Browse Author: David B.

Other chemotherapies

Other chemotherapies have been looked at. Suffice it to say that all these really do not have much activity except cisplatin, and I’ll show you a recent study that suggests that there is synergism with Adriamycin. Other drugs, actinomycin-B, vincristine, VP-16, are really used more for the small round cell sarcomas, Ewings sarcoma and rhabdomyosarcoma, which we see more in kids. Now this is a recent study out of Czechoslovakia which was randomized, looking at the use of epirubicin and Adriamycin derivative, versus epirubicin and platinum and as you can see, looking at the response rates, there are almost double for platinum and epirubicin.

So you are going to see, in the next few years, in addition to ifosfamide and Adriamycin being used, sometimes having cisplatin incorporated in the studies as well. There are many new agents. Most of these agents have not panned out. We do have the liposomal doxorubicin compounds. The initial studies have shown very low response rates, but they were all done in patients who were treated with many other treatments. There has been a randomized study done by the ERTC recently which suggests that it may have equivalent activity to Adriamycin, but it had a very low response rate. I think the jury is still out as to whether liposomal doxorubicin can be substituted. So I would, at this point in time, use either Adriamycin or epirubicin, but not one of the liposomal compounds as a standard treatment. Two newer drugs, gemcitabine, appears to have some activity of about 15-20% and there is one single study from the Dana Farber that was presented at ASCO that suggests that Navelbine may have a small amount of activity, specifically in angiosarcomas.

When we combine treatment; an older study from intergroup comparing Adriamycin/DTIC to the MAID regimen, which was the standard regimen in the 80’s and early 90’s. As you can see, the response rate was higher but there was no difference in survival. This study sort of suggested that in older patients and those patients with low to intermediate grade tumors, you are probably just as well off to use Adriamycin and DTIC, which is less toxic and you can always give ifosfamide afterwards rather than combining all three drugs.

The ERTC did a study comparing Adriamycin, Adriamycin/ifosfamide to the old 5A/DIC regimen of M.D. Anderson. Again, no difference in response rates, survival is the same. They then increased the dose of Adriamycin up to 75 and added a growth factor and showed an increase in the response rate. More recently they did a randomized study of this dosage versus this dosage, where there was an increase in the Adriamycin alone but a very low dose of ifosfamide, and showed no difference in survival. The group at M.D. Anderson has then given much higher doses of Adriamycin and ifosfamide, and you can see here that the dose of Adriamycin is up to 75 mg per meter squared, but ifosfamide is given at 10 gm per meter squared.

They have really obtained the highest response rates for the treatment of sarcoma. Many institutions now, including our own, tend to use this A/I regimen at a dosage of either 9-10 gm per meter squared of the ifosfamide plus Adriamycin with growth factors. In terms of our feeling that these two drugs are the two most active and that adding dacarbazine only adds toxicity without benefit and compromises then the dosages of Adriamycin and ifosfamide that you can use. This is a fairly tough regimen and this was in a group of selected patients with good performance status, under 65 and have had radiation to less than 20% of their marrows. Otherwise the patient is going to get marked myelosuppression.

Low grade soft tissue sarcomas

In a randomized study there is no benefit for low grade soft tissue sarcomas. So if you have a patient who has a recurrence or who has positive margins, or close margins, with a low grade soft tissue sarcoma, they need external beam radiation therapy. They should not receive brachytherapy. What has been tried at the NCI and at Howard University, where there is a radiation therapy unit in the OR specifically for retroperitoneal tumors. It’s intraoperative radiation and the problem with that is that there is increased neuropathy with this, despite the fact that you get decreased GI toxicity and local recurrence. In terms of survival, it has not made much of a difference. It’s also extremely expensive to have a unit in the OR. So this really hasn’t fully caught on. This is just a comparison of studies looking at preoperative, postoperative and brachytherapy. As you can see, with limb-sparing surgery that the recurrence rates are from about 5-15%. There can be problems with radiation therapy; severe fibrosis, lymphedema, fracture of the bones, ulceration, poor wound healing, ileus requiring surgery, nerve palsies, loss of functional capacity, decreased fertility if it’s a medial thigh lesion, and development of secondary malignancies – leukemia and lymphomas.

