Browse Category: Cancer Treatment

Cisplatin or carboplatin

Now, what do you put? Cisplatin or carboplatin? I hope to goodness you are not going to be asked to distinguish between those two. But there have been three studies of this issue now, and we actually have an answer. There was a Dutch trial that only had 182 patients on it, too few patients to allow any reasonable conclusions to be made. But there have been two subsequent studies, GOG protocol 158 and a German trial from the AGO group, both of which had almost 800 patients – 798 patients each. That’s enough patients to have equivalency conclusions to be drawn. Let’s look at those two. First the AGO study, presented at each of the last two ASCO’s. These studies randomized patients with IIb-IV disease – that is the both the large volume and small volume patients – to either Taxol over three hours plus cisplatin or Taxol over three hours plus carboplatin. And yes, they got a lot of neurotoxicity with three hour Taxol/cisplatin. They allowed up to six cycles of therapy. What they found was no difference. The trends all favored Taxol/cisplatin. The response rate 80% versus 70%. Clinical complete response rate 36% versus 30%, progression-free survival median 73 versus 69 weeks. Survival at one year 92% versus 91%. The trends here are very small, with cisplatin no significant difference.

GOG158 was done in a patient population with small volume residual stage III disease. Again, the randomization here was the same but the Taxol/cisplatin regimen used 24 hour Taxol plus cisplatin, which gives much less neurotoxicity. The Taxol/carboplatin regimen used an AUC of 7.5 for the carboplatin because that was the MTD on the phase I study. Each regimen given every three weeks for six cycles. Here are the results. Pathologic complete response rate, 45% with Taxol/cisplatin, 52% with Taxol/carboplatin. Progression-free survival essentially identical between the two arms. If anything here, the trends favor Taxol/carboplatin. And what that speaks to is there is literally no difference between a combination of Taxol/carboplatin and a combination of Taxol/cisplatin. The disappointing thing is that there is also no difference in neurotoxicity between the two. In the GOG study the neurotoxicity in these two arms was exactly the same. In fact there was slightly more nausea and vomiting on the Taxol/cisplatin arm. There was more nephrotoxicity on the Taxol/cisplatin arm. There was more myelosuppression on the Taxol/carboplatin arm. So that while Taxol/carboplatin did have an advantage in terms of therapeutic index, it was not as great as we would have anticipated going into the study.

The weight of evidence suggests that three hour Taxol/carboplatin is a reasonable treatment for ovarian carcinoma. In fact I can tell you that it is used by over 80% of you in treating ovarian carcinoma, based on a survey that was done by Bristol-Meyers Squibb. Now how much of these drugs should we use? Cisplatin, carboplatin and Taxol which are the major three drugs in ovarian carcinoma. Let’s look at each of the three. First, cisplatin. There have been two metaanalyses published on cisplatin; 2006 in the Journal of Clinical Oncology, 1993 in the Journal of the National Cancer Institute. What these two metaanalyses do, combined, is to establish a clear dose-response relationship up to a cisplatin dose of 60 mg per meter square but not beyond that. No advantage to increasing the cisplatin dose beyond 60 per meter square. There have been three randomized trials internationally now looking at the issue of 50 mg per meter square versus 100 mg per meter square of cisplatin. One GOG study and two Italian studies. No differences in response rate, no differences in survival by going up to the higher dose of cisplatin. So by the best evidence that we have to date there appears to be no advantage to going beyond a dose of cisplatin in the range of 50-60 mg per meter square every three weeks.

