In regards to chemotherapy Dr. Myers said that Taxotere is the most effective showing an effect in 40 - 45% of men. When combined with Calcitriol this percentage jumped to 70% with no increase in side effects. About Dr. Charles Myers: Charles E. Myers, M.D., is Founder and Director of The American Institute for Diseases of the Prostate (AIDP) and President of the Foundation for Cancer Research and Education. He is a professor of Internal Medicine at the University of Virginia where he was the Director of the Cancer Center from 1994 to 2001. Dr. Myers is an internationally recognized expert in prostate cancer research and treatment and is well known for his warm, personable style, and his ability to explain technical aspects of prostate cancer and its treatment. He is a frequent and popular speaker at support group meetings such as USTOO, PAACT and Man-to-Man. Dr. Myers is a co-author of “Eating Your Way to Better Health,” and is Editor of the Prostate Forum, a monthly newsletter for prostate cancer patients and their families http://www.hormonerefractorypca.org --------------------------------------------------------------- http://www.pslgroup.com/dg/226622.htm Vitamin D plus Taxotere Title: Combining Vitamin D with Taxotere Provides Benefits for Advanced Prostate Cancer Treatment URL: http://www.pslgroup.com/dg/226622.htm Doctor's Guide January 3, 2003 PORTLAND, OR -- January 2, 2003 -- The addition of high-dose calcitriol to weekly treatment with the chemotherapy agent docetaxel (Taxotere®) appears to improve the therapeutic response in men with androgen- independent prostate cancer without compromising safety, according to results published Jan. 1 in the Journal of Clinical Oncology. Calcitriol is the active form of vitamin D. Data from a phase II clinical trial suggest the combination of docetaxel/calcitriol is as much as twice as effective as the use of docetaxel alone, as measured by prostate-specific antigen (PSA) response rate. The results were so promising that a phase III trial has been launched at 15 sites throughout the United States. "We're excited by these promising results, especially since there is no acceptable standard treatment for this type of prostate cancer," said Tomasz Beer, MD, an oncologist at the Oregon Health & Science University (OHSU) Cancer Institute in Portland, Oregon, and lead investigator of the study. In the study, 31 of 37 patients, or 81 percent, who were treated with the combination regimen cut their PSA levels by more than half. In fact, 59 percent of patients achieved a confirmed PSA reduction of greater than 75 percent. Studies of docetaxel alone have reported a 42 percent PSA response rate. PSA is a substance produced within the prostate gland, and a high PSA level may indicate the presence of cancer. In patients with advanced prostate cancer, PSA correlates with the amount of cancer in the body. In addition to PSA response, eight of 15 men in the study with measurable disease responded with significant reductions of their tumors. "Based on this data we've opened a much larger study nationwide that should tell us whether these preliminary findings continue to hold true in larger patient populations," said Beer. Patients in the study received oral calcitriol on the first day of the treatment cycle, followed by an infusion of docetaxel the next day. The treatment was repeated weekly for six weeks of an eight-week cycle until there was evidence of disease progression or unacceptable toxicity, or until the patient requested to be withdrawn from the study. Calcitriol is not the same as over-the-counter vitamin D, which could be harmful if taken in large doses. About Prostate Cancer Prostate cancer is the most common malignancy among men and the second leading cause of cancer death in men in the United States. The American Cancer Society estimated that in 2002 approximately 189,000 men were diagnosed with prostate cancer, and about 32,200 died as a result of the disease. Overall, roughly one in six American men will develop prostate cancer during his lifetime. If detected early, however, treatment can be highly effective. About Oregon Health & Science University Oregon Health & Science University is a health and research university focused on improving the well-being of people in Oregon and beyond. OHSU educates health practitioners, bioscientists, high-technology professionals, and environmental scientists and engineers, and it undertakes the indispensable functions of patient care, community service and biomedical research. SOURCE: Oregon Health & Science University ------------------------------------------------------- http://groups.google.com/groups?q=taxotere+and+prostate +cancer+group:sci.med.prostate.cancer&hl=en&lr=&ie=UTF- 8&oe=UTF- 8&group=sci.med.prostate.cancer&selm=R2fW4.15483%24S31 .418418%40newsread2.prod.itd.earthlink.net&rnum=1 From: timothy roome (thyroome@yahoo.com) Subject: "Dramatic" View: Complete Thread (3 articles) Original Format Newsgroups: sci.med.prostate.cancer Date: 2000/05/22 Taxotere/Estramustine Gives Longer Prostate Cancer Survival Combined use of docetaxel (Taxotere) and estramustine phosphate (Emcyt) is highly active in men with an advanced form of prostate cancer-and use of the combination may dramatically improve survival, investigators reported at the 36th annual meeting of the American Society of Clinical Oncology (ASCO). The study was conducted by a group from Columbia Presbyterian Medical Center in New York City and was the largest to evaluate the combination of docetaxel and estramustine in men with hormone-refractory prostate cancer. In all, 37 patients with hormone-refractory prostate cancer were treated with 280 mg of estramustine three times a day for 5 days, followed by 70 mg/m² of docetaxel given on the second day of the treatment course. The treatment was repeated every 3 weeks. Of the enrolled patients, 25 men had a 50% or greater decrease in their prostate-specific antigen (PSA) levels, and 14 men had an 80% or greater decrease on two consecutive measurements at least 2 weeks