The NCI a couple of years ago did a randomized study of 91 patients who were randomized to adjuvant radiation therapy or no adjuvant radiation therapy after surgery, and the median follow-up is almost ten years. They found that adjuvant radiation therapy did reduce the local recurrence rate significantly, but there was no difference in overall survival. And it’s not surprising because this is a local treatment, not a systemic treatment. In terms of quality of life; there was significantly worse limb strength and edema and range of motion but there were few effects on daily activities or global quality of life. What they have suggested now; there probably are a selected group of patients, even with sarcomas – maybe more superficial high grade sarcomas – that have a low risk of local recurrence and do not require radiation therapy. If you look at this month’s JCO, the October issue, there is another article from the Dana Farber group emphasizing this as well, in a small group of patients who also just had limb-sparing surgery without radiation and had a very low recurrence rate of approximately 7%. The problem is to figure out specifically which group of patients that is.

Our next modality is chemotherapy and our three most active drugs are Adriamycin, dacarbazine and ifosfamide. Adriamycin is the active standard. It has a steep dose response, so those patients who have received 40 mg per meter squared versus 50, versus 70 or 75, those patients who received 75 mg per meter squared have a higher response rate. There is dose-limiting cardiotoxicity but this can be decreased if you give it as a continuous infusion over 2-3 days. Dacarbazine has severe GI toxicity but this can be reduced also by giving it as a continuous infusion, and it has significant activity in both extremity and specifically uterine leiomyosarcomas, not GI leiomyosarcomas. Ifosfamide is the new kid on the block. It has at least equivalent activity to Adriamycin. It is superior to Cytoxan. There is no cross resistance so those patients who received Cytoxan can respond to ifosfamide. Those patients who have failed other regimens have about a 25% response rate. There is also a dose-response curve for ifosfamide, and you want to give at least the minimum of around 8-9 gm per meter squared. If given alone, we usually give about 12-14 and those patients who have received around anywhere from 6-10 gm per meter squared in a regimen where they have received chemo along with the ifosfamide, can then respond afterwards approximately, about 20-30% of these patients, to higher dose single dose ifosfamide at a dose of 14 gm per meter squared. It is schedule-dependent, and the group at M.D. Anderson has felt and shown that giving it as a bolus of 2-4 hour infusion appears to have a higher response rate than giving it as a continuous infusion. There is significant activity for synovial cell. You need to be aware that there are not only problems with myelosuppression but you also need to watch the kidneys well because the patients, some of these patients, can develop RTA and you also have to be aware of the encephalopathy, which can sometimes be very concerning for the patient, the family and the physician. But it usually goes away in about 3-4 days. We can treat it with either methylene blue or Valium. If you are going to treat it with methylene blue you want to make sure that the patient is not G6PD deficient or else you will have a severe hemolytic anemia on your hands.

So what you want to avoid are the surgical errors

So what you want to avoid are the surgical errors. Avoiding the shelling out procedure. If it’s a surprise diagnosis on frozen section, closing up, seeing what the pathology really is, and then probably getting the patient to a center that does a lot of this surgery, to make sure that the margins are documented. So that will help the radiation therapists and help know whether that patient is at high risk for local recurrence. And if the margins are positive, to – instead of going right to radiation – if possible, and especially in an extremity, to consider first doing a re-resection and then consider giving radiation therapy.

Well, what about our next modality, radiation therapy? For the most part, for the majority of times, these patients are going to receive postoperative radiation therapy. This is an adjunct to surgery. It’s usually for those patients who have had limb-sparing surgery with no more than 1-2 cm margins, or less, or where the tumor is adjacent to bone or nerve where you can’t get good margins. We usually give about 6500 centigray; usually about 5000 to the whole tumor and then another 1500-2000 boost. The advantage of this is that the port is encompassed but it is fully defined because you know what the tumor margins are, having gone in. There is rapid surgical recovery and you have a pathology of an un-irradiated specimen, if you are still concerned that you don’t know what the specific histopathology is. But there are other modalities. There is preoperative radiation. The advantage of that is there is a smaller port size. It could inhibit potential metastatic deposits, this could facilitate limb-sparing surgery and increase operability, if this were a very large 15 cm lesion. But the problems with it is that you may have to delay surgery, there may be problems with wound healing, and in a prospectively randomized study by the NCI of Canada recently finished, comparing preoperative to postoperative for extremity lesions, there was about twice the amount of wound complications. In terms of survival, how the patients did in terms of the amount of limb-sparing surgery that was performed, there was no mention of that and the numbers that were included in the study were probably not large enough to give us a definite answer for that.