Current surgical treatment

PANCREATICODUODENECTOMY

Current surgical treatment is based on the procedure of pancreaticoduodenectomy as described in 1935 by Whipple and coworkers. Their two-stage pancreaticoduodenectomy consisted of biliary diversion and gastrojejunostomy during a first operation and, after the patient recovered (usually about 3 weeks later), resection of the duodenum and pancreatic head.By 1941, the world experience totaled 41 cases, and the perioperative mortality rate was 30%. Before 1940, the pancreatic remnant was not reanastomosed to the small bowel, and the high mortality rate was largely due to pancreatic fistula from the oversewn pancreatic remnant. In 1941, Whipple modified his reconstruction to include a pancreaticojejunostomy, with the entire procedure done in one operation. In 1946, Waugh and Clagett from the Mayo Clinic described their modification of the one-stage procedure to its current form. The goals of surgical therapy outlined by Waugh and Clagett have not changed in the past 50 years: (1) there should be reasonable opportunity for cure, (2) the risk of death should not outweigh the prospects for cure, and (3) the patient should be left in as normal a condition as possible.

Recent advances in operative technique, anesthesia, and critical care have resulted in a 30-day in-hospital mortality rate of less than 2% for pancreaticoduodenectomy when performed at major referral centers by experienced surgeons. At such centers, mortality rates remain less than 2% despite the use of multimodality therapy, the frequent need for complex vascular resection and reconstruction, and the referral of many patients following an initial unsuccessful attempt at tumor resection. Recently reported mortality rates from other institutions, including university centers and the Department of Veterans Affairs hospitals, range from 7.8% to more than 10%. Data from New York State have demonstrated that hospitals performing fewer than nine pancreatic resections per year have an unacceptably high perioperative mortality rate (12%). Patient outcome will be optimized and costs minimized by the referral of patients requiring major pancreatic resections for malignant disease to centers with active multidisciplinary treatment programs. Surgical resection, however, benefits only patients who undergo a negative-margin resection. Therefore, it is essential that surgery be done only on patients with localized, potentially resectable pancreatic cancer. In the absence of significant innovations in systemic therapy, the only potential for major improvements in the quality of life of patients with pancreatic cancer lies in our ability to limit surgery-related morbidity to those patients most likely to benefit from surgical intervention (i.e., to avoid laparotomy in patients with unresectable disease). Therein lies the importance of how the clinician defines resectability. CT criteria for resectability include the following: (1) the absence of extrapancreatic disease, (2) a patent SMPV confluence, and (3) no direct tumor extension to the celiac axis or SMA.

ADJUVANT ELECTRON-BEAM INTRAOPERATIVE RADIATION THERAPY

EB-IORT is a means of delivering a higher dose of radiation to the pancreatic bed and high-risk nodal groups to decrease the risk of local tumor recurrence. The effectiveness of EB-IORT in controlling the primary tumor in patients with unresectable disease, combined with early results from Japan utilizing EB-IORT after pancreaticoduodenectomy, served as the foundation for a study from MDACC of preoperative chemoradiation, extended pancreaticoduodenectomy, and adjuvant EB-IORT. To improve local-regional tumor control in patients with resectable disease, EB-IORT was delivered following resection of the specimen but before initiating gastrointestinal reconstruction. Using a dedicated operating suite containing radiotherapy equipment, the MDACC system of EB-IORT required only an additional 30 to 40 minutes of operating room time because patient relocation was not necessary. The dose of EB-IORT delivered varied from 10 to 15 Gy; these radiation doses were based on preclinical and clinical studies demonstrating the safety of 20 Gy or less. The EB-IORT treatment field included the retroperitoneum and tumor bed extending from the transected bile duct superiorly, to the right kidney laterally, and to the pancreatic remnant medially. The pancreatic remnant and bile duct were excluded from the EB-IORT field. The major retroperitoneal blood vessels (aorta, celiac axis, SMA, SMV, portal vein, and inferior vena cava) included in the EB-IORT field are not as susceptible to radiation injury as are hollow visceral and solid organs. Initial results support the safety of adjuvant EB-IORT and suggest improved rates of local-regional disease control. However, these results are likely multifactorial, being due to accurate preoperative imaging, a standardized approach to surgical resection, and chemoradiation.

