written and compiled by doctordee August 2002
|Search LMS site|
|Why Choose Chemotherapy?|
Tumors that are chemotherapy or radiation sensitive can be cured by these methods. Some examples are Hodgkin's Lymphoma, and Acute Lymphocytic Leukemia in children. LMS is not curable by chemotherapy or radiation. And sarcomas, as a group, are relatively resistant to chemotherapy and radiation, although there is variation within the group. There is even variation within the group of leiomyosarcoma tumors, as to response to chemotherapy and/or radiation.
Surgical resection with clear margins is the gold standard of treatment for Leiomyosarcoma. For LMS, chemotherapy and/or radiation will not bring a cure, but can sometimes bring a remission, or will enable surgical resection.
One considers chemotherapy in the following situations:
The targeted molecular drug that will cure or control our LMS may be announced next month. It is worthwhile hanging in there, troops.
Adjuvant Chemotherapy while in Remission
To have it or not to have it, That is the question.
Letter from the ACOR LMS List
I have been in your shoes, so I can really empathize with your dilemma. After my first recurrence I had radiation, no chemo because there was nothing left to measure success or failure by. Second recurrence, no one wanted to do surgery so I had chemo. I still have the original abdominal tumor diagnosed in 9/01, plus lung mets. I developed two new lung mets while on chemo. I had Doxil (2 cycles) and Adriamycin and Cisplatin (3 cycles). It didn't seem to do anything but make me sick, so I am off chemo for the summer. If my Sept. scan shows significant growth I will try Gemzar, but in the meantime, my body is resting. I am inoperable. Chemo is my only weapon at this point.
YOU are not in that position right now. YOU have no active tumors. YOU have no symptoms. YOU can make the decision. If you have another recurrence it may be resectable. Surgery is definitely a better option than chemo if you have the choice. Why the rush? I'd prefer to hold the chemo for when I REALLY needed it. Chemo resistance develops in tumors. You don't have life-threatening tumors, so why burn up your chemo options now?? Some also have lifetime maximums. Food for thought. In your shoes, I personally would opt for regular scans and deal with what comes up when it actually is there to assess. I haven't seen much to prove that adjuvant chemo extends your life. Having taken "industrial strength" chemo and being pretty miserable, I wouldn't do it unless and until I absolutely had to. Then, I would gladly take it if it would help extend my life. No one can decide for you. It's a tough call, but trust what you have learned and how you feel about this treatment option at THIS time. Ask for research that proves scientifically that adjuvant ifosfamide will help you long-term. My best wishes to you.
[Recurrent uterine primary, Stage 4b, dx 8/96, total hysterectomy, recur 1/00, surgical removal of two large tumors and a foot of colon, 5 weeks of twice a day external radiation, 3 sessions of high dose internal radiation, recur 10/01, 6 cm tumor, Doxil 11/01 -1/02 no shrinkage, too much toxicity, new lung mets 1/02, 3 rounds of Adriamycin and Cisplatin, all lung mets inoperable]
Chemotherapy and De-differentiation
[For further explanation of de-differentiation see the web page "Testing Your Tumor" on this site.]
Differentiation is the process by which the original fertilized egg, and its descendants, change from being identical to each other to being different...e.g. hair follicle cells and muscle cells and nerve cells and blood cells... and so on. Differentiation refers to the process by which the cells become different from each other as they become more sophisticated, specialized types of cells.
In a cancer tumor, as the cancer cells accumulate more and more mutations, the specialized nature of the original cell is lost. For instance, if it originally had an estrogen receptor on its cell membrane, often that receptor is lost. The cell with more and more mutations loses its abilities because of those mutations, and becomes less specialized and more primitive. And as more and more damage accumulates, the cell becomes more and more primitive, aberrant, and bizarre. This process is called de-differentiation. It occurs in all cancers, it is inevitable, and it is a function of time, as it takes time to accumulate the mutations. It will usually occur more quickly in tumors with high reproductive rates, and can be hastened by chemotherapy or radiation. It might result in tumors that suddenly grow uncontrollably - even while being treated with chemotherapy AND radiation.
Treating LMS tumors with radiation or chemotherapy might increase de-differentiation in the surviving tumor cells. If LMS is treated by radiation or chemotherapy, there will almost always be surviving tumor cells. Increased de-differentiation could possibly result in aggressive, fast-growing LMS tumors, utterly unresponsive to chemotherapy or radiation. This is one of the risks of treating LMS tumors, and another reason to perhaps limit chemotherapy and radiation to specific situations where the benefits are clearly apparent, or clearly life-preserving. In other words...stop the cascade of metastases, and deal with later de-differentiation problems when and if they occur-LATER. Shrink the tumor so it can be surgically removed, and deal with late effects-LATER. Use the chemotherapy agents one by one, palliatively, to extend survival time. By all means, USE chemotherapy when it is clearly of proven benefit. But be aware that everything has a price, and increased de-differentiation may be part of the price for chemotherapy usage.
