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Perioperative Cancer Treatment Results

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.


After surgery, the body’s physiology shifts to a wound healing mode for about 1 month. One important component of wound healing is new blood vessel formation. It has been proven that the composition of the blood for the first 2 to 4 weeks after surgery is changed such that it encourages new blood vessel development. These conditions, in addition to helping wounds to heal, may also encourage blood vessel development and growth in unknown tumor deposits that remain after surgery.1 Also, tumor cells that remain in the circulation after surgery may find it easier to form a metastases and grow in the post-surgical environment. In addition to the human evidence, there are a good number of published small animal studies that have reported increased tumor formation and growth after a full length abdominal incision when compared to results after just anesthesia alone.2,3 Thus, there is evidence that tumor growth may be accelerated and encouraged immediately following surgery.


Why don’t Doctors start anti-cancer therapy during the month before and immediately following surgery? The reason is that most standard chemotherapy drugs might inhibit wound healing after surgery and, thus, would probably increase the chances of complications. What are needed for this time period are drugs that inhibit tumor growth but do not impair wound healing.


During the last decade Dr. Whelan’s research laboratory has been looking for and testing drugs with anti-cancer effects that could be safely taken before and soon after surgery. Other researchers around the world have done small clinical studies in which drugs that inhibit tumor growth have been given to cancer patients during the “perioperative” period. A number of drugs have been shown to be safe to take just before and after surgery. There is also weak evidence that several drugs may, indeed, improve the survival rate of cancer patients.


What is needed to definitively prove that a candidate drug improves survival is a large study, usually involving over a thousand patients. Unfortunately, in regards to colorectal cancer, there have been no large randomized studies done yet to test anti-cancer drugs given during the month before or the first month after surgery. Therefore, for now, we have only encouraging preliminary results for a number of drugs that suggest these drugs are beneficial. Importantly, there is safety data for a number of these drugs.


Who should get Early Postoperative Anti-Cancer Treatment?


Currently, standard chemotherapy is uniformly recommended for patients found to have cancer cells in the lymph nodes of the colon segment removed at surgery (Stage 3 disease). This group of patients is at high risk for developing a recurrence. Chemotherapy is also advised for patients who, unfortunately, have tumor metastases in the liver, lungs, or other location (Stage 4 disease).


The reason that routine postoperative chemotherapy is not recommended for patients without lymph node involvement or metastasis is that it has not been proven that chemotherapy in this group is beneficial. This doesn’t necessarily mean that some Stage 1 and Stage 2 patients would not be helped by the chemotherapy. It is harder to demonstrate a decreased rate of tumor recurrence in this group because the anticipated numbers of cancer recurrences are fewer than in Stage 3 patients. In fact, some oncologists will give chemotherapy to consenting higher risk Stage 2 patients. Very large studies involving several thousands of patients would need to be done to prove that there was a “significant” benefit from chemotherapy for Stage 2 patients. Within 7 to 10 days of the cancer resection operation the pathology results will be available and the final tumor stage will be known. As mentioned, this information will decide whether standard chemotherapy, started 4-6 weeks after surgery, will be recommended. Certainly, it makes sense to give Stage 3 patients early postoperative anti-cancer agents, shown to be safe to take early after surgery, during the month after surgery in anticipation of standard chemotherapy. In Dr. Whelan’s opinion, it also makes sense to give early postoperative anti-cancer therapy to all colorectal cancer patients provided it is safe and the chances for complications or side effects of this treatment are small. Although the benefits are difficult to prove one or more of these agents may decrease the chances of recurrence. Each patient will need to make their own decision as to whether they want to take any of the drugs or supplements discussed below.


Disclaimer


Below, the existing evidence regarding a number of medicines and supplements will be provided. None of these drugs or agents are considered “routine” anti-cancer treatments. Although, for many, there is some evidence that the drug in question may be effective against cancer, for none of these drugs is there conclusive evidence. Also, it is important to realize that every drug or supplement may have side effects and that a small number of people may develop a complication related to taking the drug. The full “citation” for each report or article (the author’s names, the Journal name, the dates of publication and the specific issue and page numbers of the article) are provided at the end of this section so that interested patients or their doctors can look at the actual articles. The decision to take one or more of these drugs is one that is made by each patient and their doctor(s). It is important to realize that not all patients who take the drugs discussed below will be helped by these drugs. For all anti-cancer drugs, only a proportion of patients respond to the drugs as demonstrated by a longer cancer free survival or lower recurrence rate. Also, because none of the drugs discussed has been definitively proven to be beneficial, it is possible that the drug or agent in question will not help any of the patients who take it.


