Research Studies
Research Studies on Colon and Rectal Conditions
The Laparoscopy and Oncology Laboratory
Director, Richard L. Whelan, MD
Introduction
The Laparoscopic Physiology and Oncology Laboratory was first opened in 1996 at Columbia University’s Health Science Campus in Washington Heights. In 2009 the lab was moved to St. Luke’s Roosevelt Hospital, until Sept. 2019 where it was relocated to our current location at Lenox Hill Hospital. Dr. Richard L. Whelan heads the laboratory. The lab is staffed by 2 fulltime PhD’s (Dr. Shantha Kumara and Peter Yan) as well as 2 full time residents or medical students (doing 1 – 2 year long research rotations). There is also a full time research nurse and a clinical data manager/statistician round out the research staff. There are often 1 or 2 post baccalaureate students working with our group as well.
The Laparoscopic Physiology and Oncology Laboratory of Dr. Richard Whelan (early years)
Background
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, we 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 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 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 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 patients 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 (Schwenk et al, Tjandra et al). Although this has not been proven yet, the lower rate of infection in the laparoscopic patients may be related to better preserved immune function.
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 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).
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.
Ongoing Research
The laboratory now based out of Northwell Health continues to investigate the effects of both open and laparoscopic surgical methods. We are trying to determine why open surgery causes suppression of the immune system and an increase in tumor growth. By discovering the mechanisms by which these changes occur we hope to be able to discover ways of preventing these changes from happening after an operation. The goal of this work is to make surgery less stressful to the body. By preserving or enhancing the body’s immune system the incidence of postoperative infection and other complications should decrease. By avoiding the period of increased tumor cell growth and implantation after a major operation it is hoped that cancer patients will develop fewer tumor recurrences and will live longer. The laboratory is also looking into new methods to further improve the results of laparoscopic and open surgery. Finally, the laboratory continues to study abdominal wound tumors and is developing methods to avoid them.
Laboratory Funding
The laboratory is headed by Dr. Richard L. Whelan. Each year 2 residents or medical students work full time in the lab. Three to six other residents, medical students, or graduate students work part time in the lab each year. 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 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 20 articles in peer reviewed journals over the last 5 years(see bibliography below). 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 5 textbook chapters regarding laparoscopic physiology, immunology, oncology, and laparoscopic surgery in general.
Patients Under 50 Years of Age Are at Risk for Colon Cancer and are More Likely to Have Advanced Disease When Diagnosed
Richard L. Whelan, MD, Chief, Colorectal surgery Northwell Health Cancer Institute
Patients Under 50 Years of Age Are at Risk for Colon Cancer and are More Likely to Have Advanced Disease When Diagnosed
Richard L. Whelan, MD
The Colorectal Surgery Service at CCCNY’s Roosevelt Hospital site, under the direction of Dr. Richard L. Whelan, completed a retrospective review of patients under 50 years of age who underwent surgery for colon or rectal cancer during an 15 year period at either St. Luke’s Roosevelt Hospital or a second institution. This study’s results suggest that the chances of a younger patient developing colorectal cancer is increasing and that advanced disease is more likely to be found when compared to patients over 50 with CRC. Further, in some cases there was a delay in diagnosis that may have been due, in part, to a reluctance of primary care physicians to refer patients for colonoscopy or other diagnostic tests.
A total of 174 young patients were treated during the time period examined. Between 2006 and 2011, patients under 50 accounted for 12 % of all colorectal cancer patients treated at the institutions in question. This percentage is notably higher than the previously published rates. Contrary to popular opinion, the vast majority of these patients (91%) did not have a parent, brother or sister who had had a CRC. Thus, most of these patients had no known risk factors for colorectal cancer. The symptom most frequently reported was rectal bleeding. Unfortunately, in some patients there was a delay of 6 months or longer before diagnostic tests were carried out.
It was also noted in this study that patients under 50 were more likely to be diagnosed with an advanced cancer than patients 50 or older. Over 50 % of younger CRC patients had Stage 3 or 4 tumors at the time of diagnosis as opposed to 35 % of patients 50 or older. Why should younger patients have worse disease when diagnosed? There are several possible explanations. One reason may be that the cancers that develop in younger patients tend to be more aggressive. Another explanation is that there is a delay in diagnosis in some cases which allows the cancer to grow and, perhaps, spread to lymph nodes or other sites.
Why should there be a delay in diagnosis in younger patients? There are numerous possible reasons including reluctance on the part of patients to seek medical assistance and lack of medical insurance coverage. Also, many patients and some physicians are under the impression that colonoscopy need not be performed until age 50. Importantly, one reason reported by some patients was that primary care physicians, upon learning of the rectal bleeding, did not immediately refer patients for colonoscopy or other tests that would lead to the diagnosis. Instead, patients were told that the bleeding was most likely from hemorrhoids or other anorectal problem and were treated accordingly. Only when the bleeding persisted or when other symptoms developed was a colonoscopy performed. Some patients were told by some physicians that colonoscopy did not need to be carried out until age 50. Where did the age 50 cut off for colon evaluation come from?