Choosing A Chemotherapy Agent
Of the traditional chemotherapy agents, doxorubicin, ifosfamide, and dacarbazine are the most effective against LMS. They are toxic. Ifosfamide MUST be given with mesna to protect the urinary system, and doxorubicin has a lifetime limit, because it destroys heart muscle. They both affect the bone marrow badly. Their response rate, if used as single agents, is in the late teens**, with very few if any complete responses. Their median response duration is often in months. If it is possible, testing of the tumor for resistance to these agents might be worthwhile before using them, because of the drug toxicity.
**[The clinical trials that established the rates of response for doxorubicin and ifosfamide included patients with GIST, previously included as a type of Gastrointestinal LMS. GIST tumors are often completely resistant to chemotherapy agents, and carried a high death rate. With the advent of Gleevec, GIST patients are no longer routinely categorized as LMS tumors. With the elimination of GIST patients from LMS clinical trials, reported response rates and survival rates will rise.]
The idea behind the AIM regimen [adriamycin, ifosfamide, mesna] is to increase the response rate by using both agents, and the rate does go up to around 30%. However duration of response and quality of response is still poor. The MAID protocol adds dacarbazine to the previous cocktail. There is no increase in survival time, but there is an increase in toxic side effects. Combinations are justified in situations where a quick response is imperative: to deal with life-threatening situations or with severe pain. If your local oncologist is recommending a combination of chemotherapy agents for you, obtain a second opinion from a sarcoma oncologist.
"The choice of combination chemotherapy versus sequential single agents is also quite controversial. Randomised prospective clinical trials on combination chemotherapy regimens such as MAID (mesna, adriamycin, ifosfamide, dacarbazine) and AIM (adriamycin, ifosfamide, mesna), have shown these to yield statistically improved rates of objective antitumour response. However, these do not translate into improvements in survival, and come at the cost of added toxicity and a decrease in quality of life. There is therefore good reason to choose sequential administration of active chemotherapy agents, to maximise the time of tumour control, and to minimise treatment-associated side-effects. The exception to this is the preference of most physicians for combination chemotherapy in patients with acute pain or an immediate life-threatening problem (e.g. impending bronchial obstruction); in such cases, the greater likelihood of objective response would be worth the increased toxicity of combination therapy in an otherwise healthy patient for whom such aggressive therapy would be reasonable." 
"Local instillation of chemotherapy, such as infusion into the peritoneal cavity as treatment for intraperitoneal STS, remains popular in certain centres. However, such local infusional therapy has never been shown to be superior to systemic administration of chemotherapy in any clinical trial. " However, there may be a place for Intraperitoneal Hyperthermic Chemotherapy. See the web page on Hyperthermia on this site.
" There appears to be a relation between the delivered dose of certain drugs, (e.g. doxorubicin and ifosfamide), and objective antitumour response rates. It is unclear whether these responses last long enough to justify the increased toxicities (myelosuppression, mucositis, nephrotoxicity, etc) that accompany therapy at higher doses. Physicians must therefore carefully weigh the available evidence and the therapeutic goals for an individual patient to decide how best to use chemotherapy. There is no global consensus on the best way to apply 'standard' chemotherapy for the management of sarcomas."
"Certain [sarcoma] subtypes have virtually no chance of major clinical response to conventional cytotoxic therapies, so whenever possible, these patients should be offered treatment with promising new agents in clinical trials. Included in this category of sarcomas with primary chemotherapy resistance would be most non-uterine leiomyosarcomas."
NOTE 1: Newer agents such as Temozolomide, Gemcitabine, Navelbine and ET-743 are useful, but also do not cure LMS. Doxil, a much less toxic form of doxorubicin than Adriamycin, is not widely tested yet.
NOTE 2: All chemotherapy agents are cell poisons. Side effects vary from agent to agent and person to person, but there are good medicines to control diarrhea, vomiting, and other side effects. These medicines make a big difference.
 Singer, S, Demetri, GD, Baldini, EH, Fletcher, CDM. "Management of Soft-tissue sarcomas: An Overview and Update". Lancet Oncology. Oct 2000
Updating Chemotherapy Response Rates
There have been cases where people with high grade tumors live a long time, and those with low grade tumors died first.
LMS survival is often a game of inches, and very unpredictable.
There is no question that some LMS is partially responsive to chemotherapy, and that the people with chemotherapy-responsive LMS have longer survival times. While chemotherapy is not a cure for LMS, it can extend survival considerably...and a cure or more effective management may be around the corner with a new drug. I think you need to have some additional information about chemotherapy.
Firstly, when the clinical trials for doxorubicin and ifosfamide were run, patients with GIST were included in the clinical trials as gastrointestinal [GI] LMS. Now GIST, currently treated with Gleevec, was often unresponsive to ANYTHING. So there was a wrongly lowered response rate [because of an inappropriate tumor being included.]
Secondly, many studies reported results as "remission" or "partial response" [greater than 50% shrinkage]. Stable disease was not always reported. The phenomenon of tumor death but no apparent shrinkage was not catalogued.
Thirdly, we all know that LMS sends tendrils out into normal tissue, beyond the periphery of the apparent tumor. It was unknown what chemo does to these tendrils... even with no apparent response. It is thought that the tendrils are badly beaten back, making pre-op chemo a way of possibly getting better clear margins.