What’s been popularized by the Memorial Sloan-Kettering Cancer Center is brachytherapy and that’s because many of their patients come from a very far distance. So they were trying to get away from having to keep the patient after surgery for another five, six, seven weeks of radiation therapy. So they popularized the use of brachytherapy. The value of that is, there’s a smaller volume treated. It’s usually started on the sixth postoperative day. There is a shorter treatment time, about 4-5 days. It’s cheaper. It’s very good for difficult anatomy where you are concerned about radiation hitting vital structures, or those patients who have had previous radiation where you can’t deliver a high dose of external beam. You need surgical input, detailed planning, and despite its use you sometimes still need external beam radiation in addition.

Other major prognostic factors

Other major prognostic factors are histopathology, and I’ll go over some of these at the end. Lymph node involvement, which is extremely rare, connotes a very poor prognosis. And you can see that with epithelioids, synovial, rhabdo and angio. For the most part though we don’t recommend doing lymph node dissections because for the most part sarcomas do not go to the lymph nodes. Age; those patients under 60 usually do better than over 60. Females, as for most tumors, do a little bit better than males. And then there’s some literature on P-glycoprotein and Ki-67 expression, and aneuploidy. Debatable literature. Ploidy, you can find in both directions, whether it has significance or not. P-glycoprotein is for measurement of MDR and Ki-67 expression, DNA synthesis. Obviously those patients who have a higher DNA synthesis do somewhat worse.

We have two major staging systems for soft tissue sarcoma. One of them is the Enneking system, put together by Dr. Enneking who is sort of the father of orthopedic oncology, who was at the University of Florida. It’s a bi-gradal system; low grade, high grade and then whether the tumor is either intra-compartmental or extra-compartmental, and then if the patient has nodes or metastases they would be stage III. This emphasizes compartmentalization. It is best suited for extremity sarcomas. It’s not good for other areas of the body, and size and depth are not included. It’s the system though that’s probably used the most by orthopedic oncologists. Now our other grading system is the American Joint Cancer Committee system and this again has been changed in 2006 from a tri-grade to a bi-gradal system. Putting well-differentiated and moderately- differentiated in one group, and poorly and un-differentiated in another. But in addition to that, it looks at size – less than or greater than 5 cm – and it also looks as to whether the tumor is superficial or deep. The tumors that specifically we want to look at, that have probably the highest rate of recurrence and where we possibly could look to give adjuvant therapy, would be in the high grades that are somewhat superficial, but more the high grades that are large and that are deep. Those are the ones that have the most potential for recurrence and where we would think possibly of giving adjuvant chemotherapy. Obviously those that do the worst are those who have nodal involvement or metastasis.

Now this is what a typical soft tissue sarcoma looks like, and I put this up to show to you that it’s critically, critically important that you get this patient to a surgeon who knows what they are doing the first time. Many of these tumors, the majority of these tumors, have a pseudo capsule around them and many many a time the patient gets the “oops” procedure. In other words, the surgeon goes in and sees, “Boy that capsule, this is easy. I’m just going to slide it right out” and the tumor is out. Then the pathology comes back and all the margins are positive. And why are the margins positive? Because there are satellite areas of tumor around that pseudo capsule, so you just don’t want to scoop it out. If possible, you want to get a wide excision with at least 1-2 cm of normal tissue around it. When we do a marginal resection, a shell-out, there is about a 90% incidence of local recurrence.

