Cervical Cancer part 2

There was indeed a significant advantage to the chemotherapy and radiation therapy arm in that progression free survival was significantly longer and overall survival 88% versus 77% were significantly better in the patient’s treated with concurrent radiation and chemotherapy.

I want to go on and talk a little bit about a difficult treatment category where the exact treatment remains to be determined. This graph shows you how with increasing tumor size, whether or not lymph nodes are present that are positive, like in the upper curve or negative, one can see that the recurrence rate constantly goes up either with positive pelvic lymph nodes, negative pelvic lymph nodes and function of the size of the tumor. This is in patient’s who had radical hysterectomy and pelvic lymphadenectomy for treatment. The same is true for patient’s with stage IB carcinoma of the cervix who have been treated with radiation therapy. Here, you can see the pelvic failure rate, the distant failure rate, the disease free survival and the overall survival and function of tumor size, and with increasing tumor size, you will see an increase in pelvic failure rates and increase in the distant failure rate, the decrease and disease free survival as well as the overall survival. So, tumor size adversely affects prognosis and outcome.

If you keep in mind what a typical dose distribution is of an intracavitary implant that is used for the treatment of carcinoma of the cervix, it has this pear shaped distribution, the white here represents the tumor, this would be a barrel-shaped lesion of the cervix, a bulky lesion of the cervix, you can see here that a substantial amount of the tumor will actually be outside this radiation field which may contribute to local failure. Not surprisingly a variety of treatment approaches have been suggested for this suboptimal treatment situation of bulky or barrel-shaped tumors of the cervix, surgery, radiation therapy, radiation followed by an extra fascial or simple hysterectomy, radical hysterectomy and radiation therapy, adjuvant chemotherapy then followed by surgery or chemotherapy followed by radiation, radiation and chemotherapy at the same time, hypofractionation, that means the different varieties of radiation therapy. None of those have really consistently been shown to be breakthroughs or advantages in treatment, and again, the gynecologic oncology group reported recently on their experience and their treatment of patient’s with bulky, defined as more than 4 cm carcinoma of the cervix. Again, 368 patient’s were entered in a study and they were randomized as follows: Regimen one was radiation therapy to the pelvis and brachy therapy in the conventional way, and at the same time, cisplatin 40 mg per meter square weekly for six courses. The patient’s then went on to have an extra fascial hysterectomy which was at the time of the inception of this study still believed to be a potentially helpful maneuver. Regimen two, radiation therapy to the pelvis, brachy therapy and extra fascial hysterectomy.

This study shows a clear survival advantage. This is overall survival in the patient’s in the upper curve here, who got radiation therapy with concomitant chemotherapy at the same time, this is approximately a 30 to 45% improvement in survival here as opposed to patient’s who got radiation therapy with extra fascial hysterectomy, no concurrent chemotherapy. In the more advanced stages of cervical carcinoma, the treatment of choice is clearly radiation therapy and radiation therapy when we talk about it as a reminder, consists of internal beam radiation therapy and brachy therapy.

Cervical Cancer

Let’s move on to the larger carcinomas of the cervix, stage IB and stage IIA. Here we have basically two treatment options; the treatment of choice in cervical cancer as a disease as a whole as you know, is radiation therapy. In these particular stages, there may be a choice in selective cases between radical hysterectomy and bilateral pelvic lymphadenectomy, this can be done vaginally or abdominally, and radiation therapy with external radiation of the whole pelvis and brachy therapy. The bottom line is simple, they are comparable local control and survival rates with both modalities. So how does one choose? Well it’s basically based, and I try to sympathize it here on a number of points such as institutional preference, physician preference and training, tumor characteristics and here, the size of the tumor appears to be an important determinant, what is the growth pattern, is it an exophytically growing tumor, is it an endophytic growing tumor which involves the endocervical canal predominantly, what is the general condition and the age of the patient, is the patient a surgical candidate, what is our concern about possibly preserving ovarian function which is also of concern in young women which is often proposed to be better with surgery than with radiation therapy. And then basically we know that there are different patterns of adverse effects with radiation therapy or radical hysterectomy. With hysterectomy, the side effects tend to be either immediate, or to occur in the short term, and surgically related. Fistula rates are lower, between 1 and 2%, urinary tract fistulas are more common with radical surgery as opposed to with radiation therapy where the intestinal fistulas tend to be more common. ‘