apart. Five patients temporarily discontinued treatment when their prostate-specific antigen (PSA) level decreased to less than 4 ng/dL. Four of these patients were retreated when their PSA levels began to rise again. Three of the four patients achieved a 50% or greater decrease in their PSA levels after retreatment with the combination regimen. This finding indicated that some patients can discontinue treatment can be discontinued to allow them to for recovery from toxicity. ------------------------------------------------------------- http://groups.yahoo.com/group/taxotere/ +prostate+cancer+taxotere http://cdmrp.army.mil/ http://cdmrp.army.mil/pcrp/ http://cdmrp.army.mil/CWG/default.htm --------------------------------------------------------------- http://groups.google.com/groups?q=%2Bprostate%2Bcancer %2Btaxotere&ie=UTF-8&oe=UTF-8&hl=en&btnG=Google+Search --------------------------------------------------------------- An overall strategy for managing HRPCa Conceptually, we believe that the most effective treatments for HRPCa are those that have already been proven. Our reasoning is that you need to get and keep this cancer under control to protect your life. There is time for experimentation after the cancer has been controlled. We also follow new therapies with great hope, and we try some that seem to offer hope without risking our well-being. Our experience tells us to be conservative in selecting treatments, to choose those that have been established as effective for most men with HRPCa. Consequently, we spend our time searching for answers in the medical literature. Each man makes his own decisions in selecting treatments; and we respect that right. We have chosen the use of clinically proven therapies as our first line of battle. The ideas we present here are rather straightforward. You may well be familiar with every treatment we suggest. What is important for you to realize is that there are a good number of available treatments that you can use to keep this disease at bay. Three vital strategies To hold back this disease, to extend your survival for years, to maintain your quality of life, you need to adopt these three strategies: 1. Keep your PSA as low as possible at all times. And verify the blood test values with bone scans and cat scans to avoid being blindsided by a tumor that doesn’t generate PSA. If at all possible, don’t let your PSA run uncontrolled for any reason! A rising PSA should never be ignored or accepted as “normal.” Although it is a truism that PCa is a slow-moving (i.e., slow-growing) cancer, you need to keep it suppressed to take advantage of that characteristic. When the PSA is low, say below 10, a number of supplemental treatments seem to be able to work, whereas they are ineffective against a larger tumor burden. When the PSA is high, say above 100, the risk of metastasis increases to an essential certainty. It is these metastases that cause pain and threaten life by damaging vital organs or leading to broken bones. 2. Prevent and suppress bone metastases with bisphosphonates. If you are on hormone therapy (testosterone blockade or orchiectomy), you must also start on a bisphosphonate. Don’t accept the argument that it is not necessary! The bisphosphonate set of drugs (Zometa, Aredia, Fosamax, Actonel) has been shown to maintain bone integrity in the face of hormone blockade. If you have had hormone therapy, you are almost certain to lose bone mass (osteopenia or osteoporosis) and suffer the risk of broken bones. Second, these drugs have been shown clinically to help suppress the cancer itself. By getting onto Zometa (a monthly IV) before you experience bone mets, you can realistically expect to postpone that unpleasant prospect indefinitely. 3. Maintain your overall health at the highest level possible. PCa brings with it the risk of heart disease, among other problems. You’ve not won the battle if you control the cancer but are killed by a heart attack, a blood clot, or an infection. The general practitioner is an important part of your medical team; explain to him that you are in a serious struggle with this cancer and that you will be relying on him to keep from being blindsided by some other unexpected health crisis. Blood clots are a concern with hormone therapy. Chemotherapy leads to a risk of infection, as well as many other health problems. You need to embrace a healthy life style. A low-fat diet, with several supplements, is best. You need to exercise to maintain your psychological health as well as your physiological systems. Do your routine preventive maintenance, including dental checkups to avoid oral infections. The basic treatments for HRPCa Most of us with HRPCa have gone through a similar battery of treatments. These are the treatments that have been shown to work in clinical trials. They have also worked for a significant number of men we know. Unfortunately, that also means that some of them don’t work sometimes. The treatments listed here are also presented in greater detail in ensuing chapters. Issues of dosing, side effects, and monitoring are discussed. The purpose of this list is to let you know that there are many treatments available to control HRPCa. The treatments are presented in the order in which they are usually tried (although there is no medical rule saying they must be done in this order). This order also runs generally from the treatments with the least severe side effects first. 1. Lupron or Zoladex. Chances are you’ve been on Lupron or Zoladex(or on one of the LHRH agonists provided outside the U.S.), perhaps for some years. Or you may have had an orchiectomy instead. In the case of Lupron or Zoladex, for example, you should plan to stay on this drug for the foreseeable future, preferably on a 28-84 day injection schedule. The Lupron or Zoladex will continue to suppress the testosterone that would otherwise stimulate the cancer cells to proliferate. HRPCa is a mixture of cancer cells, some of them still sensitive to hormone blockade. The Lupron or Zoladex you continue taking keeps those cells under control. 