The Laparoscopic Physiology and Oncology Laboratory of St. Luke’s Roosevelt Hospital - Dr. Richard L. Whelan, Director
For the vast majority of our lives our bodies are able to defend us from the countless bacteria and viruses that we come in contact with on a daily basis. When we do get sick our immune systems are most always able to contain and limit the infection. In a similar way, some doctors believe that our healthy bodies are able to detect and destroy individual cells and small groups of cells that are malignant or on the pathway to becoming cancers, thus preventing malignant tumors from forming. In short, when healthy, our bodies do a tremendous job in protecting us from external threats (bacteria and viruses) as well as internal dangers (mutated human cells).
It has been well established that major surgery performed through a large incision in the abdomen suppresses the immune system for 6 to 9 days after an operation. This means that at a time when the body is at high risk for developing an infection or complication the immune system is weakened. What part of the operation suppresses the immune system? There are many factors that may contribute to this suppression including: 1) anesthesia, 2) the abdominal wall incision, 3) the bowel resection or procedure that is carried out inside the abdomen, and 4) the underlying health of the patient. It makes sense that if it were possible to maintain or better preserve the function of the immune system after an operation it would be in the patient’s best interests. Until recently, the role that the abdominal wall incision played in the development of postoperative immunosuppression was unknown. Furthermore, until the 1990’s, there was no alternative method available that could provide adequate access to the abdominal cavity such that a major operation could be performed.
Since the introduction of advanced laparoscopic methods in 1991 it is now possible to remove part or all of the colon without making a lengthy abdominal wall incision. Through 3 to 5 small incisions (most 3/8” in size) and a single 1 ½” to 3” incision (to remove the specimen and put the bowel back together) it is possible to carry out even complex colon and rectal resections (please see the minimally invasive surgery section of this website for details). The proven advantages of minimally invasive surgical approaches are: 1) less postoperative pain, 2) less pain medication requirements, 3) faster resumption of bowel function (and thus an earlier return to diet), 4) earlier discharge from the hospital, 5) an improved cosmetic result, and 6) better preserved immune and physiologic function. Also, most often patients are able to return to work and full activity more rapidly. Cancer patients who require chemotherapy can also start those treatments sooner because of the faster recovery.
Improved Immune Function
The Laparoscopic Physiology Laboratory headed by Dr. Whelan was founded in 1992 to explore the physiologic, immunologic, and oncologic effects of open(large incision) and laparoscopic(minimally invasive) surgery. Stated in a simpler way, the purpose of the lab was to determine how the methods used to gain access to the abdominal cavity alter the body’s ability to heal itself and to deal with infection and cancer in the days and weeks following surgery. This information will, hopefully, lead to a better understanding of how the body deals with the trauma associated with surgery and will also lead to new strategies and treatments that would limit these stresses.
Initial animal studies (mostly rats and mice) carried out at Dr. Whelan’s Laboratory revealed that laparoscopic bowel resections resulted in significantly less post-operative suppression of the immune system than after an equivalent open resection. In these studies the animals immune systems were evaluated by performing skin tests similar to the tuberculosis skin tests that we have all undergone at some point. When given a small injection of foreign material (antigen), to which the animals have previously been exposed to, the healthy immune system reacts by sending a variety of white blood cells into the area. This results in a swelling or induration at the injection site. The size of the swelling gives us an idea of how well the immune system is working (the bigger the swelling the better the response). The response to an antigen is determined before and after the operation and the results compared. Significantly larger areas of swelling were found after surgery in the laparoscopic groups than in the open (large incision) groups.
Other studies were also carried out by Dr. Whelan’s Laboratory that looked at the immune system in a different way. Specifically, the lymphocytes ability to proliferate was assessed after both types of surgery. These studies also showed that immune function was better preserved after a laparoscopic procedure than after an open(large incision) operation. Finally, in a human study carried out by Dr. Whelan while at Columbia Presbyterian, in conjunction with a Texas Hospital, it has been demonstrated that immune function was better preserved 3 days after surgery in patients who underwent a laparoscopic colon resection than in those who had a standard open colon resection. This study used the tuberculin like skin injection testing method described above to evaluate the patient's immune function. A second similar human study, also carried out by our research group, confirmed that immune function, as measured by the skin tests, is not significantly suppressed after a laparoscopic bowel resection.
The Whelan research lab has also investigated post-operative infection following both types of surgery. It has been shown that animals that have undergone a laparoscopic bowel resection are better able to limit and contain a postoperative infection than those that had the equivalent open operation. The improved immune function seen in the laparoscopic group, no doubt, is one of the reasons why this group can better limit infections.