What follows is a list of drugs that have either been used in human trials or are being considered for such studies based on preliminary investigations.


Cimetidine (Tagamet)


Some promising clinical studies have been done using the drug cimetidine (Tagamet) that is an anti-ulcer medicine now available over the counter without prescription. This drug is well tolerated with an impressive safety profile and low rates of serious side effects (see final paragraph in this section).4,5 Small studies done on colon cancer patients who took cimetidine before and/or after surgery suggest this drug may be beneficial (see below). There are several mechanisms of action that have been proposed to account for cimetidine’s anti-cancer effects. One popular theory is that cimetidine acts by inhibiting a sub-population of white blood cells (suppressor T lymphocytes) that suppress the body’s immune response against tumors.6 Another theory is that cimetidine prevents cancer cells in the bloodstream from attaching to the cells that line the blood vessels.7 This is important since in order to start a metastasis, tumor cells in the blood need to attach themselves to and then penetrate the vessel wall in order to get into the surrounding tissue. Yet another anti-cancer mechanism that has been suggested is that cimetidine inhibits the growth of blood vessels in the tumor.8,9 Colon cancers cannot grow without new vessel development (called angiogenesis). Another theory is that cimetidine prevents histamine (a protein) from stimulating tumor growth by blocking the Histamine-2 receptor.


What is the human evidence? Several small randomized human studies have been carried out and the results suggest that cimetidine may be helpful if taken before and/or soon after surgery. Randomized trials are the best kind of study because patients with the same disease are randomly assigned to either get or not get the treatment in question after which their outcomes are compared. In the first study patients were given cimetidine (1600 mg/day) for 5 days before the surgery (Kelly et al).10 Although not conclusive, as per the authors, there was a slight trend toward better survival in the patients who took the cimetidine.


In a small Japanese study, 64 colon and rectal cancer patients were given an oral chemotherapy drug, 5-fluorouracil (5-FU), daily, for about 1 year after their cancer resection.11 In addition, half of the group received cimetidine (800 mg/day) on a daily basis for the same time period. At the time of publication the average follow up time, from surgery, was 31 months (60 months is the usual follow up period). The survival rate for the colon cancer patients at that point was 96.3 % for the cimetidine group (number of patients = 27) and 68 % for the group that got the 5-FU alone (number of patients = 19). In regards to the rectal cancer patients, the survival rate was 100 % for the cimetidine patients and 53.3 % for the 5-FU only group. Although these differences seem large, the results of the two groups were not statistically significant. These results suggested, but did not prove, that the addition of cimetidine to the 5-FU improved the results.


In a Danish study published in 1995 a total of 145 patients who had undergone “curative” colorectal resection (meaning patients with known metastatic disease were excluded) were randomized to get daily cimetidine (800 mg/day) or a placebo, by mouth, for 2 years.12 No difference in the survival rate (cancer specific mortality) was found when the results of all the patients in the 2 groups were considered. However, when the results of the Stage 3 patients were considered alone, there was a trend toward better survival in the cimetidine group. No differences in survival were noted for the Stage 1 and 2 patients.


In an Australian study, half of a group of 35 patients with metastatic colorectal cancer who received chemotherapy were also administered daily cimetidine (800 mg/day).13 Although no differences in the survival rates after treatment were found between the groups, significantly more patients in the cimetidine group had a notable drop their CEA blood levels (CEA, Carcinoembryonic Antigen, is a marker for colorectal cancer).