Dacarbazine, Ifosfamide, and Doxorubicin are the classic chemo agents, and their clinical trials with LMS response rates run about 20% with all the caveats above, so the actual response rate is probably significantly higher.
Some of the newer chemotherapy agents, gemcitabine + taxotere, and temozolomide, may have response rates of about 50% for Uterine LMS... but not a long response interval for everyone. But for a median survival of 5 months, half of the people have a LONGER survival... possibly a year or more. Navelbine and ET-743 are other agents with some activity against LMS.
Aggressive metastasectomy, and careful and discriminating use of chemotherapy and radiation for control and neoadjuvant treatment, have extended the survival time of LMS patients with active disease. Some LMS survivors hit 20 years, but it is not unusual for people to survive 7 or 9 years with high grade tumors.
So your wife has a much better chance than you think.
Take her out to lunch today and celebrate that you are both alive and in love.
Do not prepare for the funeral right now, but rather live well and positively. GET PSYCHOLOGICAL SUPPORT. I URGE you. It made all the difference to me. Studies have shown that it increases survival time in other cancers.
|Late Effects of Chemotherapy|
For people taking chemotherapy, there are EARLY side effects, which are the direct effects of the agent upon body tissues. These tissues either die, or recover from the effect of the chemotherapy completely, or somewhat. For instance, early side effects for many chemotherapy agents are known to be nausea and vomiting, diarrhea, hair loss, and so on. These are symptoms which are temporary and which go away. The tissues involved might be damaged somewhat, but recover sufficiently to function well.
Other side effects may involve bone marrow destruction, or specific damage to certain organs [like the heart for doxorubicin, or the urinary tract for ifosfamide, or lungs or liver for gemcitabine.] These effects may be permanent. Sometimes these effects will show immediately, and the agent is stopped. However, sometimes the damage is not so great, but as time goes on and the normal aging of tissue occurs, the damage becomes more apparent because the organ's reserve is gone.
LATE effects [the euphemism for permanent damage and further risks which may not be apparent at the beginning] can be from tissue damage that is subtle, and take longer to show itself. The heart failure from doxorubicin's destruction of heart muscle does not show early on. Pulmonary fibrosis from BCNU is a late effect. Myelodysplasia [failure of bone marrow to produce enough blood cells] and secondary cancers [often leukemia] from chemotherapy, as well as the cognitive late effects are described in separate sections below.
Additionally, each chemotherapy agent has its own spectrum of possible late effects/permanent damage. If these are known, they are listed in the package insert for the agent. One should be aware of these, so that if there are related early side effects, they are quickly noticed and the agent stopped.
Chemotherapy Damage to Bone Marrow
I cannot emphasize enough, how the number of toxic treatments is limited because of cumulative bone marrow damage, and how LMS is radiation and chemotherapy resistant.
Myelodysplastic [pronounced MY-eh-low dis-PLAH-stik] Syndromes are conditions that affect the bone marrow. Myelodysplasia simply means that the bone marrow isn't growing right.A syndrome is a collection of symptoms that are associated with each other frequently. A viral syndrome would consist of runny nose, sore throat, etc. So Myelodysplastic Syndromes would be the symptoms that would come from the bone marrow not working well.
The bone marrow makes blood cells:
Myelodysplasia is caused by damage to the stem cells of the cell line[s] affected. The stem cells are the parent cells of the cells that are eventually released into the blood.
Patients treated for cancers with high dose radiation have a higher incidence of therapy-related Myelodysplastic Syndromes [MDs]. Alkylating agents used in chemotherapy are known to induce [MDs]. There are other causes, too, but these are two causes that are important to the LMS list.
If the red blood cell line is affected, the patient becomes anemic, and requires transfusions. Eventually there is an iron build up in the body, called hemosiderosis, which can cause further problems to liver, heart, and other organs. If the white blood cell line is affected, the patient is more prone to get seriously ill with infections. Sometimes some of the white cell line transforms to leukemia. If the platelet cell line is affected, the patient is prone to hemorrhage, and internal bleeding.
The progress of Myelodysplasia depends upon which cell lines are affected and how badly, and whether leukemia develops. The incidence of Myelodysplasia Syndromes will be high in treated LMS survivors, because of the many courses of high dose chemotherapy and radiation treatment that were necessary. Because cancer treatment kills cells that are dividing quickly...cancer treatment often kills many normal bone marrow cells. Protective medicines like mesna, amifostine, and dexrazoxane may prevent some of the damage done to normal tissues by chemotherapy. Colony-stimulating factors (CSFs) are administered after chemotherapy to rescue the bone marrow and stimulate bone marrow recovery; use of these agents has facilitated the intensification of chemotherapy and has significantly lessened the damage from chemotherapy to normal cells. Both leukin and neupogen are used to increase the number of white blood cells that fight off bacteria. Leukin or neupogen are given to increase the white blood cell counts [so that the patient is less likely to get infected] and they affect different cell lines. There is no indication at this time that one is necessarily better than the other. Procrit (epoetin) is used to increase the red blood cell count. There is also a colony stimulating factor that has been developed for the platelet line of cells. These are normally given during the first two weeks after chemo, by injection. The neupogen may cause achiness that may be helped by taking Tylenol or Panado beforehand and by administering the neupogen at room temperature.