2. Bisphosphonate. See the discussion above. 3. An estrogenic drug, such as DES (diethyl stilbestrol). This drug has been used more frequently since the herbal remedy PC SPES was taken off the market. That remedy contained rather strong phytoestrogens. Although there is a general search underway for a replacement for PC SPES, we know of no equivalent at this time. With an estrogen, one must be aware of the risk of blood clots. Interestingly, these estrogenic drugs have been shown to work for some period of time with HRPCa, even in addition to the Lupron. 4. HDK + HC or LDK (high-dose ketoconazole plus hydrocortisone). Ketoconazole is an anti-androgen. It works by blocking the hormone receptors on the cancer cells, thus preventing access by cancer- stimulating testosterone. In the advanced stage, prostate cancer cells often acquire an overabundance of additional hormone receptors, with the result that even a minuscule amount of testosterone is sufficient to stimulate proliferation. The hydrocortisone is needed to replace the steroid lost when the ketoconazole shuts down that production by the adrenal glands. Some men have great success with taking HDK, and others have great difficulty with the side effects. Life most of these treatments, we only know if they are effective for a given individual when that person actually takes the drug. 5. Taxotere is the first of a number of chemotherapies that work with HRPCa. It is the most effective one against HRPCa. There are mixed feelings about using chemotherapy to fight cancer. The reactions include (1) a fear of the side effects and (2) a concern that the use of chemotherapy will disqualify them from consideration for clinical trials. The decision is up to the individual. However, it is unwise to let the PSA increase to the point at which there are widespread metastases. It is true that chemotherapy is not an easy treatment; the side effects include fatigue, some nausea, and peripheral neuropathy (numbness in feet and hands) to mention the most bothersome. However, it does bring down the PSA, and it does extend survival (despite some medical claims) when used in a series of treatments. Insofar as the concern about clinical trials goes, one should not let the PSA run out of control purely for the hope that something experimental might work. Most of the members of our support list have had chemotherapy treatments and can answer any questions about the experience. 6. At this point, there are a number of supplemental treatments that are being used to enhance the effectiveness of chemotherapy or to achieve some other advantage against HRPCa. These include megadoses of calcitriol to enhance the chemotherapy; Dostinex to suppress the prolactin level and reduce the PSA; Celebrex to inhibit one of the enzymes that promotes cancer growth; Periostat to suppress angiogenesis the aids cancer growth. Evista (raloxifene) and HDK are being evaluated as alternating treatments between bouts of chemotherapy. The selection of appropriate supplemental treatments depends on the individual and the disease status. The important thing about these supplements is that they have been shown to help in some cases, with no undue risk due to side effects. The regimen needs to be worked out with a knowledgeable physician—the expert on your medical team. 7 If the Taxotere fails to work, then Emcyt may be added. This chemotherapy, which includes an estrogen, enhances the effectiveness of the Taxotere (or other chemotherapy). The Emcyt causes some problems with nausea. 8. The next chemotherapy may be a combination of Navelbine and Emcyt. Or it may be another combination recommended by your expert. Different chemotherapy regimens work for different people for different periods of time. 9. Next in line is the combination of Taxol (in the taxane family with Taxotere), carboplatin, and Emcyt. Sometimes this combination is used without the Emcyt. There seems to be no way to ensure ahead of time whether a particular chemo regimen will work for a particular individual. 10. At this point, it is important to realize that some drugs fail due to protective mutation by the body’s cells. However, several months off the drug often results in the disappearance of the protective change; and the drug again becomes effective. The second time around may be shorter than the first; nonetheless, the reuse of a drug means that survival time is extended. 11. Another chemotherapy that often works is Novantrone plus prednisone (steroid). Adriamycin is also used sometimes, although there is a risk of cardiotoxicity. This list of treatments will, hopefully, provide years of extended survival, years in which we will continue the search for better answers. Even during the few years that our support group has been in operation we have seen new ideas introduced that extend survival and improve the quality of life. --------------------------------------------------------------- Frequently Asked Questions Below are some common questions about Taxotere® (docetaxel) for Injection Concentrate. What is Taxotere and how does it work against cancer? Like other anticancer medications, Taxotere works by attacking cancer cells in the body. Different medications attack cancer cells in different ways. Most chemotherapy drugs stop cancer cells from dividing by interfering with the cell's DNA, but Taxotere acts quite differently. Taxotere damages the supporting structure of the tumor cell, which is like a skeleton, thereby preventing the cell from growing and dividing. How often is Taxotere treatment given? Taxotere is given intravenously (through a vein) every 3 weeks. Each treatment takes about 1 hour. Again, every person is different. Only a doctor can determine what dose of Taxotere is right and how often to give it. Is it necessary to take other medications with Taxotere treatment? As part of a treatment plan, a doctor may prescribe other medications to lessen some of the side effects during treatment. A corticosteroid such as dexamethasone may prevent fluid retention (holding extra