In a second study by the same researchers, 50 colorectal cancer patients were randomized to either get cimetidine or nothing.14 The cimetidine patients were given the drug for 5 days before and for 2 days after surgery (800 mg/day). The goal of this study was to determine if cimetidine preserved the patient’s immune function after colorectal resection which is known to temporarily suppress immune function. The numbers of the different types of immune system cells in blood samples were counted and the ability of blood lymphocytes to proliferate (multiply) in a test tube, after being removed from the body, was determined. The post-surgery lymphocytes from the cimetidine patients grew normally whereas those from the surgery alone grew at a rate 60 % less than they had before surgery. Also, whereas the number of B-lymphocytes (immune system cells which make antibodies) decreased in the surgery alone group, in the cimetidine group the number of B cells remained the same as before surgery. The results of this study suggest that cimetidine preserves immune function after surgery which is desirable.


Is it safe to take cimetidine? Because this drug has been on the market for over 30 years there is quite a bit of safety data available in the medical literature. The drug is well tolerated and has an excellent safety profile.4,5 To quote a published article regarding the safety profile of cimetidine, “The safety profile of low-dose maintenance therapy with H2-antagonists for duodenal ulcer disease suggests that these agents can be given safely for several years and probably much longer.”5 Of note, there is no evidence that cimetidine impairs or inhibits wound healing. It is important to realize that all drugs can cause side effects or may be poorly tolerated. Most drugs can also trigger, in a very small number of patients, a severe allergic reaction called anaphylaxis (difficulty breathing, tightness in the chest, swelling of the mouth) which can be life threatening. The severe side effects that have been reported in a very small number of patients taking cimetidine include: agitation; anxiety; breast enlargement; breast lumps; confusion; depression; disorientation; fatigue; hallucinations; hair loss; joint or muscle pain; pain; skin flushing or redness; sexual difficulties; and slow or fast heartbeat. For more information regarding cimetidine you can consult your pharmacist, physician, or do a computer search.


G.M.C.S.F.


Dr. Whelan’s research group did a small randomized study involving 59 patients wherein the prescription drug G.M.C.S.F. (an immune system modulator) was given to colorectal cancer patients for 3 days before and 4 days after minimally invasive cancer resection. In small animal studies done by a number of investigators G.M.C.S.F. and similar drugs had been shown to inhibit tumor growth. In the human study, G.M.C.S.F. was well tolerated and did not increase the rate of complications. Surprisingly, the drug did not improve immune function, as measured, immediately following the colorectal resections when compared to the group of patients that got a placebo. However, analyses of blood samples from before and after the drug was given suggested that in patients who received the drug, the blood was significantly less supportive of cancer growth and of new blood vessel formation (important to tumor growth). This anti-angiogenic effect, in theory, should inhibit tumor development. The results of this study were published in 2007 and 2008.15,16 Presently, despite the encouraging results, there is no open study wherein GMCSF is being given just before and after surgery to cancer patients.


EGCG and Siliphos Phase 1 Human Study


Alternative and complementary medicines have gained attention in recent years. Within this area of study, the use of molecules and compounds derived from plants has proven beneficial for many disease processes. Green tea extract and Silibinin (from the milk thistle plant) have both been shown in experimental studies to have anti-cancer effects as well as limited side effects and toxicity. A major component of green tea is Epigallocatechin-3-gallate (EGCG) which has been shown to prevent and limit tumor growth in small animal studies.17-19 Silymarin, which is extracted from the seeds of the milk thistle plant, is used clinically in Europe to protect the liver. Its major active component, Silibinin, is well tolerated and largely free of adverse effects.20,21 In recent mouse studies, Silibinin has been shown to inhibit the growth of lung, bladder, liver, prostate, and colon cancer.22,23 Silibinin and EGCG have similar anti-cancer mechanisms including: 1) interruption of the cell growth cycle, 2) encouragement of self induced tumor cell death, and 3) suppression of new blood vessel growth.24,25


Last year Dr. Whelan’s lab completed a series of studies in mice that demonstrated that a combination of green tea extract and siliphos (main component is Silibinin), when given for a week before and for 3 weeks after surgery, significantly inhibits the growth of cancer during the month following surgery. It was also determined that this drug combination did not impair or inhibit wound healing (abdominal wall and gastric wound strength was assessed). Thus, this drug combination appears safe for perioperative use. The results of the final study were presented at a national surgical meeting last year and should be published soon.