Probably our most important prognostic factors

Probably our most important prognostic factors, specifically if you are going to be giving neoadjuvant induction chemotherapy, is histologic tumor necrosis. That’s probably the gold standard. In those patients who have at least 90% necrosis or a Houvus score of IV – which I will show you what that is – have an extremely good prognosis. Surgical margin quality is important. You want to have negative margins. Those patients who have positive margins have a high incidence of local recurrence and then have a worse prognosis. So again, this is where pathology becomes important and you want, if we are going to give neoadjuvant induction chemotherapy at our institution we have a pathologist, Barry Schmukler, who samples multiple areas in a grid fashion of the bone, and looks in all these areas for the amount of necrosis and then gives us a number of the amount of tumor cells that are destroyed. This is based on work by Dr. Houvus who was a pathologist at Memorial Sloan-Kettering who developed the Houvus classification of I-IV, IV being no histological evidence of any tumor. This is now at many institutions been changed to greater than 90% being a good response.

In terms of work-up now. What kind of a work-up do you do for osteogenic sarcomas? Well, on plane x-ray you can see a sunburst sign. You need, as I talked to you before for soft tissue, you have to have a properly placed core on incisional biopsy. We usually obtain alkaline phosphatases and LDH’s as markers because they can be elevated, but they are not always elevated. We want to obtain an MR or a CT scan of the bone area plus a chest CT scan because this metastasizes to lung, plus a bone scan because it can metastasize to other bones. We use angiograms and thallium scans to assess the response to induction chemotherapy. If limb salvage is contemplated, if possible you want to have the surgeon who is going to perform the definitive operation do the incision placement, because if it’s not placed properly that may unfortunately mean that the patient will require an amputation. This is the sunburst sign that I was talking about. There can be elevation of the periosteum, which we call Codman’s triangle. This is this paraostial osteogenic sarcoma, which is low grade, which has the better prognosis.

In terms of staging, our staging again is a bi-gradal system, as for soft tissue sarcomas. Whether the tumor is in the cortex or beyond the cortex, size although important is not part of the grading system. And then metastasis. So it’s actually I, II, IV with nothing in the stage III group. So this is very similar to the previous Enneking staging system I showed you.

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.

Cancer Prevention, Detection, and Chemotherapy 4

Now, some of you are aware of the Lynch Syndrome I and there’s a Lynch Syndrome II. It’s a very interesting type of illness. The mean age of onset is 45. It’s found in the proximal colon so when you’re trying to get it and find it and reverse the deaths due to the colon cancer, you have to think about the proximal colon. It has an unusually good prognosis which is usually found in all these types of syndromes and it’s an autosomally dominant type of inheritance.
Lynch Syndrome II is the same as I except multiple tumors, high frequency of colon, endometrium and ovary and less frequent breast, stomach and lymphoma. I have to bring this up because there’s a lot of fights and discussions over in Europe particularly about these two entities and the people felt that this really didn’t jive – that there wasn’t an increased incidence in these Lynch syndrome II. However, they found a number of families with this kind of a syndrome and it pretty well cleared this up. Indeed, this is a cause by the high incidence of the various types of cancers that are listed there.
Here’s a family that’s pretty prolific and as you can see there are seven cases with cancer and five without and you can see the various ages that they had this. Here’s one at 46 years of age. Here’s another one at 55, 42 and certainly a real problem and some of these patients get to the point they just don’t want to talk about it anymore and don’t get the proper studies that they should be getting.
The hereditary aspects of colorectal, again, in familial adenomatous polyposis, percent of colon cancers is less than 1% interestingly enough and that’s one that gets a lot of publicity. Chromosome 5Q21 and gene APC are found. In hereditary nonpolyposis you can see the incidence goes up from 1% to 9%. Chromosome is 2Q3P and then it’s chromosome COCA-1 which you probably know about as well as I do. Now when we’re screening for colorectal cancer, you want to do a digital rectal every year starting age 40. Fecal occult blood test every year age 50. Sigmoidoscopy every 3 to 5 years at age 50. Colonoscopy, first degree relatives of cancer patients at age 50 or less. Age 35 to 40, 2, 3 to 5 years for this test. You will find different groups will do this in a little bit different manner and you may not find the exact type of suggestions as is listed here.
Hemoccult testing. As you know, if the test is positive, 10% of these patients will have cancer and 23% will have polyps. So it’s not a very good test in terms of getting all the cancer patients involved with this. The Hemoccult II only screening test if we use it only like that for asymptomatic colorectal cancer, 50-60% will remain undetected. So not the best test.So if you look at what we’re doing with colorectal cancer, occult blood is a poor marker for colorectal cancer. Most cancers are missed and most bleeding is due to other causes. The HemoQuant is a specific test for blood and some groups are using these too in their studies but there’s really no improvement in picking up the cancers by using this newer test. Both are equally insensitive and we need better screening markers in order to do better in detecting this.