Current CRC screening guidelines from most authorities suggest that the first colonoscopy be done at age 45 in patients without a close family history (parents or siblings) of CRC. These guidelines are based on the fact that the great majority of CRC patients are 45 years or older. Most national health systems and insurance companies use these guidelines to determine eligibility for colon screening exams. For these reasons, as well as others, primary care physicians and patients are more likely to minimize or discount symptoms that in older patients would lead to an immediate colonoscopy. As alluded to above, another factor contributing to delay is that, historically, it has been more difficult to get approval from insurance companies for colonoscopy and other diagnostic tests in younger patients. This study’s results suggest that there should be a lower threshold for performing colonoscopy in patients under 45 with symptoms such as rectal bleeding, a change in bowel habits, abdominal or rectal pain.
Long Term Survival After Hybrid Laparoscopic / Open Resection Method for Rectal Cancer
Long Term Survival After Hybrid Laparoscopic / Open Resection Method for Rectal Cancer
Richard L. Whelan, MD
Although the use of minimally invasive surgical (MIS) methods for the resection of colon cancer has been well studied and accepted there is less data available regarding MIS rectal cancer resection methods. Rectal resections, the vast majority of which are done to remove a cancer, are more complex and demanding operations. Presently, several multicenter randomized trials comparing the traditional (large incision) and MIS methods are underway, however, the long term cancer survival and recurrence results are not yet available. Thus, it has not yet been proven that the long term outcome after MIS rectal resection is comparable to “open” (large incision) resection results. Critics worry that MIS rectal resections may be less thorough or radical than the “open” operation.
There are a number of different MIS rectal resection methods that have been introduced including laparoscopic, laparoscopic-assisted, hand-assisted laparoscopic, and “hybrid” laparoscopic / open methods. The goal of all of these methods is to minimize the size of the abdominal wall incision used to remove the cancer. Dr. Richard L. Whelan, the chief of colorectal surgery at CCCNY’s St. Luke’s Roosevelt Hospital. and other colorectal surgeons in New York City embraced the MIS “hybrid” laparoscopic / open method rectal resection method in the late 1990’s. Recently, the survival results of 131 patients who underwent these hybrid rectal cancer resections have been determined and the results reported in a paper submitted for publication.
The standard “open” rectal resection requires a vertical incision in the middle of the abdomen that is usually 8 to 12 inches in length. In contrast, the hybrid laparoscopic / open approach removes the rectal cancer using a combination of open and laparoscopic methods. The laparoscopic part of the operation is done first via four or five 1/4 to ¾ inch incisions after which the procedure is completed using “open” methods through a 3 to 4 inch long incision located below the belly button. A good deal of the mobilization (freeing up) of the rectum from the surrounding tissues, the removal of the rectal segment containing the tumor, and the reconnection of the remaining bowel ends is done through the open incision. In a previously published study about the hybrid rectal resection method, Dr. Whelan’s team noted that the final hybrid incision was, on average, a little more than 3 inches long as opposed to 6 ½ inches long after open rectal resection.1 The thoroughness of the cancer resection, in regards to the number of lymph nodes and the size of the specimen removed were similar for the 2 methods. Of note, the hybrid patients had their first BM and were discharged from the hospital significantly sooner than the open rectal resection patients.
As mentioned, the long term results of 131 hybrid rectal cancer resection patients have recently been determined. After an average follow-up of 5.2 years the mean overall survival (includes alive patients with and without recurrent cancer) was 76 percent. In addition, the disease free survival was 70 percent which is better than the 64 % figure reported by the National Cancer Institute’s “Surveillance Epidemiology End Report” (SEER) data base. Thus, these results suggest that the hybrid laparoscopic / open MIS rectal resection method is safe and associated with long term survival rates, at least, as good as those following the standard open approach.
Of note, Dr. Whelan, in addition to the hybrid method now also uses the laparoscopic-assisted and hand-assisted laparoscopic methods for rectal cancers. These latter methods are associated with incisions 2 to 4 inches in length. It is important to realize that although some surgeons remain skeptical about MIS rectal resection methods, many experienced surgeons believe they are the best surgical method. The intermediate cancer outcome results from a large randomized trial comparing laparoscopic-assisted and open rectal resection are due to be released soon.
Reference:
1. Vithianathan S, Cooper Z, Betten K, et al. Hybrid Laparoscopic Flexure Takedown and Open Procedure for Rectal Resection is Associated With Significantly Shorter Length of Stay than Equvilant Open Resection. Diseases of the Colon and Rectum 2001; 44(7): 927-35.
Anti-cancer Drugs during the Month before and After Colorectal Cancer Resection
Currently, in the United States no anti-cancer treatment is given during the month leading up to surgery. Provided it was safe, it would make sense for patients to take a drug that would limit tumor growth while they were waiting for surgery. Similarly, during the first 4 to 6 weeks after surgery no anti-cancer therapy is currently given. If individual cancer cells or undetectable cancer deposits remain in the body after surgery the best time to attack them is early after the primary cancer has been removed because at that time the fewest number of cancer cells remains in the body. One of the basic principles of oncology is “The fewer the cancer cells the more likely an anti-cancer treatment will be successful”. Another reason to give anti-cancer drugs during the first postoperative month is that this is a particularly dangerous time for patients with residual cancer deposits.