In summary, in regards to both immune function and infection, significantly better results have been found in the laparoscopic groups than in the open groups of animals and patients. In our opinion, the prospect of preserving a patient’s immune function after major surgery is a more compelling reason to recommend a laparoscopic operation than the other reasons mentioned above. Of note, several investigators who recently analyzed most or all of the published studies which compared laparoscopic and open colorectal resection techniques have noted a significantly lower rate of wound infections after laparoscopic surgery.
Tumor Growth After Surgery
The laboratory, under Dr. Whelan’s direction, has also carried out many studies in mice that determined the impact of both types of abdominal surgery on the rate of tumor growth in the postoperative period. It has been demonstrated that tumors grow at a significantly faster rate in mice for the first 7-10 days after an open (large incision) operation than after a minimally invasive procedure. Similarly, we demonstrated that there is a much greater chance that new tumors will form in the open surgery animals than in those subjected to a laparoscopic procedure. Furthermore, the rate of tumor cell death (a desirable event) has been shown to be higher after laparoscopy than after an open operation. It has also been shown that the immune function differences mentioned above contribute to the different behavior of tumors after these two types of surgery.
The laboratory has also carried out numerous human studies on patients with colorectal cancer as well as those with benign problems. In one human study it was demonstrated that major open surgery was associated with blood protein changes the first day after surgery that altered the blood plasma such that it stimulated the growth of tumor cells in a test tube culture when compared to the tumor cell growth noted in an identical culture into which a sample of the same patients preoperative blood plasma was added. These results suggest that if there were any tumor cells left in the blood stream after cancer resection (a situation which is known to occur in some patients) that they would grow at a faster than normal rate in patients who had open (big incision) operations. Importantly, blood plasma samples taken from patients who underwent an equivalent laparoscopic operation did not stimulate test tube tumor growth. These results suggest that early after cancer resection open surgery patients are at a disadvantage and are at somewhat higher risk than patients who have laparoscopic cancer resection. The protein thought to be responsible for these effects in the open surgery patients is called insulin-like growth factor binding protein 3 (IGF-BP3).
It is important to note that the latest human study results from randomized multi-center trials (the best kind of study) have demonstrated that the 5 year survival and tumor recurrence rates after laparoscopic and open colon resection are similar. Thus, despite the small animal and human evidence that the laparoscopic approach is less supportive of tumor growth, the long term results of the two different methods are similar. It may be that the benefits are real but that the studies performed thus far are not large enough to detect the difference in results between the two methods.
More recently, studies from the Whelan research group have noted important late blood protein changes that occur during the 2nd through 4th postoperative weeks that, collectively, stimulate the development of new blood vessels which is of critical importance to tumor growth. It is thought that these changes are the result of the body’s efforts to heal the surgical wounds. Thus, if there were any small tumor deposits unknowingly left behind after cancer resection (a situation that exists in between 30 and 40 percent of colon cancer patients) they are likely encouraged to develop new blood vessels and to grow during the first month after surgery. It is important to note that these late surgery-related blood compositional changes appear to be similar in open and laparoscopic colorectal resection patients. Thus, in regards to the late blood changes, laparoscopic and open (big incision) operations appear to be similar. These latest findings have made it clear that researchers need to find safe and effective anti-cancer drugs that can be taken during the month prior to and the month immediately following cancer surgery. In this way the negative, cancer growth promoting, effects of surgery can be counteracted and overcome. Please see the section on perioperative anti-cancer therapy on this website for further information.
Abdominal Wound Tumor Recurrences (Port Tumors)
After either open or laparoscopic surgery for cancer a small percentage of patients may develop tumor recurrences in one of the abdominal wounds. This has been documented in two large studies of open colon cancer patients, one of which was from the Mayo Clinic. These studies found that up to 1.0 percent of patients developed an abdominal wound tumor after a “curative” open colon resection. In the first decade after the introduction of laparoscopic-assisted colon resection methods there were great fears that laparoscopic methods would result in a much higher rate of tumors in the laparoscopic wounds, also known as port sites. This fear was based on early publications that collectively reported that 40 of these tumors had been noted. These concerns led to the organization of a number of randomized multi-institutional studies that compared laparoscopic and open colon resection methods; in addition, a large number of rodent studies were also done in an attempt to better understand why and how these tumors formed. The Whelan laboratory published at least 5 articles on this topic during the 90’s. The conclusion of our lab’s studies was that wound tumor formation is most likely related to traumatization of he tumor (cuts or cracks in the surface) and not to the surgical method used to remove it. The Whelan lab also demonstrated in a mouse study that irrigation of the abdomen after bowel resection with a dilute iodine solution decreased significantly the number of abdominal wound tumors.