Cancer Prevention, Detection, and Chemotherapy 3

Primary liver cancer is associated with hepatitis, aflatoxin exposure and malnutrition. As you know, this is the most common cancer throughout the world.

Of course, AIDS is associated with a huge number of cases. That’s going up all the time and that is associated primarily with Kaposi’s sarcoma and lymphoma.

There will 186,000 new female breast cancers in the U.S. in 2006 and 46,000 deaths. There’s been no change over the last two or three years and as you know this is very hopeful and gratifying that maybe we’re finally going to start getting a handle on this and decrease this. At the present time, there are 20,000 less deaths than from lung in women. As we discussed, breast cancer, 186,000 and 45,000 deaths, no change.

High risk factors include family history, nulliparity, early menarche, infertility, first pregnancy after age 35. Negative risk factors include negative family history, first birth before age 20, surgical menopause before 40, pituitary insufficiency, early menopause and normal weight and low fat diet.

Now, caffeine, as you know, is associated with painful breasts and we seem to have an awful lot in this country of that and it’s associated with caffeine. If we use danazol, we can cut down the pain and discomfort by about 60% and the tenderness also. There’s no evidence that it does anything in terms of hyperplasia. However, if the patient has atypical hyperplasia, the incidence of cancer goes up about 4-fold.

The other thing we can mention is what about women who have osteoporosis. I’m sure you get this as a real problem all the time. What should we do about these? If we give them estrogens is that bad? Well, I think most of us who are in this business feel that that’s okay and if you use estrogen and progesterone at the same time, the incidence of developing the cancer is going to be so low that I don’t think it’s anything to worry about.

Now, the next thing as we come to a close in this area, if I came around and I said, “Hey, I can cut down the cancers that you’re seeing in your patients by 50%, would you like to do that?” Well, of course, everybody would just be enthralled if you could do that. If we look for lifestyle cancer control, you see in one group, the Mormons, all cancers are down one-third to one-half, lower save prostate. So in other words, we can cut it down by one-third to one-half and the diet is the same except no tea, coffee, tobacco or alcohol. That’s the only difference between the way these people eat and the difference with the cancers being reduced to one-half is really quite remarkable.

Some in terms of cancer control, asbestos and lung are associated, as you know, with being exposed to asbestos in the lung increases the likelihood. I know chloride, which is found in the chemical factories down in the south part of our country cause an increase in hemangiocarcinomas of the liver, dyes such as aniline dyes used by the Germans are associated with an increase in bladder cancer and you already discussed pesticides which are associated with an increase in lymphomas and leukemias.

Now viruses, again, you did discuss this a bit. Epstein-Barr is associated with lymphomas as you know. Papilloma viruses in the cervix cancer. Hepatitis B with hematoma, again, the most common cancer in the world, HIV, lymphomas and Kaposi’s sarcoma as we’ve already discussed.

The family physician is in a unique position to detect cancer based upon the evaluation of the family history, particularly as regards to breast, colon, endometrium and ovary. In the colon, we have approximately three types. As you know, familial polyposis in 100% of these patients eventually, ulcerative colitis in 25% over 25 years and this has to be a constant exposure. It can’t be just sporadic in order for it to be a real factor in this problem. The family cancer syndrome in 50%.

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