water in the body), and may also reduce any allergic reactions to Taxotere. If needed, a corticosteroid is usually taken 1 day before Taxotere treatment and continued for a total of 3 days. However, people receiving Taxotere should always follow their doctor's or nurse's instructions about how to take medications. If a patient forgets to take their prescribed corticosteroid as directed, the doctor or nurse should be alerted before the next Taxotere treatment. A doctor or nurse should be notified of any problems with taking a medication. Your doctor may also prescribe certain medicines to prevent nausea and vomiting. To learn more about an Aventis Pharmaceuticals product for the treatment of nausea and vomiting, click here. ---------------------------- What are some of the side effects of corticosteroid pretreatment? Use of a short course of a corticosteroids such as dexamethasone can cause side effects, although they are generally mild in nature. These side effects can include flushing, temporary mood changes, increased appetite, elevated blood sugar, and stomach irritation. Patients who have previously had side effects while taking corticosteroids should alert their physician or nurse before receiving treatment with Taxotere. --------------------------- Are there any medications that can't be taken during Taxotere treatment? Some medications should not be taken because they might interact with Taxotere. Interactions can cause side effects and they may keep the medications from working. Patients should take only medications that the doctor prescribes and be sure that the doctor who is giving them Taxotere knows about all other medications they are taking, including nonprescription (over-the-counter) products and those prescribed by other doctors. Likewise, any other doctors who treat patients receiving Taxotere should know that they are receiving chemotherapy. ------------------------- Side Effects Chemotherapy medications are powerful so they can work to destroy cancer cells. But because they are so powerful, side effects with chemotherapy are common. Like all anticancer agents, there are some side effects associated with Taxotere® (docetaxel) for Injection Concentrate that may be bothersome or difficult to tolerate. These may include low white blood cell count, hair loss, fatigue, fluid retention, numbness, mouth irritation, cutaneous changes, nausea and diarrhea. ---------------Interaction With Other Drugs It is very important that people take only medications that their doctors prescribe for them. During treatment for cancer, people may take many different types of medications, both to treat cancer and to ease bothersome side effects. Since it can be confusing to remember all the names of the medications, it's important to keep a written record of all current prescription and non-prescription (over-the-counter) medications. Certain medications can react with each other (even simple over-the- counter drugs) and cause unwanted side effects, or even become ineffective. It's important that the doctor who is administering Taxotere® (docetaxel) for Injection Concentrate knows about all other medications a person is taking. People should tell their doctor about non-prescription drugs, nutritional supplements, and herbs they use and medications prescribed by other doctors. Likewise, it's important that other doctors treating a person know that he/she is receiving chemotherapy. ***************************************************** http://www.cancerbacup.org.uk/info/taxotere.htm Possible side effects Temporary reduction in bone marrow function. This can result in anaemia, risk of bruising or bleeding and infection. This effect can begin about 7 days after the treatment has been given and usually reaches its lowest point at 10-14 days after the chemotherapy. Your blood count will then increase steadily and will usually return to normal within 21 days. The extent to which your blood count is reduced depends on the dose of chemotherapy you receive and which other chemotherapy drugs, if any, are given in combination. Your doctor can advise you how likely it is that your blood count will be lowered by the chemotherapy. Your blood count will be checked regularly to see how well your bone marrow is working. If your temperature goes above 38C (100.5F), or you develop any unexplained bruising or bleeding, or you suddenly feel unwell, even with a normal temperature, contact your doctor or the hospital straight away. Nausea and vomiting. This is usually mild. There are now very effective anti-sickness drugs to prevent or substantially reduce this. If it does happen it may begin a few hours after the treatment is given. If the sickness is not controlled, or continues, tell your doctor. They can prescribe other anti-sickness drugs which may be more effective. Mouth sores and ulcers. If your mouth becomes sore, or you notice small ulcers, let your doctor know. They can prescribe suitable mouth care for you. Diarrhoea. This can usually be easily controlled with medicine but let your doctor know if it is severe or persistent. It is important to drink plenty of fluids if you do get diarrhoea. Hair loss. This usually starts 2-3 weeks after the first dose of docetaxel, although it may occur earlier. Hair may be lost completely or may just thin. You may also experience thinning and loss of eyelashes, eyebrows and other body hair. This is temporary: the hair will return to normal once the treatment is finished. CancerBACUP has a booklet called Coping with hair loss which we would be pleased to send you. Skin changes. Docetaxel can cause a rash. Your doctor can prescribe medicine to help with this. Soreness and redness of the palms of the hands and soles of the feet (sometimes known as Palmar Planter syndrome). This is temporary and will improve when treatment is finished. Allergic reaction. Signs of an allergic reaction include skin rashes and itching, high temperature, shivering, redness of the face, a feeling of dizziness, headache, shortness of breath, anxiety and a need to pass urine. You