Browse Author: David B.

Brain Cancer

Neoplastic transformation appears to be a multistep process in which the normal controls of cell proliferation and cell-cell interaction are lost, thus transforming a normal cell into a brain cancer cell. This tumorigenic process involves an interplay between at least two classes of genes: oncogenes and tumor suppressor genes in some relation to cellular phone radiation. Oncogenes are abnormally activated versions of cellular genes that promote cell proliferation and growth associated with cellular phone electromagnetic radiation. Activated oncogenes thereby result in an exaggerated impulse for a cell to grow and divide. Tumor-suppressor genes, on the other hand, are normal genes that act to inhibit cell proliferation and growth. The inactivation of these genes results in tumor formation or progression. The most common scenario for inactivation of both copies of a tumor suppressor gene is mutation of one allelic copy, followed by loss of all or part of the chromosome bearing the second allelle. As a consequence, the identification of consistent regions of chromosomal loss in specific tumor types suggests a tumor-suppressor gene in that chromosomal region related to cellular phone electromagnetic radiation. These basic themes of oncogene activation and tumor-suppressor gene inactivation coupled with chromosomal homozygosity underlie the current molecular understanding of human tumor formation and cellular phone electromagnetic radiation.

Cervical Cancer Part 4

In terms of moderate and severe adverse effects, as expected with these combinations of radiation and chemotherapy, one can expect to see leukopenia, thrombocytopenia and other hematologic toxicities, but if you can look through this, you will see that in the patient’s with the complex regimen here, consisting of the three drugs, incidence of leukopenia was clearly higher, also thrombocytopenia as opposed to patient’s who got the weekly cisplatin together with radiation therapy.

In will conclude here by pointing out that we seem to have been able with combining chemotherapy and radiation therapy to demonstrate that there is somewhat of a survival benefit when both treatments are given simultaneously, that means not one before or after the other. In truth, however, the magnitude of the benefit remains somewhat in doubt because in some of the studies that the gynecological college group has done, the radiation therapy time is not considered to be optimal because of it being more than eight weeks, and in some cases the total dose which was given would be considered at the present time to be less than what we want to give in some of these larger tumors. So which drugs or which regimens do we want to use remains to be determined, although a the present time, weekly cisplatin seems to have a therapeutic ratio that is advantageous compared to the other ones.

Cervical Cancer Part 3

I want to summarize some important facts to keep in mind. Obviously, when one delivers radiation therapy, the radiation field needs to encompass the tumor at least, portals need to be designed with the best information available to encompass the tumor. The dose needs to be appropriate for the amount of cancer one wants to eradicate. High energy equipment needs to be used which is not a problem in this day and age in most instances, the combination of external beam therapy needs to be used together with brachy therapy and then the length of treatment needs to be sufficiently short so that no in adverse effects can be seen as a result of that. This is a typical radiation portal when measured on the patient would be 15 x 15 cm. For smaller tumors, one can put the upper limit of this radiation field here at L5-S1, for larger tumors, L4-5 and even higher up for extended radiation fields. This can be extended upwards to T12, L1 to include paraortic nodes. Similar attention has to be paid to the design of the lateral ports.

It’s important, and that has been realized in recent years, to keep all this radiation treatment within a certain amount of time because when the treatment time is longer than what it should be, for instance in this lower curve where treatment exceeds nine weeks, one can see a decrease in survival as a result of prolonged treatment time. So who are the patient’s who fail with cervical carcinoma, what are the patterns of failure. I basically already explained to a certain extent. In patient’s who have disease that is not bulky and confined to the cervix, a lot of the relapses have a component of distant metastatic disease, 85% of them. So if we want to expect further improvements in the treatment of those patient’s, that will have to wait until we can define effective systemic therapy because systemic disease is the problem. In patient’s with bulky pelvic disease, we see that pelvic failures are an important component of the failure rate. So by improving pelvic control of the disease, one may be able to improve survival. The reality is, at the same time, still 60% of the relapses in patient’s with advanced cervical cancers are going to include distant component, so when I say that better pelvic control may improve survival, at the same time, this statement indicates that the expected rate of improvement or magnitude of improvement is going to be modest.

The gynecologic oncology group looked at a fairly large group of patient’s with carcinoma of the cervix that was stage IIB, III, stage IVA, these patient’s were surgically staged and shown to have negative paraortic nodes. By the way, surgical staging of carcinoma of the cervix is clearly more accurate than clinical staging but has no place in common clinical practice. It has not been shown to lead to improved outcomes, and therefore, is not recommended outside clinical trial such as this. Patient’s were randomized between the following regimens; regimen one, radiation to the pelvis and brachy therapy and concurrent cisplatin given weekly; regimen two, radiation and brachy therapy with cisplatin 5FU and hydroxyurea and regimen three, radiation therapy and hydroxyurea which is given orally. These are the outcomes in terms of progression free survival, progression free survival in the patient’s who are treated with cisplatin together with radiation or with cisplatin and 5FU and hydroxyurea was significantly better than progression free survival in patient’s who got radiation therapy and hydroxyurea only. The same is true for survival where patient’s who got the cisplatin based regimen which are the two overlapping top curves here did significantly better overall as opposed to the patient’s who were treated with radiation therapy and hydroxyurea

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.