Search Pubmed for: myelodysplasia and cancer
ChemoBrain & Chemotherapy-Induced Menopause and Andropause
Cognition is the ability to think. It includes being able to concentrate, and to remember words and events. Chemotherapy agents can create difficulties in thinking - cognitive deficits -- in the patients who take them. This issue has not been identified clearly nor studied comprehensively. It is a probable late-effect from the use of chemotherapy, and probably more evident in high-dose chemotherapy.
Lack of estrogen will also cause some deterioration in cognitive function in women. Tamoxifen, aromatase inhibitors, and other agents that block the estrogen effect, will allow the cognitive defects related to estrogen depletion to occur. Estrogen has shown to cause improvement in cognitive function in women.
Most chemotherapy agents will induce temporary or permanent menopause in women, as the chemotherapy agent also affects the ovaries. Menopausal symptoms and risks will become applicable. Perhaps the most noticeable will be the hot flashes [vasomotor symptoms] and mood changes.
However, Hormone Replacement Therapy [HRT] may not be the way to go, because of the possibility of:
1. uterine LMS having estrogen receptors and being stimulated by estrogen-containing-HRT
2. the 7.5% of LMS patients who will develop a second primary cancer... the possibility of breast cancer looms.
Note, also, that many herbal or alternative treatments of menopausal symptoms involve plant estrogens [phytoestrogens]. It is unknown but probable that these estrogens of vegetable origin might stimulate LMS tissue that has estrogen receptors. It might be a better choice to go to nonhormonal methods of control of menopausal symptoms [beta blockers, antidepressants, exercise and diet]. For further discussion, go to the webpage on Hormones and LMS on this website.
Chemotherapy also produces temporary or permanent sterility in men, because of the effect upon the testes. If chemotherapy promotes andropause [the male equivalent of menopause, with falling hormone levels and symptoms], then it can also promote cognitive deficits in men secondarily from lowered testosterone or other sex hormone levels.
Chemotherapy can produce a direct effect of cognitive deficit, which might be longlasting. Chemotherapy also, because of direct effects upon ovaries and testes, can produce a secondary effect of cognitive deficit due to low production of sex hormones. This cognitive deficit effect might be reversible.
However, pain, pain medication, anxiety, anxiety medication, depression, depression medication, nausea, anti-nausea medication, fatigue from any cause, anemia, and just feeling awfully sick - any one of these can cause difficulties in thinking and remembering.So chemotherapy is not just chemotherapy, there are a lot of other things that can go on.
Best advice is to take care of yourself, get adequate rest and proper diet, and not to make major decisions while undergoing chemotherapy. Do what you can, but do not stress yourself. READ the National Cancer Institute [NCI] publications about chemotherapy and what to do during it. They are linked in the Before You Start Chemo Read This Section on this page
Search PubMed for: Cognitive function and estrogen
Search PubMed for: Cognitive function and andropause
Search PubMed for: Cognitive function and chemotherapy
ChemoBrain Discussion on the ACOR LMS Listserv
Ehud is saying his clear mind and memory are not the same as they used to be. Has anyone experienced it?
Ophir- Am I remembering correctly that Ehud has had prior chemotherapies? Sounds like something I remember called chemobrain. Apparently many chemotherapy patients report trouble in memory and thinking abilities following chemotherapy. My grandmother experienced some of this following her chemotherapy for lung cancer. Hope this helps. I know of no cure, but it may make him feel better to know why this is happening.
Melissa in KC
Kathy also has been experiencing some disturbing memory problems over the past year or so. She mentioned it to her oncologist who ran an MRI of her brain. Nothing there explained the problem. She was sent to neurologist who specializes in memory problems and after much testing, blood work, etc., told her that it was due to the numerous general anesthetics she had been given over the past four years. She has never had chemo, but she has undergone seven major surgeries. Apparently these anesthetics can accumulate in your system and cause memory "glitches".
Hi, I almost forgot to write! I also have...... had memory problems, I call them brain farts ! I was going to ask a herbologist the other day what I could do for it .........I forgot..... its terrible. It comes in handy with your kids some time, I'm not your mom !!, I don't have a husband..... ha ha ha ha. I will call today to ask ... if I can remember. and I will pass it on to all of you.. It is interesting about the surgery thing I too have had 4 surg in the past 3 yrs 2 were 2 mths apart..... maybe they didn't give me enough oxygen???? I heard on paul harvy that people who underwent open heart surg had the same problems too but they have not yet discovered the problem... they think they know but I forgot! I am only 42 should it be this bad? I too had a brain scan and they said they did not see anything......Hmmmm maybe that's it ! well let me know what you find out and I will do some investigating on my end.
Tammy Brain farting in Oregon.
[Yo, Tammy Rules! Ed.]