With radiation therapy, adverse effects can occur within six months, from six months to a year or after a year, in which case they are called late adverse effects which are of concern in young patients and include intestinal dysfunction which can be protracted fistulas. In patient’s who undergo a radical hysterectomy, we have learned there are a number of factors that can be found that will affect prognosis, and they are, the presence of positive pelvic lymph nodes, positive margins, parametrial extension of the tumor, deep stromal invasion, large tumor volume, lymphovascular space invasion is less consistently shown to be an adverse prognostic factor. This is just a compilation of a number of studies where patient’s who had a radical hysterectomy were treated with adjuvant radiation through the whole pelvis because of the presence of one of these poor prognostic factors, and you can see there is a range here of patient’s between 9% all the way up to 38%, 35% of patient’s who had a radical hysterectomy and then went on to have pelvic radiation therapy.

The problem here is that you can see there is also a significant rate of complications, and I should point out that those are severe complications, those are not just minor complications occurring anywhere from 3 to 30% in those patient’s. The message I want to share with you here is that if at all possible, we would prefer to stay out of this kind of situation where patient’s are subjected to two radical treatment modalities; one is surgery, another radiation therapy, which means that I would be an advocate of trying to do either one but not both, so selection of the patient’s will be important. It has traditionally not been shown beyond any doubt that adding radiation therapy after radical hysterectomy when lymph nodes were involved really added to survival. Last year, a study was reported where 243 patient’s were accrued, they had radical hysterectomy and pelvic lymphadenectomy for stage IAII, IB and IIA carcinoma of the cervix, they have negative paraortic nodes and they were randomized between two treatment regimens; regimen one was radiation to the pelvis with concurrent cisplatin and IV 5FU given every three weeks for intended course of four cycles, and regiment two was radiation therapy to the pelvis alone.

Treatments for Anal Cancer 3

We know that 5-FU is a good radiation sensitizer. We also know that cisplatin is a radiation sensitizer. Widely used with radiation in other sites in the GI tract, esophageal especially. So what about 5-FU platinum radiation versus mitomycin? Well, we don’t know the answer versus mitomycin really, but we do know in a couple of studies – and these are studies with locally recurring disease – that there was a 55% complete response rate. Then in patients in a study from France from Bordeaux, Rene Brunet, using 5-FU platinum and radiation in patients with primary tumor had results that were very similar; complete response rates of about 82%, similar to what you would expect with mitomycin. There now is an active RTOG Inner Group study that many of you can certainly participate in that looks at the standard arm of 5-FU mitomycin versus an experimental arm of 5-FU platinum and radiation. The way the 5-FU platinum is given here is it’s given as an induction initially and then followed, and then given concurrently with the radiation. So this study, which is accruing patients fairly rapidly, will look at the comparison of mitomycin versus cisplatin as a radiation sensitizer.

Now just to remind you again of the point of abdominoperineal resection, these are a collection of patients from various series in the literature, pointing out that about one-half to two-thirds of patients who have recurred or who have not had a complete response with anal cancer can be salvaged with abdominoperineal resection. Of course the price you pay is they have a permanent colostomy. But it is an effective therapy and certainly would be something to suggest to patients who have recurred.