Even with wide excision, there can be about 50% in older series. When we do a radical, it is less than 15%. Sometimes we still have to do an amputation, and this is really based on the biopsy site and the biopsy being done properly, as I said before, whether there is neurovascular or compartmental involvement, the size of the tumor, and what the anticipated function is. If the patient, after the surgery, is left with very poor function then there is no point in doing a limb-sparing procedure. So in terms of surgical treatment, there has been a transition from doing a shelling out, where there is 90% local recurrence, to an amputation, to now limb-sparing surgery plus radiation, where there is about a 5-15% local recurrence rate. In a trial done at NCI comparing limb-sparing surgery plus radiation, versus amputation, there was no difference in survival.

Soft tissue sarcomas

Now we’ll first talk about the soft tissue sarcomas, and these are usually solitary, painless and palpable. The majority occur in the extremities. In the lower extremity, 40% of these are the highest amount and 75% of these are above the knee. They can also occur in the trunk where the most common area is the retroperitoneum, and then also rarely in the head and neck area. In terms of sites and histologies, usually in the extremity its MFH, synovial, lipo and fibro and most of these patients develop lung mets. The tumor usually avoids the liver. In the retroperitoneal area, lipos, leiomyosarcomas, there’s intraabdominal spread as well as liver and lung mets. In the chest wall, desmoid, lipo, leiomyo. The GI tract, leiomyosarcomas and then the newer-named GI stromal and GI autonomic tumors, which are extremely resistant to chemotherapy. In the GU tract, leiomyos and mesodermal mixed. Now what’s extremely important when you first see these patients, especially if this is an extremity sarcoma, is that you obtain the tissue in the right format. It’s really recommended that if possible you refer these patients to surgeons who have experience in doing the ultimate procedure. Really, if you are going to do a biopsy, you want to do an incisional biopsy, not an excisional biopsy unless it’s a very small lesion. And you want to make sure that the plane of that dissection is longitudinal to the muscle and not perpendicular. If you have the facilities, probably now at most major centers the majority of biopsies are done as a core true cut. I would say at our center about 95%, 98% of our biopsies are done by our radiologists. The advantage to that is that under CT guidance they can hit different areas of the tumor, because sometimes some of these tumors have necrotic areas and you may get no tissue or you may get a low grade tissue in one area and a high grade in another.

This is a study, an old study. There have been two other studies more recently. One from our institution, one from Memorial, looking at the value of core and needle biopsy compared to FNA. And you can see there is a much higher sensitivity, specificity and accuracy. Really it’s recommended to get at least three core and needle samples. We usually only use FNA’s to confirm a recurrence. Because it’s real important not only to determine, if possible, the exact histopathology of the sarcoma, but also to determine the grade. What’s critically important also is that you have a pathologist who has some experience in reading these and has some familiarity with the different immunohistochemical stains. You need to be aware that for some of these, in terms of helping delineating the type of sarcoma you are dealing with; angiosarcomas having CD34 factor 8; leiomyosarcomas having desmoid muscle-specific and smooth muscle actin; Ewings sarcoma having HB71013. None of these are absolutely specific but they can be very helpful in delineating the type of sarcoma you are dealing with. In addition, more recently now, there have been several different fusion genes based on different translocations that have occurred for some of these sarcomas, that are fairly diagnostic. One of them being the translocation of 11-22 for Ewings or primitive neurectodermal tumors. Also for synovial sarcoma, a translocation of X and 18. Looking at SID and SS-1 and SX-2 and we have found now that not only can these be somewhat diagnostic for diagnosing the sarcoma, but in this instance with synovial sarcoma it can tell whether you are dealing with a biphasic or a monophasic tumor. The biphasic being SS-1, the monophasic being SX-2 And not only is it helpful in delineating that but also in prognosis. The monophasic tumor being all spindle cell, having a much better prognosis than a biphasic tumor where there is an epithelial component as well.