Subject: Re: [LMS] Sti memory problems
I have Sti chemo-brain. I move through the fog of a dull brain, and it seems to be worse than what I experienced with previous chemotherapies. I have no short term memory. Yesterday, I became temporarily confused while driving down a very familiar highway. Well-intentioned people may tell me that they too have forgetfulness. However, I reply that chemo-brain is different than the occasional lapses of concentration that healthy people have. I read recently that c-kit receptor is involved in learning processes. I hypothesize that Sti, by binding to c-kit receptors in the brain, is interfering with my cognitive abilities.
Hello, I have memory problems bad. I cannot remember hardly any of 1998. 1999 a little. Last year through chemo and all, more than any of the other years. There are some years I cannot remember at all. My oncologists said that it should get better within a year after radiation and chemo. It will be a year in August. I have had quite a bit of surgeries myself. I hope this helped and please let your mom know she is not alone out there.
Subject: Re: [LMS] memory problems
I have experienced the same thing.. I thought that the radiation killed brain cells!
Before I started chemo, my onc explained memory problems and 'chemobrain or fog'. Told me that I shouldn't make important decisions without discussing them with someone first.
1. I don't know when chemobrain develops with respect to chemotherapy, but it is possible for late effects to show. Chemotherapy is a major assault on your body, you will be tired & need rest, and be anemic as well, probably.
2. PAIN is a very good reason for people to have difficulty remembering and concentrating.
3. PAIN MEDICATION --even just acetaminophen & codeine--is a very good reason for people to have difficulty remembering and concentrating. [Wheeeeeeeee!]
4. FATIGUE is a very good reason for people to have difficulty remembering and concentrating. It is often accompanied by irritability. I see a lot of infectious mononucleosis relapses, and the main complaint is often "I can't think" or "I'm losing my mind, I snap at everyone" rather than " I'm so tired I can't think straight." [Zzzzzzzzz.]
5. ANEMIA is another good reason.... especially if previous chemo has exhausted bone marrow.
6. Renal problems, or liver problems, or heart problems [he was on adriamycin?] can also present with fatigue...& not being able to think right.
7. The LMS itself can secrete substances that make you feel tired and sick...the mets he already has may be doing so...and being tired and sick doesn't let you think so good either. [is he thirsty? check calcium levels in blood as well as for sugar in urine and blood, hypoglycemia has been known to occur with some tumors.]
8. Sure it's possible that it's brain tumor. but it is so much more likely to be something else...especially since Ehud is not having focal signs...like focal or early morning headaches, or a paralyzed eye or unable to move something, ...stuff like that. He does need to have a neurological exam...and even possibly a scan...but not necessarily a scan...he must be seen by a doctor.
I. Take Ehud to see a doctor who will check for these things.
II. Give Ehud extra B Vitamins [large amounts...high potency tablets...even more than one brand...but the complete range of B Vitamins]. They are harmless [if fingers or nipples tingle, decrease the B6 and the tingle will go away]. B Vitamins are required in excess for convalescence and repair of tissues, especially nerve tissues, brain, liver... The complete B Vitamin range, including folate. Or take 20 to 30 yeast tablets a day. (500gram tablets). Check this with your doctor first.
III. See if Ehud feels better and thinks better when he isn't tired. Instead of taking sugary things when tired, go to bed. I usually put people on bed rest for a week, while we are waiting for the test results.
|Protective Agents Against Chemotherapy and Radiotherapy Damage|
The toxicities of chemotherapy and radiotherapy:
The development of protectants to lessen or eliminate chemo and radiotherapy toxicities on normal tissues without lessening the antitumor effects of the cancer therapy has proceeded apace. The ideal protectant would prevent all toxicity, without affecting antitumor activity, and be easy to administer and nontoxic itself. However, most agents developed to date have a much more narrow spectrum of abilities and properties.
For guidelines for the use of some of these agents, see specific Clinical Practice Guidelines at the American Society of Clinical Oncology website
and/or J Clin Oncol 1999 Oct;17(10)
American Society of Clinical Oncology clinical practice guidelines
for the use of chemotherapy and radiotherapy protectants.
Hensley ML, Schuchter LM, Lindley C, Meropol NJ, Cohen GI, et.al.,
American Society of Clinical Oncology, Health Services Research
Department, Alexandria, VA 22314, USA. firstname.lastname@example.org
[with doxorubicin and epirubicin]
This abstract was edited for copyright reasons.
Cancer Prev Control 1999 Apr;3(2):145-59
Use of dexrazoxane as a cardioprotectant in patients receiving doxorubicin or epirubicin chemotherapy for the treatment of cancer.The Provincial Systemic Treatment Disease Site Group.
Seymour L, Bramwell V, Moran LA. National Cancer Institute of Canada, Kingston, Ont.
1) Should dexrazoxane be used routinely in patients with advanced or metastatic cancer who are at risk of developing cardio toxicity when receiving chemotherapy containing doxorubicin or epirubicin? 2) Do the available data support the use of dexrazoxane when anthracyclines are being used in the adjuvant setting for patients at risk of developing cardiotoxicity?
