Contributions to Cancer Research

Dr. Phillip A. SalemSince starting my medical career in 1968, my work as a cancer researcher can be divided into three major sections:

  • Research on immunoproliferative small intestinal disease (IPSID).
  • Research on lymphomas other than IPSID.
  • Research on new agents and new treatments.

Immunoproliferative Small Intestinal Disease

I believe the most important research I have done is my research on immunoproliferative small intestinal disease (IPSID). IPSID research has had a major impact on how we treat cancer and how we conduct cancer research today. IPSID is a disease of people in the Middle East and on the Mediterranean shores. When I started research on this disease, I was a professor at the American University of Beirut. My initial work in the Middle East set the stage for the explosion in knowledge that followed from that research. Several researchers in the Middle East and Europe have published on IPSID, but I believe that my team and I defined its clinical and pathological profile and have published most extensively on it.

What are the lessons I learned from my research on IPSID that had a major impact on future cancer research?The first and most important concept is that a chronic, repetitive infectious insult to the gastrointestinal mucosa can eventually lead to inflammatory changes that, if left untreated, can progress to malignancy. Our studies on IPSID in the 1970s were the first to show that repeated chronic infection in childhood led to the development of lymphoma in the small intestine ten to fifteen years later. We could not determine the precise nature of the infectious microorganism, but patients who were treated with tetracycline at an early stage rarely developed the lymphoma. This was a strong argument that the process that led to lymphoma was infection related. Other investigators followed this concept with research in the late 1980s and early 1990s that showed association between H. pylori, an infectious agent in the stomach, and stomach cancer. In the 1990s it became clear that H. pylori had a causative relationship to peptic ulcer and to stomach cancer. In 2005 two Australian physicians who worked extensively on H. Pylori’s relationship to stomach cancer won the Nobel Prize in Medicine and Physiology. In its award citation the Nobel Prize committee emphasized the importance of the different avenues of research, including research on IPSID, that led to the development of the research on the causative association between H. pylori and stomach cancer.

The second concept is that the process of inflammation resulting from a chronic, repetitive infectious insult to the gastrointestinal mucosa is reversible. My team and I identified the benign phase of IPSID and treated those patients with antibiotics. Most patients achieved a complete remission and avoided the progression from inflammation to cancer. This was among the earliest evidence that cancer in humans is chemopreventable. Chemoprevention is the reversal of the neoplastic process after it begins. We have proven beyond doubt that treating the infectious or the inflammatory phase of the neoplastic process of IPSID with antibiotics like tetracycline can reverse the process and prevent the deterioration of the inflammation to malignancy. The concept that was generated in IPSID research is the cornerstone of chemoprevention of cancer today. It was the cornerstone of the two national trials conducted in the United States on chemoprevention of breast cancer and other solid tumors.

I was the principal investigator of two clinical trials under the sponsorship of the National Surgical Adjuvant Breast and Bowel Project (NSABP) at St. Luke’s Episcopal Hospital in Houston, Texas. These clinical trials have shown that breast cancer in women at high risk for the disease may be prevented in the majority of women if they take tamoxifen or raloxifene over a period of five years. The first study was part of the NSABP’s breast cancer prevention trial, which compared tamoxifen to placebo for breast cancer prevention. The first trial proved that tamoxifen reduces the risk of breast cancer in high-risk women by 50%. The second NSABP study compared the efficacy of two drugs, tamoxifen and raloxifene, for prevention of breast cancer in women at high risk. The study revealed that raloxifene was as effective as tamoxifen in prevention of breast cancer but had fewer side effects and perhaps more benefits.

The third concept is the observation that the neoplastic process goes through a histopathologically benign–appearing phase before it progresses to frank malignancy. My team and I were among the first to describe this so-called benign phase of IPSID. At this phase, at least histopathologically, there are no changes that can be diagnosed as cancer. However, the disease may be already malignant at the molecular level. Very few studies have been done in IPSID to determine the molecular nature of the lesion when it is still in the benign phase. However, whether the benign phase is malignant at the molecular level or benign at the histopathological level, this phase remains reversible by the use of antibiotics like tetracycline. This so-called benign phase has also been shown in breast cancer, colon cancer, and mouth cancer. When we described this benign phase in the early 1970s, it was a novel idea and concept that cancer can go through a benign phase before it becomes frankly malignant.

I believe that the above three concepts made a major impact on how we treat cancer now and how we try to prevent it. They also made a major impact on the evolution of cancer research and its funding. I cannot think of a more important preventable cause of cancer than infection, and I believe that modern cancer research should focus on the relationship of infection to cancer. The model of the Gardasil vaccine and the prevention of cervical cancer is only the tip of the iceberg in the story of the impact of infection on cancer. I would not be surprised if in in ten to twenty years from today we learned that many of the diseases we treat, including leukemias, lymphomas, and some solid tumors, are infectious in nature and could be easily prevented in the early stage. I cannot think of more important and more urgent research.

Lymphomas Other Than Immunoproliferative Small Intestinal Disease

In addition to my work on IPSID, my team and I have done a lot of research on lymphomas in patients in the Middle East. My research in this area has delineated the special features of lymphomas in the Middle East that distinguish them from those seen in the West. In addition to the presence of IPSID in the Middle East, we were the first to show the high incidence of extranodal lymphomas there. Almost half of the lymphomas seen at the American University of Beirut Medical Center were extranodal, and among these extranodal forms, intestinal lymphomas were most common. We have also delineated the rarity of follicular lymphomas in Middle Eastern patients and found that in children the most common lymphoma was Burkitt’s.

New Agents and New Treatments

In my research on new agents and new treatments, I have made two major contributions:

Cisplatinum. In the early 1970s, when cisplatinum was discovered as an agent for the treatment of cancer, it was found to be extremely toxic when given in one single dose. While I was serving as visiting professor of cancer medicine and research at MD Anderson Cancer Center in 1976, I worked on the fractionation of the dose of cisplatinum. Instead of giving the whole dose over a period of 1 to 2 hours, I fractionated the dose to be given over five days. My research in this area eventually showed that fractionation of the dose of cisplatinum made it more efficacious and significantly less toxic. Cisplatinum is now used all over the world in a fractionated manner as a result of the work I did on this drug in the mid-1970s.

Intra-arterial hepatic infusional study. This research explored the value of administering a higher dose to cancer confined to the liver versus giving the drug intravenously, with a smaller dose reaching the liver tissues. This approach has shown success in several cancer categories, specifically in cancers that are limited to the liver, and it is currently used to treat primary and metastatic liver disease.

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