Now what do we do in terms of a work-up? Well, first of all we want to find the local extent of the tumor and probably the best test for extremity, trunk and head and neck is an MRI. But in addition to that, if it’s in the retroperitoneal area or an intraabdominal sarcoma, we want to get a CT because we want to look at the abdominal contents and also evaluate the liver where the tumor can metastasize to. Then in addition, for all these sites, they have the potential to metastasize to the lung. So we want to get a chest CT as well. Now there are several major prognostic factors. Histologic rate is extremely important. Low grade tumors tend to stay locally, tend not to metastasize, tend to have a much better prognosis. We need to know the extent and location of surgical margins and those should be delineated by the surgeon. We want, if possible, to get margins of at least 1-2 cm. That is not always possible, depending where the tumor is. It’s much harder if it’s in the retroperitoneal area, much easier in the extremity area. Size becomes important. Those tumors greater than 5 cm and even greater than 10 cm are much more likely to recur and have a worse prognosis. The primary site becomes important. Distal tumors usually do better than proximal tumors, they are picked up earlier, usually easier to resect. Those tumors that are subcutaneous usually do better than deep. Those tumors that are intra-compartmental usually do better than extra-compartmental. Those tumors that are in the extremities usually do better than the trunk, and head and neck usually do better than the retroperitoneum. Retroperitoneum tumors are usually picked up late because they are usually very big, the patient doesn’t have any symptoms, then once they are picked up they are usually very near vital structures and it’s very hard to do an adequate full resection to remove all the tumor. In fact, for most patients who are at major centers getting surgery for retroperitoneal tumor, approximately 75% of the time a vital organ or part of a vital organ has to be removed in addition to the sarcoma.

Sarcoma

Sarcoma
A sarcoma (from the Greek ‘sarx’ meaning “flesh”) is a cancer of the connective or supportive tissue (bone, cartilage, fat, muscle, blood vessels) and soft tissue. This is in contrast to carcinomas, which are of epithelial origin (breast, colon, pancreas, and others).
Sarcomas are quite rare tumors, tumors that you don’t see that often. There are approximately 7,800 soft tissue sarcomas occurring in the United States, and this is about equivalent to the number of non-Hodgkin’s lymphomas, a little bit more than Hodgkin’s disease, but it’s a much rarer tumor than colon, lung, breast which are 170,000 to 180,000 a year. There can be the classical type of extremity and trunk, visceral involving the GI tract the GU tract, also KS and mesothelioma, and then even rarer are the bone sarcomas, approximately 2,600. The major one being osteogenic sarcoma but also chondrosarcoma, Ewing’s and MFH of bone. Although these tissues arise from about 75% of the average body weight, the just represent less than 1% of all adult and 15% of pediatric malignancies.

In terms of etiologies, exposure to radiation is certainly a cause of the development of sarcomas. Anywhere from 2000 to 7800 centigray and mostly we see osteogenic sarcomas, but also MFH, angio and fibrosarcomas. There is literature on chemical exposure and this comes from Vietnam and also from the farm belt in which exposure to herbicides and dioxin and oxyacetic acid can increase your chances of developing sarcoma. But there is quite a lot of debate in the literature about this. Also exposure to vinyl chloride and arsenic evolving into an angiosarcoma. Patients who’ve had renal transplants, chronic lymphocytic leukemia, autoimmune hemolytic anemia, can develop Kaposi’s. Then in terms of viral etiologies, the Kaposi’s sarcoma virus, HHV8, and also some literature looking at Epstein-Barr virus in children. Those children exposed to Epstein-Barr virus having a higher incidence of smooth muscle cell tumors. There is some literature, small usually, case reports of different injuries; scars, burns leading to fibrosarcoma. Implants and bone infarcts leading to osteogenic. There is the postmastectomy lymphedema, Stewart-Treves syndrome in which you develop an angiosarcoma. There’s a higher incidence of osteogenic sarcoma in those patients who have had Paget’s disease, and then certain benign forms of bone disease can also lead to osteogenic sarcoma.