will be monitored for any signs of an allergic reaction during the treatment. Tell your doctor or nurse if you have any of these symptoms. A course of steroids is often prescribed to reduce the chance of developing an allergic reaction and to help reduce other side effects. Tiredness and a general feeling of weakness. It is important to allow yourself plenty of time to rest. Fluid retention. You may notice that you gain weight and/or that your ankles and legs swell. This decreases slowly once your treatment has finished. Sometimes drugs can be given before you receive docetaxel to limit the fluid retention. Less common side effects Numbness or tingling in hands or feet. This is due to the effect of docetaxel on nerves. You may also notice that you have difficulty doing up buttons or other fiddly tasks. Tell your doctor if you notice any numbness or tingling in your hands or feet. This usually improves slowly a few months after the treatment is finished. Changes in nails. The colour of your nails may change. This change grows out over several months once the treatment has finished. Pain in the nail bed may occur, but this is rare. Pain in the joints or muscles. It is important to tell your doctor about this so that appropriate painkillers can be prescribed. -------------------------------------------------- MEDLINE SEARCH 1: J Clin Oncol 2003 Jan 1;21(1):123-8 Weekly high-dose calcitriol and docetaxel in metastatic androgen- independent prostate cancer. Beer TM, Eilers KM, Garzotto M, Egorin MJ, Lowe BA, Henner WD. Oregon Health & Science University and Portland VA Medical Center, Portland, OR 97239, USA. beert@ohsu.edu PURPOSE: To determine the safety and efficacy of weekly high-dose oral calcitriol (Rocaltrol, Roche Pharmaceuticals, Basel, Switzerland) and docetaxel (Taxotere, Aventis Pharmaceuticals, Bridgewater, NJ) in patients with metastatic androgen-independent prostate cancer (AIPC). PATIENTS AND METHODS: Thirty-seven patients were treated with oral calcitriol (0.5 micro g/kg) on day 1 followed by docetaxel (36 mg/m(2)) on day 2, repeated weekly for 6 weeks of an 8-week cycle. Patients maintained a reduced calcium diet and increased oral hydration. Prostate-specific antigen (PSA) response was the primary end point, which was defined as a 50% reduction in PSA level confirmed 4 weeks later. RESULTS: Thirty of 37 patients (81%; 95% confidence interval [CI], 68% to 94%) achieved a PSA response. Twenty-two patients (59%; 95% CI, 43% to 75%) had a confirmed > 75% reduction in PSA. Eight of the 15 patients with measurable disease (53%; 95% CI, 27% to 79%) had a confirmed partial response. Median time to progression was 11.4 months (95% CI, 8.7 to 14 months), and median survival was 19.5 months (95% CI, 15.3 months to incalculable). Overall survival at 1 year was 89% (95% CI, 74% to 95%). Treatment-related toxicity was generally similar to that expected with single-agent docetaxel. Pharmacokinetics of either calcitriol or docetaxel were not affected by the presence of its companion drug in an exploratory substudy. CONCLUSION: The combination of weekly oral high-dose calcitriol and weekly docetaxel is a well- tolerated regimen for AIPC. PSA and measurable disease response rates as well as time to progression and survival are promising when compared with contemporary phase II studies of single-agent docetaxel in AIPC. Further study of this regimen is warranted. Publication Types: Clinical Trial Clinical Trial, Phase II PMID: 12506180 [PubMed - indexed for MEDLINE] 2: Nippon Rinsho 2002 Dec;60 Suppl 11:266-71 [Therapy for hormone-refractory prostate cancer] [Article in Japanese] Nishimura K, Takahara S, Nonomura N, Okuyama A. Department of Urology, Graduate School of Medicine, Osaka University. Publication Types: Review Review, Tutorial PMID: 12599583 [PubMed - indexed for MEDLINE] 3: Nippon Rinsho 2002 Dec;60 Suppl 11:205-10 [Chemotherapy for prostate cancers] [Article in Japanese] Naito K. Department of Specific Organ Medicine, Yamaguchi University School of Medicine. Publication Types: Review Review, Tutorial PMID: 12599572 [PubMed - indexed for MEDLINE] 4: Urology 2002 Dec;60(6):1111 Fatal respiratory failure associated with treatment of prostate cancer using docetaxel and estramustine. Morris MJ, Santamauro J, Shia J, Schwartz L, Vander Els N, Kelly K, Scher H. Genitourinary Oncology Service, Department of Medicine, Memorial Sloan- Kettering Cancer Center and Cornell University Weill Medical College, New York, New York, USA. Chemotherapy that targets microtubular trafficking induces responses in most patients with prostate cancer. One regimen under investigation is the combination of docetaxel and estramustine. We report on 2 patients with androgen-independent disease who received continuous weekly docetaxel and estramustine and who died of irreversible respiratory failure. The clinical, pathologic, and radiographic data support drug toxicity as the likely etiology. Inclusive of these patients, only 17 cases (10 fatal) of acute pulmonary toxicity using docetaxel have been reported, despite its wide use. We recommend that patients receiving weekly docetaxel, with or without estramustine, have frequent treatment breaks and be evaluated with computed tomography of the chest every 8 weeks. Publication Types: Review Review of Reported Cases PMID: 12475686 [PubMed - indexed for MEDLINE] 5: Australas J Dermatol 2002 Nov;43(4):293-6 Docetaxel-induced nail dystrophy. Nicolopoulos J, Howard A. Department of Dermatology, Royal Melbourne Hospital, Melbourne, Victoria, Australia. A 73-year-old man with metastatic prostate cancer treated with weekly docetaxel chemotherapy for 5 months developed an acute nail dystrophy restricted to the fingernails. This was characterized by onycholysis, subungual haemorrhage and acute paronychia, progressing to a subungual abscess of the right index finger. Nail bed hyperaemia and haemosiderin- like nail bed discoloration were present. Nail plate avulsion was performed to decompress the acutely painful subungual abscess. The right thumb, middle