The current therapies for anal cancer for the very unusual tumors, the T-1’s the T-2’s, small tumors, local resection is certainly the reasonable thing to do. For more advanced tumors or tumors of higher grade the 5-FU mitomycin and 5-FU platinum it can be done. Many people use 5-FU platinum and there are a whole host of other radiation sensitization issues. The heart of this combined modality therapy is radiation sensitization, really. Whenever the radiation at a lower dose with a sensitizer is compared to higher dose radiation, the lower dose with the sensitizer works. So one could say, “Well, we know that the best radiation sensitization, for example in adjuvant therapy for rectal cancer, is low dose continuous infusion 5-FU. What about that?” These continuous infusion 5-FU regimens are of course only 96 hours per gram per M2 and that’s a perfectly reasonable question to ask. Obviously the other question with radiation sensitization is that everything we have talked about here requires intravenous therapy. What about capecitabine or UFT or one of the other oral fluorinated pyrimidine’s as a radiation sensitizer? And that would certainly be a reasonable thing to ask, and I think one of the problems … if this were esophageal cancer where nothing was working very well – and you are talking about marginal differences with combined modality therapy – people would jump to asking those questions. But since we have the analogy here of MOP chemotherapy in Hodgkin’s disease, people are a little reluctant to move far from the 5-FU mitomycin or 5-FU platinum standard therapy. So I think innovation will be relatively slow.

This is in your handout actually, sort of an algorithm of how to approach these patients. Obviously a tissue diagnosis is important and there can be confusion with tissue diagnosis. Many patients who are seen by particularly primary care physicians who have an anal fullness or what appears to be an anal mass, or misdiagnosed -for example – as having hemorrhoids and there may be misdiagnosis for awhile. The anorectal surgeons, the colorectal surgeons are very much in tune to this disease, and particularly now in a … like in Greenwich Village in New York we have a large population of gay males and it’s a very common diagnosis, so we are very tuned into it. But it’s important to make a diagnosis in people. The standard therapy is still 5-FU mitomycin. If the patient has a complete response, and complete response by clinical exam, in other words, for six weeks after you’ve finished your therapy you can do a rectal exam and you can’t feel anything abnormal – when this slide was made two years ago most people would biopsy. Now many people are saying, “Why biopsy? Because a deep biopsy may have some compromise on anal sphincter. Just follow the patient. The likelihood is that they won’t have any disease. And just follow them and if you find anything that appears abnormal, begin to biopsy. But the vast majority of these patients are cured. If they are not cured, if they have a PR or a CR and they have a macroscopic recurrence or a macroscopic failure to respond, then many people would go directly to an AP resection. If they have microscopic disease or smaller amounts of disease, or they’ve had an 80% response or something like that, then there are a variety of investigational approaches that have been used. Many people would add 5-FU platinum in then to try to get chemotherapy cyto-reduction of a patient who is failing. Local excision plus brachytherapy is something that is done, and again the risk here is that you end up with a dysfunctional sphincter. If none of these things work, then one could go again to the APR, the abdominoperineal resection.

Treatments for Anal Cancer 2

Now there are other data that show some important aspects of this regimen and these studies just point out that it’s important to intercalate the radiation and chemotherapy, in other words, to give them together not to give them sequentially. And that radiation combined with chemotherapy is better than chemotherapy alone at a higher dose. Very similar to studies done on esophageal cancer. But the original Wayne State experience with 122 patients showed a complete response rate of 93%. What they tried to do at Memorial-Sloan-Kettering was to give 5-FU mitomycin as an induction therapy then follow it by radiation, and that was not nearly as effective. I think everyone would agree with that. Princess Margaret in Toronto also did a study that was a randomization between 5-FU, mitomycin and what is a more standard dose of radiation these days, the 5,000 centigray versus 6,000 centigray alone and showed that the combined modality therapy was better than the higher dose of radiation therapy alone. So I think we’ve come to believe that that’s correct. What this slide is showing is that if you look at tumors that are greater than 4 cm you have a considerably higher relapse rate. So you want smaller tumors to treat.

Now this is a randomized study that was published about two years ago. It was a randomized study that was published in the JCO and it was from EUROTC and essentially it was comparing radiation alone to a mitomycin/radiation therapy arm. What it showed was local regional control was better with the combined modality therapy versus radiation alone. It also showed that colostomy-free survival was better with radiation therapy combined with chemotherapy than radiation therapy alone. This is important because obviously again we are talking about sphincter sparing. Now the next slide is interesting because what it shows is the overall survival is no different. That gets back to this whole issue of keeping the abdominoperineal resection in reserve because it can salvage at least 50% of patients who don’t respond to combined modality therapy. But I think that randomized studies like this have been very helpful in convincing us that there is no doubt that the combined modality approach with 5-FU, mitomycin C and radiation is the standard of care for patients with anal cancer.

