. Lastly, anti-angiogenic therapies likely will have few side effects since endothelial cells in other areas of the body are rarely proliferating. Thus, blocking endothelial cell proliferation should have few side effects.
There was great enthusiasm for anti-angiogenic therapy in the late 1990’s when Dr. Judah Folkman and his colleagues at Children’s Hospital in Boston discovered new protein fragments that were very effective in mouse models of cancer. This enthusiasm waned as early human clinical trials demonstrated disappointing results. These trials in general enrolled patients with epithelial cancers such as colon cancer. There is reason to believe that anti-angiogenic therapies may be more effective against sarcomas than other types of cancer. Sarcomas tend to grow in locations that are poorly vascularized such as the subcutaneous tissue and retroperitoneum. It may be easier to inhibit new blood vessel formation in these regions than in more vascular regions. The majority of animal models demonstrating the efficacy of angiogenesis inhibitors involved tumors grown in subcutaneous tissue.
There is preliminary evidence from recent studies I have performed with Dr. Benjamin Cohen at Memorial Sloan Kettering Cancer Center that anti-angiogenic therapy may be effective for patients with sarcoma. As tumors grow and invade adjacent structures, they cause the release of proteins that inhibit angiogenesis. One of these factors is called endostatin. We have demonstrated that patients without metastases from sarcoma have high levels of endostatin in their blood while patients with metastases have very low levels of endostatin. This suggests that during formation of metastases, endostatin levels become suppressed and allow the growth of distant metastases. Treating patients prior to the development of metastases with endostatin or another anti-angiogenic agent may prevent metastases from forming.
Other anti-angiogenic agents have progressed in clinical trials. The most effective anti-angiogenic agents thus far have targeted vascular endothelial growth factor (VEGF) and its receptors. VEGF is a growth factor that is specific for endothelial cells, and cells depend on VEGF to grow. Strategies to block this pathway include antibodies and soluble receptors that bind VEGF, antibodies that block VEGF receptors, and small molecules that inhibit downstream signaling of the VEGF receptors. A new family of soluble factors (angiopoietins) and their receptors (Tie-1 and Tie-2) have been discovered to be nearly completely unique to endothelial cells, and targeted disruption of this pathway has shown encouraging results in animal models.
I would caution that we may see more disappointing results from clinical trials using angiogenesis inhibitors in the near future. New research demonstrates that tumor angiogenesis is a very complicated process with different tumors utilizing a variety of different angiogenic growth factors and signaling pathways and having varied responses to specific angiogenesis inhibitors. It may take some time to sort out which combinations of anti-angiogenic agents are most effective against a specific cancer.
Oncologists feel a sense of urgency in our research as cancer continues to take its toll on the lives of our patients and their families. I feel that sense of urgency every time I think about Mrs. Smith and her family. I am optimistic that we will continue to make significant progress toward a more effective therapy.