Clinical and subclinical cardiotoxicity, noncardiac toxicity and impact on efficacy outcomes such as response and overall survival are considered. The evidence supports the use of dexrazoxane to provide protection against the cardiotoxicity associated with conventional-dose doxorubicin in patients with advanced but anthracycline-sensitive cancer, in whom the continued use of anthracycline-containing chemotherapy is indicated in the opinion of the treating physician and who have received 300 mg/m2 or more of doxorubicin. The evidence supports the use dexrazoxane to provide protection against the cardiotoxicity associated with conventional-dose epirubicin in patients with advanced but anthracycline-sensitive cancer, in whom the continued use of anthracycline-containing chemotherapy is indicated in the opinion of the treating physicians. There are no data indicating the optimal cumulative dose of epirubicin at which dexrazoxane should be instituted. For doxorubicin, use of dexrazoxane is recommended after the cumulative dose reaches 300 mg/m2 (i.e., 55% of the recommended maximum). A similar formula could be used for epirubicin, that is, institution of dexrazoxane when the cumulative dose of epirubicin reaches 550 mg/m2, as the recommended maximum cumulative dose in Canada is 1000 mg/m2. Preclinical studies did not show any cardioprotectant effect for dexrazoxane when used with mitoxantrone, and no clinical studies have been done. Therefore, dexrazoxane is not recommended for use with mitoxantrone. There is no evidence for or against the use of dexrazoxane in the adjuvant setting for any tumour type. Because of concerns that dexrazoxane may reduce the efficacy of anthracyclines, and because data are not yet available on long-term toxicities, further studies should be performed before the drug is used in this setting.
Fetch Practice guideline PMID: 10474762
Search PubMed for: Dexrazoxane and Protection in Cancer Situations
Lupron Depot Use
[for protection and preservation of fertility during cancer treatment]
[This abstract was re-written because of copyright. Ed.]
Gynecol Oncol 2001 Jun;81(3):391-7
Use of GnRH analogs for functional protection of the ovary and preservation of fertility during cancer treatment in adolescents: a preliminary report.
Pereyra PachecoB, Mendez Ribas JM, Milone G, Fernandez I, KvicalaR, Mila T, DiNotoA, Contreras OrtizO, PavlovskyS. Pediatric and Adolescent Gynecology Section, Hospital de Clinicas, Universidad de Buenos Aires, Argentina. email@example.com
They studied whether leuprolide acetate [aka lupron depot], a gonadotropin-releasing hormone (GnRH) analog, could protect the ovary during polychemotherapy and thereby protect fertility. The patients were divided into three groups: Group A was a control group of 5 young children who were not given lupron depot. Group B were 12 teenagers with normal menses who received treatment with lupron depot prior to chemo, and monthly injections while on chemotherapy. Group C were 4 teenagers with normal menses who received NO lupron depot. All groups received the polychemotherapy regimens CAVPE, CVPP, ABVD, TAMO, ARA-C, and MTT.
After treatment, Group A patients had normal onset of periods between 12 and 18 years of age, normal menstruation, and normal ovulatory cycles, and three became pregnant. After treatment, Group B patients continued with normal menses, and two patients became pregnant. Group C patients no longer had periods because of decreased estrogen production despite adequate stimulatory hormones. They concluded that GnRH analogs [lupron depot] before and during polychemotherapy protect ovarian function and fertility. A larger study needs to be done. Copyright 2001 Academic Press. Controlled clinical trial
Fetch PMID: 11371127
Search PubMed for: Lupron and Protection in Cancer Situations
Granulocyte Colony-Stimulating Factors
[for increasing White Blood Cells]
See Clinical Practice Guidelines at the American Society of Clinical Oncology
J Clin Oncol 2000 Jul;18(14):2676-84
Randomized phase III study comparing conventional-dose doxorubicin plus ifosfamide versus high-dose doxorubicin plus ifosfamide plus recombinant human granulocyte-macrophage colony-stimulating factor in advanced soft tissue sarcomas: A trial of the European Organization for Research and Treatment of Cancer/Soft Tissue and Bone Sarcoma Group.
Le Cesne A, Judson I, Crowther D, Rodenhuis S, Keizer HJ, et. al., Institut Gustave Roussy, Villejuif, London, United Kingdom. firstname.lastname@example.org
This randomized multicenter study was designed to compare the activity of a high-dose doxorubicin-containing chemotherapy regimen with a conventional standard-dose regimen in adult patients with advanced soft tissue sarcomas 314 patients were randomized to receive a standard-dose regimen (arm A), containing doxorubicin (50 mg/m(2) on day 1) and ifosfamide (5 g/m(2) on day 1), or an intensified regimen (arm B), combining doxorubicin (75 mg/m(2) on day 1), the same ifosfamide dose, and recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF; sargramostim, 250 microgram/m(2) on days 3 to 16); all courses were repeated every 3 weeks.