Now many people are concerned about mitomycin. Mitomycin is certainly a very old drug and mitomycin sort of from the word go had gotten a bad reputation. Because mitomycin was developed at a time in the 1960’s when the standard way to do a phase I study was to give daily doses of the therapy until you got toxicity and then see what happens. Of course all of you who have used mitomycin can imagine that after three or four weeks of giving low doses of mitomycin, when the platelets finally got down, they were never going to come back. So it was not a … the pharmacokinetics of the drug and the way, the timing of myelo-suppression wasn’t well understood. And of course mitomycin is also associated particularly in patients with minimal disease, with a hemolytic uremic syndrome which can be essentially a TTP-like syndrome, and people can die of it in renal failure. The thing that is particularly concerning is that it tends to occur in patients with minimal disease.

Treatments for Anal Cancer.

What about the results? The standard therapy for anal cancer, before 20 years ago -18-20 years ago – was abdominoperineal resection. Obviously abdominoperineal resection is something that can’t be taken too lightly since you are removing the whole anorectal mechanism and you leave a patient with a permanent colostomy. In a review of some 460 patients this was done with, what I consider as relatively high – and of course these were patients treated in the 60’s and 70’s – with relatively high operative mortality. The cure rate was about 50% with this procedure. So it’s important in one sense to be absolutely sure – particularly in the context of taking the Boards – that you never want to do an abdominoperineal resection as the first line therapy for a patient with anal cancer. But the other thing is to keep abdominoperineal resection in your back pocket, because as I’ll show you, it’s still an effective salvage rate for patients who recur or who don’t respond.

Looking at radiation therapy alone in the treatment of patients with anal cancer, and you get a local control rate of somewhere from 60-70% and a five year survival rate of somewhere around 50-65%. So radiation alone has some benefit. Now the radiation therapists are in a sense like chemotherapists in that if a little radiation is good someone is always going to say, “Well, a lot of radiation is better.” These are data from France from Papillion, and what he did was to do brachytherapy or interstitial radiation in patients with anal cancer, and he had some 64 patients and he was able to render about two-thirds of them without any evidence of disease. However, there was a significant incidence of radionecrosis that occurred. And the other thing that is not mentioned in this slide, which I think is an important consideration to keep, what we are talking about is the potential for sphincter-sparing surgery here. Now if you spare the sphincter but it doesn’t work, you haven’t done the patient any favors really. So you need to look at functional benefit in these patients, after whatever sphincter-sparing approach you are going to use. With this much radiation many people would agree, we would be very concerned about the function of the residual sphincter.

Well, when the modern era arrived where data, using the combination of mitomycin, 5-FU and radiation in patients with basaloid and squamous cancers of the anus. The original work was done at Wayne State University by Dr. Nigro and his colleagues. Many people picked up on it and initially the combination of 5-FU, mitomycin and radiation was used in patients with larger anal cancers, or patients who were thought to be very poor surgical risks, or patients who refused to have abdominoperineal resections. What was found was that this tended to be very effective therapy. The way it’s given, and the way it’s given still, is interesting because there are all kinds of innovations in combined modality therapy and people are constantly looking at how best to modulate the radiation-chemotherapy, for example in esophageal cancer. What’s happened is that in the early 1980’s, late 1970’s, we stumbled upon this and it works real well and people are reluctant to leave it. I’ll show you that we are looking at new approaches but it’s like MOP chemotherapy in Hodgkin’s disease. You have to have a real good reason to want to change it. This therapy is really quite simple to give. You give a gram per M2 (meter square) per day for 96 hours of 5-FU by continuous infusion, and most people do this now with a pump as an outpatient. It used to be that the patient would come to the hospital. Mitomycin C is given on the first day, either 10 or 15 mg. For many people 10 mg is probably plenty. Radiation has changed somewhat in that the radiation dose has been increased. Most radiation oncologists give about 5,000 centigray. In this original study, one of these studies from San Francisco by Flamm et all, there were 11 patients who were treated and they ran ED and had a very good response; essentially 100% response rate.