The results of the human randomized studies are summarized in the introduction of the Minimally Invasive Surgery section of this website. The final results, in regards to port site tumors, was that there was no difference in the percentage of patients that developed an abdominal wound tumor (either in big wound or port wound) in the laparoscopic and open (big incision) groups. Regardless of surgical method, about 1 % of patients or less developed such tumor recurrences. Thus, the latest human results suggest that there is a similar chance of such tumors forming after either type of surgery and that there is nothing inherently more dangerous about laparoscopic surgery provided the surgeon is experienced and uses good cancer surgery technique.
The laboratory at St. Luke’s Roosevelt Hospital continues to investigate the effects of both open and laparoscopic surgical methods. We are focusing on trying to identify the proteins that are involved in new blood vessel formation after surgery. An understanding of this process which stimulates not only wound healing but the growth of residual tumor, may lead to new anti-cancer treatment strategies.
The laboratory’s main mission presently, though is to identify and to test new anti-cancer drugs that can safely be taken during the month immediately before and the month just after colorectal resection. These two months are not presently utilized for any type of anti-cancer treatment. The above mentioned studies from the St. Luke’s lab and other researchers strongly suggest that the month after major surgery is a very dangerous one for cancer patients regardless of which surgical method is used. The laboratory has completed one human study wherein 59 patients were randomized to receive an immune stimulating drug called GMCSF or a placebo (saline alone). This drug in animals has been shown to decrease the growth and formation of tumors after surgery in mice. The patients were given 3 daily injections during the week before surgery and then daily injections for the first 4 postoperative days. The patients tolerated the drug well and there was some indication that the group receiving the GMCSF had a lower tumor recurrence rate than the placebo group. These results need to be corroborated with a larger study before any firm conclusions can be reached.
Currently, Dr. Whelan is carrying out a Phase 1 study wherein patients are receiving the anti-cancer drug Cetuximab (also known as erbitux) once a week for 3 weeks prior to surgery and for 3 weeks after the operation. The hope is that this drug will help decrease the recurrence rate and improve survival after cancer surgery.
The St. Luke’s lab is also looking for new safe anti-cancer agents that can be used safely just before and after surgery. The drugs silibinin, pinocembrin, Poly E (a green tea extract), and CPG are currently under evaluation in small animal studies. It is our hope to do human studies to assess the most promising of these drugs.
When a new drug is identified studies are done to verify that the drug indeed does kill cancer cells and limits the growth of tumors. Next the impact of the drug on wound healing is determined in additional small animal studies. Only drugs that effectively kill tumor cells while not impairing or weakening the healing wounds are considered for use during the month before and after surgery. Phase 1 human studies are the first studies to be done. If the drug is proven safe then a Phase 2 drug study is then designed. Finally, if the results are encouraging, a Phase 3 randomized trial is carried out.
The laboratory is headed by Dr. Richard L. Whelan. Two full time PhD’s staff the lab along with 2 residents who rotate through the lab each year. A full time Study RN and Study coordinator (the same person) and a statistician round out the research team. There are usually 1 or 2 medical students or post baccalaureate students also working in the lab. The laboratory is funded by via three different sources: 1) peer reviewed grants from surgical and oncological organizations and societies, 2) support from surgical manufacturer’s and pharmaceutical companies, and 3) contributions from grateful patients and friends of the lab. Without the generous private donations that the laboratory has been fortunate enough to receive in the past it would not have been possible to carry out many of the important research studies discussed above. Only through the future generosity of friends and supporters will we be able to continue performing quality research studies.
This St. Luke’s Roosevelt research laboratory is recognized as one of the leading laparoscopic physiology laboratories in the world. To date, the laboratory has published over 100 articles in peer reviewed journals. Last year, the results of eight original studies were presented at 4 different national and international surgical meetings and accepted for publication in a variety of journals. In addition, the lab has written over 15 textbook chapters regarding laparoscopic physiology, immunology, oncology, and laparoscopic surgery in general.
To make a tax deductible donation or to obtain further information regarding St. Luke’s Roosevelt’s Laparoscopic Physiology and Oncology Laboratory call (212) 523 8172.