A Phase 1 human study has just been opened at St. Luke’s Roosevelt Hospital. Consenting patients who are to undergo large bowel resection for cancer will have the opportunity to take these two drugs for the week prior and for 3 weeks after their operation. FDA approval for this study has been obtained. The human investigations research committee (Institutional Review Board) of St. Luke’s Roosevelt Hospital has also approved this study. The goal is to enroll 30-40 patients. More information about the green tea extract and siliphos follows.


Green Tea Extract:


Green tea has long been celebrated for its health benefits but more recently numerous investigators have discovered that a concentrated form of the most active components of green tea have important anti-cancer effects and have been shown to inhibit tumor growth in animal studies. The green tea extract that will be used in this study is decaffeinated. In regards to side effects related to taking green tea extract, in a previous study of leukemia patients, between 3 and 39 % of patients (taking a dosage similar to that being used in the current study) reported the following side effects; nausea, diarrhea, abdominal pain, anorexia (loss of appetite), indigestion, flatulence (gas), and fatigue. In most cases the symptoms were self-limited and in none of the patients were the symptoms severe enough that the patients stopped taking the green tea pills or dropped out of the study.


In the study to be carried out at St. Luke’s Roosevelt Hospital, commencing 1 week before the surgery date, patients will take 3 green tea extract capsules (250 mg EGCG/capsule) twice daily with food (total EGCG dose per day is 1,500 mg). Drug administration, at the same dose will be resumed when the patient is started on clear liquids after surgery (usually postoperative day 1 or 2) and will be continued until postoperative day 30.


Siliphos:


In regards to the Siliphos pills, at the dose being used for this study no toxicities have been reported in prior human studies. Siliphos contains a concentrated extract of the silybum marianum (milk thistle) plant and is commercially available in 300 mg capsules. The active agent, Silibinin, accounts for 29-36 percent of each capsule (89-109mg per 300 mg capsule). Patients in the study will be instructed to take 3 capsules three times per day (total Silibinin dose of 0.8-0.98 gm daily). Similar to the green tea extract, the Siliphos will be taken for 1 week prior to surgery and, after oral liquids are resumed following surgery, daily until postoperative day 30.


Risks of Entering this Study:


Based on the available information regarding patients who have taken green tea extract and Siliphos the investigators believe that taking these drugs before and after surgery will not increase the rate of complications. However, the reader should note that, because these 2 medications have never been given to patients before large bowel surgery, no one knows for sure if they will have any negative effects. This study will provide that information.


Wound healing is the main area of concern when giving medications before and after surgery. Wound healing complications that can arise after intestinal surgery include; leakage from the rejoining point of the colon or rectum, an abscess in the abdomen, an abdominal wall wound infection, sudden separation of the abdominal wound (called a dehiscence), and hernia formation in the abdominal wall incision. Although infrequent, these complications do occur in a small percentage of patients. As already stated, there is no evidence that either Green Tea extract or Siliphos has any affect on the healing of wounds. The mouse wound healing study, mentioned above; found no difference in healing in mice that were given both these drugs when compared to a group of mice that got no drugs.


To get more Information about this Study:

Patients interested in entering this study should contact Dr. Whelan’s office (212 523 8172).


Chemoprevention


The basic concept behind chemoprevention is that by taking supplements or drugs daily or almost daily for a long period of time it is possible to decrease the chances of a cancer developing. Over the past several decades there has been quite a bit of research carried out in this area. Chemoprevention drugs and supplements tend to have subtle anti-cancer effects that may, over time, make it more difficult for a cancer to develop. Because these drugs have weak effects they can be taken daily for long periods of time. Stronger agents, such as standard chemotherapy, cannot be safely taken indefinitely because they inhibit cell growth in general and can result in dangerously low white blood cell counts and may inhibit normal function in other organs.


For some chemopreventive agents there is evidence that, if taken regularly, they may decrease the chances of cancer recurrence and may improve survival in cancer patients who have undergone resection or treatment. Chemoprevention drugs, in this setting, are not meant to replace standard chemotherapy in cancer patients. Instead, they would be taken after the standard chemotherapy has been finished for a long period of time and would, hopefully, further decrease the chances of a recurrence developing. Would these chemoprevention drugs also inhibit tumor growth if they were taken during the weeks before and immediately after surgical resection of colorectal cancer?