finger and left index finger demonstrated early, proximal white subungual collections of pus obscuring the lunula (onychophosis). Central nail plate fenestrations with a surgical drill led to exudation of purulent material. Cultures of the subungual abscess material yielded mixed organisms, possibly related to administration of flucloxacillin for 1 week prior to presentation. The patient completed a further two courses of docetaxel without sequelae, and the nail dystrophy appears to be resolving. Docetaxel-induced nail changes are a common adverse effect, occurring in 30-40% of patients. Mild changes do not usually warrant the discontinuation of treatment. Publication Types: Review Review of Reported Cases PMID: 12423438 [PubMed - indexed for MEDLINE] 6: Cancer Res 2002 Oct 15;62(20):5720-6 Inhibition of growth and metastasis of orthotopic human prostate cancer in athymic mice by combination therapy with pegylated interferon-alpha- 2b and docetaxel. Huang SF, Kim SJ, Lee AT, Karashima T, Bucana C, Kedar D, Sweeney P, Mian B, Fan D, Shepherd D, Fidler IJ, Dinney CP, Killion JJ. Department of Urology, The University of Texas M. D. Anderson Cancer Center, Houston 77030, USA. We evaluated whether treatment of orthotopic human prostate cancer in nude mice with pegylated IFN-alpha-2b (PEG-IFN-alpha-2b) and docetaxel could represent a two-compartment targeting of primary tumor (tumor cells and tumor-associated endothelial cells) and inhibition of regional lymph node metastasis. The antiangiogenic properties of IFN were combined with the cytotoxic properties of docetaxel, resulting in apoptosis of both tumor cells and endothelium and hence significant inhibition of primary tumor growth. We first determined the optimal biological dose of PEG-IFN-alpha-2b (70,000 IU/week) necessary to down- regulate the expression of basic fibroblast growth factor, matrix metalloprotease-9, and matrix metalloprotease-2. The therapeutic dose of docetaxel (10 mg/kg/week) was determined by efficacy and minimal body weight loss. Therapy beginning 3 days after orthotopic implantation of PC3-MM2 prostate cancer cells reduced tumor weight by 37% in mice treated with PEG-IFN-alpha-2b, by 60% in mice treated with docetaxel, and by 83% in those given both drugs. PEG-IFN-alpha-2b also induced apoptosis of tumor-associated endothelial cells and hence a significant decrease in microvessel density. Our data indicate that the combination of PEG-IFN-alpha and docetaxel inhibits neoplastic angiogenesis by inducing a decrease in the local production of proangiogenic molecules by tumor cells, resulting in increased apoptosis of tumor-associated endothelial cells. Publication Types: Evaluation Studies PMID: 12384530 [PubMed - indexed for MEDLINE] 7: J Urol 2002 Oct;168(4 Pt 1):1496 Prompt resolution of acute disseminated intravascular coagulation with docetaxel and cisplatin in hormone refractory prostate cancer. Avances C, Jacot W, Senesse P, Culine S. Department of Medical Oncology, CRLC Val d'Aurelle, Montpellier, France. PMID: 12352431 [PubMed - indexed for MEDLINE] 8: Semin Urol Oncol 2002 Aug;20(3 Suppl 1):1-3 Editorial: the coming revolution in the treatment of prostate cancer patients. Petrylak DP, de Wit R. Publication Types: Editorial PMID: 12198631 [PubMed - indexed for MEDLINE] 9: Semin Urol Oncol 2002 Aug;20(3 Suppl 1):31-5 Chemotherapy for androgen-independent prostate cancer. Petrylak DP. College of Physicians and Surgeons of Columbia University, Columbia- Presbyterian Medical Center, New York, NY 10032-3789, USA. While men with metastatic prostate cancer frequently show a good initial response to androgen ablation, few options have been available for progressive hormone-refractory prostate cancer, and survival following chemotherapy has not exceeded 9 to 12 months. The combination of prednisone and mitoxantrone has significant palliative effects on bone pain but does not extend survival. The combination of estramustine phosphate (EMP) with the taxanes paclitaxel or docetaxel produces greater than additive cytotoxicity in vivo, and phase I and II studies of taxane-based therapy demonstrate improved survival in hormone- refractory prostate cancer compared to historical controls. Docetaxel appears to have relatively high activity as a single agent and in combination with EMP. Further studies are needed to clarify the optimum dose of EMP, taking into account potential cardiovascular toxicity. Phase III studies of its combination with docetaxel are in progress. Copyright 2002, Elsevier Science (USA). All rights reserved. Publication Types: Review Review Literature PMID: 12198636 [PubMed - indexed for MEDLINE] 10: Cancer Res 2002 Jul 1;62(13):3743-50 Identification of human uroplakin II promoter and its use in the construction of CG8840, a urothelium-specific adenovirus variant that eliminates established bladder tumors in combination with docetaxel. Zhang J, Ramesh N, Chen Y, Li Y, Dilley J, Working P, Yu DC. Cell Genesys, Inc., Foster City, California 94404, USA. Uroplakins (UPs) are a group of integral membrane proteins that are synthesized as the major differentiation products of mammalian urothelium. UPII gene expression is bladder specific and differentiation dependent, but very little is known about its transcription response elements. To identify the promoter elements, a DNA fragment of 2239 bp upstream of the UPII gene was amplified by PCR and linked to a promoterless firefly luciferase reporter gene. Transient transfection experiments showed that the DNA segment located between -1809 and +1 bp resulted in preferential expression in bladder carcinoma cells with negligible expression in nonurothelial cells. This promoter was engineered into adenovirus (Ad) type 5 to drive the expression of the E1A and E1B genes and to create an attenuated replication-competent Ad variant, termed CG8840. Viral replication and the cytopathic effect of CG8840 were evaluated by virus yield and 3-(4,5-dimethylthiazol-2-yl)- 2,5-diphenyltetrazolium bromide (MTT) assays in bladder transitional cell carcinoma (TCC) cell lines RT4 and SW780; nonbladder cancer cell lines G361 (melanoma), LNCaP (prostate cancer), PA-1 (ovarian cancer), and U118 (brain cancer); and human primary cells including lung fibroblasts, bladder smooth muscle cells, and mammary epithelial cells. CG8840 replicated in and eliminated bladder TCC efficiently with high specificity (10,000:1) in comparison with nonbladder cells. The antitumor activity of CG8840 was examined in BALB/c nu/nu mice carrying s.c. human TCC xenografts. Intratumoral and i.v. administration of CG8840 in RT4 human bladder cancer xenografts caused significant (P < 0.01) inhibition of tumor growth. Synergistic antitumor efficacy was observed when CG8840 was combined with docetaxel, resulting in significant regression of RT4 bladder cancer xenograft tumors within 6 weeks after i.v. administration of CG8840 (3.33 x 10(9) plaque-forming units/animal on day 1) and docetaxel (20 mg/kg on days 2, 6, and 9). These results demonstrate the utility of the UPII promoter in the generation of urothelium-specific adenoviral vectors and provide a potential foundation for the development of bladder tumor-specific oncolytic viral therapies. PMID: 12097284 [PubMed - indexed for MEDLINE] 11: Cell Mol Life Sci 2002 Jul;59(7):1198-211 Survival of docetaxel-resistant prostate cancer cells in vitro depends on phenotype alterations and continuity of drug exposure. Makarovskiy AN, Siryaporn E, Hixson DC, Akerley W. Department of Medical Oncology, Rhode Island Hospital/Brown University School of Medicine, Providence 02903, USA. We evaluated in vitro the effect of paclitaxel and docetaxel on PC-3 and DU-145 prostate cancer cell lines to understand better the downstream events in drug-induced tumor cell death. Taxane treatments of DU-145 cells induced rapid cell death by apoptosis, but in PC-3 cells, treatments achieved growth arrest, followed by extensive karyokinesis resulting in multinucleation, giant-cell formation and delayed cell death. To determine if the giant multinucleated cells were able to produce proliferating and drug-resistant survivors, we first delineated the kinetics of drug activity and cytotoxic dose range. Analysis of both lines by colorimetric and cell viability assays demonstrated improved cytotoxicity of taxanes applied continuously. Selected doses and schedules of docetaxel were used to induce giant multinucleated cells that gave rise to docetaxel-resistant survivors, which remained sensitive to paclitaxel and other chemotherapeutics. Growth and morphology of the recovered clones was similar to parental cells. The resistant phenotype of these clones determined by immunofluorescence and immunoblot was associated with transient expression of the beta-tubulin i.v. isoform and was independent of P-glycoprotein, bcl-2 and bcl-xL. Resistant clones will be useful to model progression of resistance to taxanes and to identify unknown and clinically important molecular mechanisms of cell death and resistance. PMID: 12222966 [PubMed - indexed for MEDLINE] 12: Can J Urol 2002 Jun;9 Suppl 1:21-5 The role of chemotherapy in advanced prostate cancer. Ernst DS. Department of Medicine, Tom Baker Cancer Centre, Calgary, Alberta, Canada. The development of hormone resistance is an unfortunate final common pathway in most patients with advanced prostate cancer, resulting in a narrowing of therapeutic options for the clinician, and limited median survival of 10-12 months for the patient. While cytotoxic chemotherapy has been utilized for many years, its efficacy has been disappointing. Quality of life assessments are increasingly used in assessing response in hormone-resistant prostate cancer (HRPC), and PSA has emerged as an important surrogate marker of response in both local and advanced disease. Estramustine and the taxanes have been investigated, as monotherapy and in combination, in the treatment of HRPC in phase 2 and 3 clinical trials, a number of which are ongoing. Substantial advances in the management of HRPC over the past decade have led to renewed optimism that improvement in survival can be achieved, and support the belief that chemotherapy plays a role in this pursuit. In tandem with the development of new agents, refined means of assessing response have been developed, and represent a key component of new research strategies in HRPC. Publication Types: Review Review, Tutorial PMID: 12121591 [PubMed - indexed for MEDLINE] 13: Curr Urol Rep 2002 Jun;3(3):232-8 Effects of docetaxel on pain due to metastatic androgen-independent prostate cancer. Beer TM, Bubalo JS. Department of Medicine, Oregon Health & Science University, Mail Code L586, 3181 SW Sam Jackson Park Road, Portland, OR 97201, USA. beert@ohsu.edu Bone pain commonly plagues patients with metastatic androgen-independent prostate cancer. Studies of mitoxantrone demonstrated that chemotherapy can substantially reduce this debilitating symptom. Two of the available studies examining the use of docetaxel with and without estramustine for treatment of androgen-independent prostate cancer include a detailed prospective analysis of pain and quality of life. One study required patients to have pain at entry and demonstrated significant improvement in pain. The second study enrolled patients with low prevalence and intensity of pain and did not demonstrate pain relief. The available results, although preliminary, suggest that patients with significant bone pain due to androgen-independent prostate cancer can experience substantial pain relief with docetaxel-based therapy. Larger randomized studies targeting patients with sufficient prevalence and intensity of pain are needed to refine our understanding of the contribution of docetaxel to pain control in this patient population. Publication Types: Review Review, Tutorial PMID: 12084194 [PubMed - indexed for MEDLINE] 14: Oncology (Huntingt) 2002 Jun;16(6 Suppl 6):63-72 Docetaxel in the integrated management of prostate cancer. Current applications and future promise. Logothetis CJ. Department of Genitourinary Medical Oncology, The University of