In addition, in terms of genetic predispositions, those patients who have had a retinal blastoma develop about one thousand times more incidence of osteogenic sarcoma, and there is even a further risk if those patients have been exposed to radiation therapy. But you can also develop osteogenic sarcomas outside of the radiation therapy site. Rp53 17P _ in which there is a high incidence of sarcomas, breast, leukemia, brain tumors. The murine double minute 2, which is an oncogene on chromosome 12, and this can inactivate both P53 and a retinoblastoma and therefore gives you similar effects. Neurofibromatosis, a higher incidence when you have both a genetic defect of 17Q, where there would be a higher incidence of neurofibromas, and then adding on the P53 17P with an increased incidence of malignant schwannomas and neurofibrosarcomas. Also with Gardeners, the APC5Q, there is a higher incidence of intraabdominal desmoids.

Off of a clinical trial

Off of a clinical trial, what we now recognize, is that there is an intermediate level of hormonal sensitivity that we call, for lack of a better term, androgen- independent-but-not-yet-hormone-refractory disease where patients will respond to alternative hormonal manipulations. So typically what we do is, for a patient who is on combined androgen blockade, we will first stop the anti-androgen, Casodex or flutamide, because in about 25-50% of patients with stopping that drug the patients will go into a remission, generally of short duration. The mechanism here is not completely known but it is felt to be mutations that occur within the androgen receptor that allow the androgen receptor to become somewhat promiscuous and be stimulated by the anti-androgen. When you withdraw the anti-androgen, those clones will die off and that’s what one see clinically.

Next, one can introduce an alternative anti-androgen, specifically high dose Casodex or flutamide, and one can see patients respond, interestingly, to an alternative anti-androgen when the other anti-androgen was used. And finally, one can use an anti-adrenal agent. My drug of choice here is ketoconazole or Nizoral, which is tolerated by most but not all people. Some develop fatigue or GI symptomatology. In general, one can use 200 mg three times a day of this drug, although higher doses have been used with greater toxicity. If one tells the patient that one should take it without an H2 blocker on an empty stomach, one can get by with lower doses because one needs acid in the stomach for adequate absorption of ketoconazole. Aminoglutethimide has been used but it has greater toxicity than ketoconazole but similar response rates.

Now what about chemotherapy in this disease? Chemotherapy had been felt not to be very active in this disease for many years as a result of pilot studies, phase II studies, randomized studies, etc. until this study was done. Very clever study done by Ian Tannic and his colleagues in Canada. A study that looked at quality of life as its primary endpoint, in 161 patients with symptomatic advanced prostate cancer. Patients were either treated with 10 mg of prednisone per day or alternatively with prednisone plus mitoxantrone at 12 mg per meter squared every three weeks. Once again, primary endpoint was pain palliation. What they found was there was a difference in the rate of pain relief and the duration of pain relief, both of which were statistically significant. Another study that we did in parallel to this study in CLGB, almost 250 patients randomized to hydrocortisone plus mitoxantrone or hydrocortisone alone. Unfortunately we looked at survival as a primary endpoint. No difference in overall survival but we also tallied quality of life endpoints and in this particular study we did see a difference in quality of life associated with mitoxantrone. So on the basis of this study and the Canadian study, mitoxantrone was approved as a first chemotherapy drug for use as palliation in patients with advanced prostate cancer. Since that time, we’ve recognized that the old drug, estromustine – which was initially made as a designer drug to be targeted to hormone sensitive cells deliver a nitrogen mustard – very modest activity by itself but when combined with microtubule inhibitors generated response rates that were very respectable. With 50% reductions in PSA seen in over 50% of patients.

So these remain the most active regimens and are now being used clinically but have never been compared to either mitoxantrone/prednisone or to no therapy, and there have been no chemotherapy agents or regimens that have ever been demonstrated to improve survival in this disease. Although we do suspect at the present time that if one did a randomized study using Estromustine-based regimens that one would see a benefit in survival. So in summary, with regard to chemotherapy, mitoxantrone is used in this context for palliation. Estromustine-based regimens have greater activity but we are still uncertain, in terms of their impact in overall survival – since no randomized studies have yet been done – and certainly no randomized studies have yet been done in the context of earlier disease using chemotherapy, although those are planned now as well. Clearly we have to move beyond chemotherapy in this disease and there are a number of strategies, experimental trials, in the clinic right now that offer potential for exciting advances in this disease.