Cancer Prevention, Detection, and Chemotherapy 6

As far as the cervical cancer screening recommendations, any woman having intercourse, initial smear normal, repeat once a year. First two smears normal, every three years to age 35 and every five years to 65. There’s some people that don’t agree with this. Low risk women over 65 with prior normal smears or in high risk such as with age, continue to do yearly.
One of my colleagues who is a gynecologic surgeon is very upset with this type of approach to how often you should do your pap smears. He says his problem is, “Okay, you can do this and you only do it every three or five years.” He says, “But that’s where all my cancers are and you can go out there and you’ll see a couple of my patients who are now dying of cervical cancer.” So he particularly feels you should do it continuously much more often. But these are the recommendations at the present time.
In Denmark, they were having a terrible time because they didn’t seem to be able to control this at all so they decided every woman is going to get a pap smear. As you can see, the incidence went up and then plummeted as the screening became effective and the mortality in these patients went up a little bit but then it was going steadily down again related to the fact that we’re doing adequate and good pap smears.
I had to put lung cancer screening in here as to effects on mortality rate and if they get a chest x-ray three times a year there’s no effect at all. If they have sputum cytology three times a year, there’s no effect at all. So in other words, our screening is of no value. It’s not effective in patients with lung cancer.
Prostate cancer is a bigger problem and you’re going to see more and more of that as time goes on. New cases now, 334,000, deaths 42,000. A significant problem that’s getting bigger all the time because we ignored a lot of people who said the screening for prostate cancer, PSA, is of no value and that’s obviously not true. It’s been proven now that it’s been a very significant improvement in our ability to pick up prostate cancer.
The PSA is a glycoprotein. It’s a serine protease lysosomal coagulation and it’s positive in 98% of prostate cancer. There’s very few things that are positive at such a high incidence and so you can see why this has been very helpful as we check on our patients.
PSA elevations are found in benign prostatic hypertrophy and inflammation and these can really cause a problem for the practicing physician. With inflammation, the PSA goes up to like 8 or 10, maybe even 20. Now you think the patient’s got the cancer and it’s actually only inflammation or BPH. So we have to be careful about that as time goes on.
Prostate cancer screening. First of all, you should be aware that the African American has a much higher incidence of these cancers than does the regular Caucasian and that goes through all these various groups. Digital rectal exam being age 50 and yearly. High risk groups, the African American age 40-45. Asymptomatic men, if the tumor is found more favorable with its stage. Digital rectal exam, DRE, less effective than PSA and I think we all know that.
Now when we’re talking about prostate cancer detection, same sort of problem as we saw in the polyposis deal and here you can see the initial screening 60 plus percent had detection of prostate and then as time went on, year 3, year 4 it went down further and further.
Adjuvant therapy of proven value with breast cancer in the premenopausal and postmenopausal and also Dukes’ C colon cancer.
The adjuvant chemotherapy of proven value in this group include Dukes’ C colon cancer treated with fluorouracil and levamisole and rectal cancers with radiation and fluorouracil.
New chemotherapy agents that you’ll be starting to work with with the oncologists include irinotecan. Cancer uses are fluorouracil resistant colon cancer. Side effect of note is diarrhea. Cladribine is used to treat hairy cell leukemia, beta cell lymphoma and is associated with fever and sepsis. Topotecan is relapsed ovarian cancer where it can be quite effective and it causes diarrhea and dyspnea in some cases.
Now we talk about new chemotherapy agents again, if we look at Taxol or paclitaxel, it works on the microtubules. Its cancer use is ovary, bladder, lung and breast. Side effects are myelosuppression, neurologic symptoms and fatigue. Vinorelbine or Navelbine, microtubule assembly. Lung, breast, myelosuppression and some neuropathy. Gemcitabine is one we’re quite excited about. It causes DNA inhibition but it’s active, although it’s not a lot, it’s definitely active in pancreas. It can cause fever and lethargy and myelosuppression.
I’ll just sum up to point out that gemcitabine, as I mentioned, doesn’t have a very high incidence of helping in these diseases. As you can see, the patients with response rate are usually in the rather low areas but nevertheless when you get a pancreas that goes two years, that’s pretty impressive.
Here’s another group which you can see ovary 22% response rate. Down here at pancreas 11%. But then they do last for a long time.
Non-small cell lung cancer. Paclitaxel and carboplatin are the best agents we feel. 62% objective response which is twice as high as it used to be and duration of response, it used to be about 20 weeks. Now it’s 53 weeks. So we’re doing better.
Here, again, we’re talking about treatment of resistant tumors and that works better with the use of these agents and this particular one is paclitaxel.
Cancer Prevention, Detection, and Chemotherapy at Cancer Treatment