If beneficial when taken after standard cancer treatment, it is possible that these chemoprevention drugs might be useful if taken during the month before and after cancer surgery. Admittedly, because the period of time that the patient is being exposed to these drugs/supplements is shorter, it is less likely that they will have an effect. However, since most of the chemopreventive drugs are well tolerated and have few side effects, the downside of taking these agents before and after surgery should be small. It must be noted that there has been no research done regarding the use of these agents in the time period just before or after surgery. Therefore, there is no data showing that taking these agents in this way is helpful. Patients who are interested in taking one or more of these chemopreventive agents while they wait for their surgery or soon after cancer resection should discuss the idea with their surgeon and physicians and obtain their approval before starting these drugs. What follows is a brief list of some chemopreventive drugs/agents for which there is evidence that they decrease the chances of colorectal cancer formation. It is left to the reader, along with his/her physician team, to decide if they want to take one or more of these chemopreventive drugs prior to or after surgery. Similarly, after completing traditional chemotherapy patients have the option of taking one of these drugs.


Aspirin


Aspirin inhibits or blocks the manufacture and release of proteins and chemicals that cause pain and inflammation. It also prevents platelets from clumping and sticking together. It also has a fever reducing effect. In addition, scientists have also determined that aspirin inhibits cancer growth and development via several different physiologic mechanisms or pathways. The specific effects that may inhibit cancer formation or growth are: 1) inhibition of the COX enzymes, 2) promotion of cancer cell death (apoptosis), and 3) inhibition of new blood vessel formation (anti-angiogenic effect).39


There is reasonable human evidence that taking aspirin (any dose higher than 75mg/day) for 5 years or longer is associated with significantly lower risk of death from gastrointestinal cancers, including colon cancer.26-28 There is also evidence that regular aspirin use is associated with a lower incidence of colorectal adenomas.29 In some studies the effect was greater in the proximal colon than in the distal colon/rectum. Also, although the data is not as strong, there is evidence that chronic aspirin use decreases both the rate of colorectal cancer recurrence and mortality in patients who have had a colorectal cancer.30,40 In another study regarding breast cancer patients, regular aspirin use has been associated with decreased cancer recurrence and death rates.41


To summarize, there is evidence that aspirin is an effective “chemoprevention” drug. Prolonged and sustained aspirin use decreases the chances that a precancerous polyp or colorectal cancer will develop and that, after colorectal cancer resection, patients that take aspirin have a lower rate of cancer recurrence and a higher chance of survival. As soon as it is judged to be safe after the cancer removal operation (hopefully, by the end of the first postoperative week, at least), it makes sense for patients to begin taking an aspirin every day (provided the treating doctors give their approval to this idea). In theory, this should provide some protection early after surgery. Having said this, it must be admitted that, thus far, there is no evidence that early postoperative aspirin treatment is beneficial (as opposed to starting the aspirin 1 or 2 months after surgery). Could aspirin be given during the waiting period before surgery?


It is logical to assume that cancer patients who have to wait more than 2 weeks for surgery might benefit from taking aspirin prior to their resection. However, it must be understood that there is also no evidence, thus far, that taking aspirin for a few weeks or months inhibits tumor growth or spread. In addition, because aspirin inhibits platelet function and impairs blood clotting, aspirin intake must be stopped 7 to 10 days before surgery since it takes about a week for the anti-platelet effect to wear off. Preoperative aspirin therapy makes the most sense for patients with rectal cancer who get preoperative radiation (RT) and chemotherapy (chemo). The usual length of the RT/Chemo treatment is 5 weeks after which most surgeons wait 6 to 10 weeks before scheduling the cancer resection. There is a greater chance that preoperative aspirin treatment would have an anti-cancer effect if it is given for 1 ½ to 2 months rather than for just a week or two.