Thirty-eight percent and 23% of patients presented with leiomyosarcomas and liver metastases, respectively. Objective responses were observed in 31 (21%) of 147 assessable patients in arm A and in 31 (23.3%) of 133 in arm B (P =.65). No change was observed in 41.6% and 46.2% of patients in arm A and B, respectively. Progression-free survival (PFS) was significantly longer in the intensive arm (P =.03). The median duration of the time to progression was 19 weeks in the conventional arm and 29 weeks in the intensified arm. There was no difference in overall survival (P =.98) between the two therapeutic arms. Toxicities were manageable in both arms. A grade 3/4 neutropenia and infection occurred in 92% and 4.6% of patients in arm A, respectively, and in 90% and 16.6% in arm B, respectively. Grade 3/4 thrombocytopenia was more frequent in arm B. CONCLUSION: The use of rhGM-CSF allowed safe escalation of chemotherapy doses. Despite a 50% increase of the doxorubicin dose-intensity, the high-dose regimen failed to demonstrate any impact on survival in patients with ASTS. The low complete response rate, the high incidence of leiomyosarcomas, and liver metastases may in part explain these results. However, the lengthening of the PFS in the intensive arm, because of the quality of stable disease and inappropriate tumor evaluation policies that potentially lead to an underestimation of antitumor activity, does not definitively refute the use of a high-dose chemotherapy regimen in selected patients with ASTS. Clinical trial, phase iii Multicenter study Randomized controlled trial
Fetch PMID: 10894866
Ann Pharmacother 2001 Jan;35(1):92-108 Comment in: Ann Pharmacother. 2001 Jan;35(1):120-2
Efficacy of colony-stimulating factors in acute leukemia.
Holdsworth MT, Mathew P. College of Pharmacy and Department of Pediatrics, University of New Mexico, Albuquerque, NM 87131-5691, USA. email@example.com
A comprehensive medical literature search was done to evaluate the literature describing the safety and efficacy of the hematopoietic colony-stimulating factors (CSFs) for the management of treatment-related adverse effects in patients with acute leukemia.
The published studies document a decrease in the time to recovery from neutropenia when patients with acute leukemia are treated with a CSF. However, a consistent reduction in infectious complications or in the duration of hospitalization has not been demonstrated when a CSF is used for either pediatric or adult patients. Very limited data exist to support the premise that CSFs meet the criteria established by the American Society of Clinical Oncology for demonstrating the value of these agents. Further careful study focused on resource utilization and pharmacoeconomics may help to elucidate how healthcare institutions may most effectively employ CSFs to treat patients with acute leukemia.
Fetch PMID: 11197591
Search PubMed for: Colony-Stimulating Factor use in Sarcoma Treatment
Search PubMed for: Colony-Stimulating Factor use in Cancer Treatment
Amifostine, formerly known as WR-2721, can protect cells from damage by scavenging oxygen-derived free radicals.
This drug arose from a United States Army nuclear warfare project was selected from more than 4,400-screened chemicals because of its superior radioprotective properties and safety profile.
Subsequently, amifostine was evaluated for its potential role in reducing the toxicity of radiation therapy as well as chemotherapeutic agents that alter the structure and function of DNA, such as alkylating agents and platinum agents. Amifostine has been evaluated as a broad-spectrum cytoprotective agent. Preclinical studies demonstrated the ability of amifostine to selectively protect almost all normal tissues except the CNS, but not cancer tissues, from the cytotoxic effects of some chemotherapeutic agents and radiation therapy.
Amifostine is a prodrug that is dephosphorylated to the active metabolite, WR-1065, by the enzyme alkaline phosphatase. WR-1065 protects cells from damage by scavenging oxygen-derived free radicals, and donating hydrogen to repair damaged target molecules. The ability of WR-1065 to be taken up in higher concentration in normal organs than in tumor tissue is how amifostine accomplishes selective protection. Essentially the uptake of WR-1065 depends upon differences in the tissue microenvironment, resulting in the slow entry of the free thiol into tumor masses.
Tumors have a relatively poor blood supply, resulting in tissue hypoxia, anaerobic metabolism, and a low [acidotic] tissue pH. The combined poor blood supply and low pH results in low rates of amifostine activation by alkaline phosphatase. Also, the distribution of alkaline phosphatase in normal and malignant tissue differs, with higher concentrations of this enzyme found in capillaries and arterioles of normal cells and lower levels of alkaline phosphatase found in tumor tissue. So selective protection is afforded normal tissues by reduced tumor metabolism of amifostine to the active protector WR-1065, and low tumor uptake of WR-1065.
The result can be as much as a 100-fold greater steady concentration of the free thiol into normal organs [e.g. bone marrow, kidney, salivary glands, heart] compared with tumor tissue. Once the free thiol WR-1065 has entered a normal cell, it can bind to the active agents [e.g. alkylating agents, platinum agents, or ionizing radiation-produced-free radicals] and detoxify them.
Amifostine and Chemotherapy
Amifostine should be administered IV over 15 minutes to patients in a reclining position and should be given within 30 minutes of radiation therapy or chemotherapy. The plasma half-life of amifostine is approximately 1 minute in humans and virtually all of the drug is cleared from the plasma within 10 minutes. Because of the extremely short half-life of amifostine, protection is unlikely against drugs that have a long half-life or that require a prolonged infusion time.
It is not known whether the 740 mg/m2 dose of amifostine is as effective as the 910 mg/m2 dose for protection against chemotherapy-associated toxicity. No additional benefit has been demonstrated to suggest that multiple doses of amifostine given with each chemo dose enhance amifostine effect.