Cancer Prevention, Detection, and Chemotherapy 5

One of the things I wanted to discuss with you because you probably have not heard about this and a lot of us haven’t either, classic familial adenomatous polyposis, the number of adenomas are usually thousands. The attenuated familial adenomatous polyposis or the FAP, only 1 to 50 cases of polyps, are never more than 100 as you can see. The morphology of the classic FAP is polyploid and the attenuated is flat and the fact that it’s flat makes it hard to realize that you’re dealing with a genetic type of disease. The location of the FAP is through the colon and proximal to the splenic flexure in the attenuated variety. The location is through the colon for the classic and proximal to the splenic flexure for the attenuated. Colorectal cancer is through the colon and proximal splenic flexure for the attenuated.

Here’s where you again can see the difficulties in making sure you’ve got the right diagnosis. Classic FAP age of onset is 39, pretty early. It makes you think about cancer. The attenuated familial adenomatous polyposis is at age 55. So it’s a little bit later and it looks a little bit more like classic but it’s not.

Fundic gland polyps is a constant feature in the classic and in the attenuated. Extracolonic cancers are preampullary, thyroid sarcomas, brain tumors and small bowel are in the classic and periampullary in the nonclassic.

Desmoid tumors are common in the classic and not identified in the attenuated. Hypertrophy of the retina is found in 70% of these patients and absent to almost gone. When we’re looking at these patients with the flat polyps, when we look for the incidence, you’ll notice that percent of the total is over 50,000 in the cecal area and it slowly goes down to the rectum where it’s less than 10%. So this is a group of patients that you should be looking for and I think you can really do some good in taking care of these people.

Guidelines for screening and surveillance then for the early detection of colorectal polyps and cancer. Repeat FOB every year. Flexible sigmoidoscopy every five years. Colonoscopy every ten years. A double contrast barium enema can be used every five to ten years.

Screening costs are really something else with this disease. As you can see, 50-70_year_olds screen every five years and the cost is over $1 billion. So we’ve got to do a little bit more conservatively than what we’re doing at the present time.

We’re talking here about breasts and breast self examination should be started at 20 and over every month. Breast physical 20-40 and over 40 every year and every three years from 20-40. Mammography 35-39 baseline and 40-49 every one to two years. As you probably know, it’s now been established that 40-49 is the way we should do this and we don’t need to do it every year for 35-39, just the baseline. But 40-49 is going to be every year now and 50 and over, of course, we’ve already talked about that being every year. So we should have an annual mammography beginning at age 40. Guidelines for women age 50 and over remain unchanged and then we just discussed the 40-49.

Mammography screening. 30% reduction of breast cancer mortality and 20% false negative are found. It’s very important to keep this in mind because I have seen a number of patients that were in litigation because they had decided that it was a false negative and nothing to worry about but it wasn’t nothing to worry about.

The typical breast has normal fat tissue. Everybody can see this one has carcinoma here. It’s spiculated and irregular in shape and a classic cancer of the breast.

The other thing that you all now know is the study on using tamoxifen in breast attenuation and decreasing of breast cancer has now been easily picked up as being very important. It does increase the likelihood of us being able to cure these patients and this has been a very significant improvement in our care of these particular patients.

Now, when we talk of cancer of the cervix, we all know that that pap smear is the best type of study that we can do – better than anything else. Here’s an area in 1994 with the number of cases being 15,000, the number of deaths being 46,000. Cancer of the cervix risk factors include early sex, parity over five, multiple partners, papilloma virus, DES in utero and non-Jewish.