Although commonly taken for a wide range of problems, aspirin can have serious side effects. The most common side effects of aspirin involve the stomach. Some patients develop abdominal pain, indigestion, nausea, vomiting, or black tarry stools. These symptoms are usually caused by inflammation of the stomach lining, called gastritis, or by an ulcer in the stomach. Occasionally, the inflamed stomach may bleed a bit which usually results in tarry, jet black, stools.30 The medical literature suggests that the risk of serious complications from aspirin range from 0.02 to 2 % per year.42 The risk of bleeding in the upper G.I. tract is increased in older patients, in males, in those with a history of ulcers and in patients who are also taking other NSAID’s (tylenol, advil, alleve, etc), COX-2 inhibitors (celebrex, viox, etc), steroids, other antithrombotic drugs, or anticoagulation agents (coumadin, warfarin, lovenox, etc). Patients with risk factors should speak with their primary medical doctor or gastroenterologist before taking aspirin on a regular basis. The same is true for patients who are taking traditional chemotherapy. Some patients at high risk for GI complications may be advised to take anti-ulcer drugs (for example: nexium, protonix, prevacid, zantac, pepcid, cimetidine, etc) in addition to the aspirin to reduce the gastrointestinal risk.


It must be remembered that if aspirin is taken before surgery it must be stopped 7 to 10 days before the operation so that the blood will clot normally during the bowel resection. In regards to restarting aspirin after surgery, patients must consult their surgeon and find out when they can begin. Most surgeons are comfortable restarting aspirin within a week of the operation.


Calcium


There is reasonable evidence that taking calcium supplements reduces the risk of benign precancerous polyp (adenoma) formation in patients who have had adenomas in the past (18 % reduction). However, there is no strong evidence, thus far, that calcium supplements reduce the chances of developing a colon cancer. Also, there is no evidence that calcium supplementation lowers the chances of adenoma formation in patients without a past history polyps.32,33


The World Cancer Research Fund/ American Institute for Cancer Research’s Continuous Update Project (CUP) Expert Panel, in a report released last Spring, concluded that that calcium supplementation probably reduces colorectal cancer risk but noted that conclusive evidence is still not available.


Since the downside of taking calcium supplements or of drinking milk are few and since there is evidence that calcium might be protective, in the author’s opinion, it is reasonable for patients to take calcium soon after and/or before surgery. Each patient, after consultation with their doctors will need to make the decision as to whether to take calcium after or before surgery.


Of note, calcium can cause constipation in some patients. Because of this effect, calcium supplementation is not advised preoperatively for patients with partly obstructing tumors. Also, in general, patients should consider taking stool softeners and/or fiber when taking calcium supplements in order to avoid problems with constipation and difficult BM’s. Other side effects of taking calcium supplements include: dizziness, flushing (sensation of warmth or heat), irregular heartbeat, nausea or vomiting, sweating, or tingling sensation. Very rarely patients taking calcium supplements may develop difficult urination or drowsiness. If any of these symptoms are noted patients should stop the supplement and contact their doctor.


Folate Supplementation


Unhealthy diet may contribute to about one third of cancer deaths. Folates, found in green leafy vegetables, may protect against cancer development by stabilizing DNA (the building blocks of genes).34 Some experts believe that folate deficiency may contribute to the development of cancer of the colon, rectum, pancreas, lung, cervix, ovary, and brain. There is evidence that people whose diets are rich in folate have a lower risk of developing colon cancer.35,36 In some studies, folate supplements were not found to be effective in this regard. In regards to colon polyp formation there is conflicting evidence. Some studies have found that folate supplementation decreased the incidence of polyp formation in patients who had a history of colon adenomas while others found that, if taken for more than 3 years, more polyps may develop.37,38 When all the data is taken into consideration, most experts agree that folate is protective against colon cancer development. Therefore, eating a diet that is rich in green leafy vegetables is probably beneficial. In addition, it appears to be more effective to get folate into the body by eating green leafy vegetables rather than taking supplements.


Certainly, before surgery, provided the cancer is not obstructing the colon, there is no reason why patients cannot increase their intake of green leafy vegetables. After surgery, patients should ask their surgeons when they can resume eating vegetables and other fiber containing foods. For most patients green leafy vegetables can be safely restarted within 1-2 weeks. One reason not to restart greens immediately is that most patients initially have loose stools after colon surgery. Adding fiber rich vegetables to the diet early after surgery may lengthen the period of loose or semi-formed stools. Also, adding ruffage and leafy vegetables may increase the number of BM’s per day at a time when patients are trying to decrease their BM frequency.


References


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What Our Patient’s Say…


Our family wishes to express our heartfelt appreciation for the kindness, excellent care and wisdom our mother, Jean Broussard, received during her hospitalization.

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