Amifostine may be considered for the prevention of low white cell counts in people who receive alkylating-agent chemotherapy. Alternative approaches to the administration of amifostine to protect against chemotherapy-induced neutropenia include dose reduction, particularly in the absence of a reason to maintain chemotherapy dose-intensity, or the use of hematopoietic growth factors, such as granulocyte colony-stimulating factor or GM-CSF. In addition, close monitoring, and hospitalization if necessary until satisfactory resolution of infection and neutropenia are alternative approaches to therapeutic intervention with amifostine or growth factors or dose reduction of chemotherapy.
Amifostine and Radiation
When given with radiation therapy, the recommended amifostine dose is 200 mg/m2/d given as a slow IV push over 3 minutes, 15 to 30 minutes before each fraction of radiation therapy. Administration of amifostine requires close patient monitoring, but side effects are fewer at this lower dose. Many patients require antiemetics. Blood pressure should be measured just before and immediately after the 3-minute amifostine infusion. The hypotension associated with amifostine at this dose is less frequent but still requires close monitoring.
Radioprotective activity of amifostine has been seen against jejunum, colon, lung, and bone marrow in laboratory and animal studies. A series of clinical studies suggest that amifostine pretreatment is associated with reduced complications from radiation therapy in humans.
Xerostomia [very severe dry mouth] is the most common toxicity associated with radiation treatment to the head or neck. Late xerostomia reflects fibrosis of the salivary gland from radiation therapy and is usually permanent. Xerostomia results in symptoms of a dry mouth; this affects the patient's ability to eat and speak. Additionally, patients with xerostomia are at an increased risk for dental caries, oral infections, and osteonecrosis. Amifostine decreases the incidence of acute and late xerostomia in patients who undergo radiation therapy to the head or neck.
This was paraphrased from an ASCO Special Article: American Society of Clinical Oncology Clinical Practice Guidelines for the Use of Chemotherapy and Radiotherapy Protectants. http://www.asco.org./
Search PubMed for: amifostine and its use in cancer treatments
"Certain [sarcoma] subtypes have virtually no chance of major clinical response to conventional cytotoxic therapies, so whenever possible, these patients should be offered treatment with promising new agents in clinical trials. Included in this category of sarcomas with primary chemotherapy resistance would be most non-uterine leiomyosarcomas." [Singer, S, Demetri, GD, Baldini, EH, Fletcher, CDM. "Management of Soft-tissue sarcomas: An Overview and Update". Lancet Oncology. Oct 2000]
Clinical trials used to develop new anti-cancer agents are labeled as phase I, phase II, phase III and phase IV. Such trials are often performed in patients with metastatic cancer.
Phase I trials are conducted in small numbers of patients to determine a drug's maximally tolerated dose and toxicity/side effect profile.
In phase II studies, the anti-tumor activity of the new agent is tested in different tumor types.
If a drug is found to be promising in phase II studies, in phase III studies it is then compared to standard therapy [randomized trial design].
In phase IV studies, the effectiveness and safety of the drug are tested in a standard clinical setting.
In oncology, phase II studies are also used to evaluate new combinations of previously approved agents.
Fetch PMID: 8853523
Websites with information on Clinical Trials
|Evaluating Chemotherapy Options for LMS|
written by Norman and doctordee
FIRST: Ask your doctor [we hope this doctor is a sarcoma oncologist]:
[Additional questions are listed in the NCI Chemotherapy and You pamphlet available online]
SECOND: Find out about the drugs yourself as well.
Drug information websites
|Before You Start Chemo Read This Section|
Chemotherapy and You. A Guide to Self-Help During Cancer Treatment
NIH Publication #99-1136. Revised June 1999
Oral Complications of Chemotherapy and Head/Neck Radiation (PDQ(r))
There are two versions of this, patient and health professional, and there are tabs so that you can switch between versions.
Best to read the Patient Version first, and then attack the Health Professional Version
Help yourself during chemotherapy
NCI Coping with Cancer Page has listed all of the above plus more and is an excellent site to browse. It lists many of the problems involved in dealing with cancer, its treatment, and its effects on lives.
For more information, call the National Cancer Institute's Cancer Information Service at 1-800-4-CANCER The call is free and a trained information specialist is available to answer your questions. The National Cancer Institute has booklets and other materials for patients, health professionals, and the public. These publications discuss types of cancer, methods of cancer treatment, coping with cancer, and clinical trials. Some publications provide information on tests for cancer, cancer causes and prevention, cancer statistics, and NCI research activities. For more information from the National Cancer Institute, please write to this address: National Cancer Institute Office of Communications 31 Center Drive, MSC 2580 Bethesda, MD 20892-2580
PDQ is a computer system that gives up-to-date information on cancer and its prevention, detection, treatment, and supportive care. PDQ is a service of the National Cancer Institute (NCI). PDQ also provides information about research on new treatments (clinical trials), doctors who treat cancer, hospitals with cancer programs, and addresses the special needs of patients with cancer and their families.
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