Texas, M.D. Anderson Cancer Center, Houston 77030, USA. clogothe@mail.mdanderson.org Docetaxel (Taxotere)-based regimens can be included among the most effective treatment options for the management of patients with advanced, androgen-independent prostate cancer. Results with docetaxel as a single agent and in combination regimens with estramustine (Emcyt) have consistently achieved a palliative response, reduced serum PSA levels by > or = 50%, and produced objective responses in patients with measurable disease. In addition, encouraging survival data have been demonstrated in several phase II trials. The ability to administer docetaxel on a weekly basis has substantially enhanced research efforts for treatment in prostate cancer patients. The results of ongoing phase III randomized trials evaluating docetaxel regimens in androgen- independent prostate cancer are eagerly awaited for their potential to definitively demonstrate a beneficial impact on overall patient survival. Docetaxel-containing regimens are likely to demonstrate a substantial role in the management of early-stage prostate cancer patients in the adjuvant and neoadjuvant settings, where clinical investigations are under way. In addition, study results from ongoing trials that integrate docetaxel with hormonal therapies for patients with biochemical recurrence following definitive local treatments will be important in refining the future role of chemotherapy for prostate cancer in general. The preliminary findings from studies conducted with docetaxel are encouraging and await final analysis. Finally, preliminary results from studies exploring combination regimens of docetaxel and novel agents that possess completely different mechanisms of action (eg, proapoptotic agents, angiogenesis inhibitors, and vitamin D analogs) have demonstrated the regimens to be feasible and safe, with promising early response data. These types of investigational studies will likely occupy a dominant position in future research initiatives for patients with advanced prostate cancer. Publication Types: Review Review Literature PMID: 12108899 [PubMed - indexed for MEDLINE] 15: Neoplasia 2002 May-Jun;4(3):255-62 Early response of prostate carcinoma xenografts to docetaxel chemotherapy monitored with diffusion MRI. Jennings D, Hatton BN, Guo J, Galons JP, Trouard TP, Raghunand N, Marshall J, Gillies RJ. Department of Biochemistry, University of Arizona Health Sciences Center, 1501 North Campbell Avenue, Tucson, AZ 85724, USA. For many anticancer therapies, it would be desirable to accurately monitor and quantify tumor response early in the treatment regimen. This would allow oncologists to continue effective therapies or discontinue ineffective therapies early in the course of treatment, and hence, reduce morbidity. This is especially true for second-line therapies, which have reduced response rates and increased toxicities. Previous works by others and ourselves have shown that water mobility, measured by diffusion-weighted magnetic resonance imaging (DW-MRI), increases early in tumors destined to respond to therapies. In the current communication, we further characterize the utility of DW-MRI to predict response of prostate cancer xenografts to docetaxel in SCID mice in a preclinical setting. The current data illustrate that tumor volumes and secreted prostate-specific antigen both respond strongly to docetaxel in a dose-responsive manner, and the apparent diffusion coefficient of water (ADC(w)) increases significantly by 2 days even at the lowest doses (10 mg/kg). The ADCw data were parsed by histogram analyses. Our results indicate that DW-MRI can be used for early detection of prostate carcinoma xenograft response to docetaxel chemotherapy. PMID: 11988845 [PubMed - indexed for MEDLINE] 16: Cancer 2002 Mar 1;94(5):1457-65 Phase II evaluation of docetaxel plus one-day oral estramustine phosphate in the treatment of patients with androgen independent prostate carcinoma. Sinibaldi VJ, Carducci MA, Moore-Cooper S, Laufer M, Zahurak M, Eisenberger MA. Department of Oncology, Johns Hopkins Medical Institutions, Baltimore, Maryland 21205, USA. sinibvi@jhmi.edu BACKGROUND: Recent clinical trials have shown antitumor activity with the combination of docetaxel plus estramustine phosphate (EMP) in the treatment of patients with androgen independent prostate carcinoma (AIPC). However, the most commonly employed treatment schedules with EMP have been associated with significant gastrointestinal, cardiovascular, and thromboembolic toxicity. The authors hypothesized that the therapeutic index of the combination of docetaxel plus EMP for patients with prostate carcinoma could be enhanced by reducing the incidence and severity of EMP-associated toxicity, which could be accomplished by shortening the duration of exposure to EMP. To preserve the therapeutic synergism between docetaxel and EMP, they designed a regimen employing higher doses of oral EMP administered on the day of the docetaxel infusion. METHODS: From June 1, 1998 through September 28, 2000, 42 patients with AIPC were registered to receive docetaxel (70 mg/m2 intravenously over 1 hour) and EMP (280 mg orally every 6 hours x 5 doses) every 21 days, up to a maximum of 6 cycles. Dexamethasone was administered prior to docetaxel and coumadin 2 mg orally every day was taken during the study treatment period. Patient characteristics included a median age of 68 years, a median Eastern Cooperative Oncology Group performance status of 1, a median prostate specific antigen (PSA) level at study entry of 110.5 ng/mL, and a median of 2 prior hormonal manipulations. Ten patients (25%) had received prior chemotherapy, and 14 patients (33%) had received prior palliative radiation therapy. RESULTS: Forty patients were evaluable for response and toxicity. Eighteen patients (45%; 95% confidence interval, 29-62%) had a decline > 50% in PSA level that lasted > 4 weeks with a median time to PSA progression and a median duration of PSA response of approximately 4.0 months. Four of 20 patients (20%) had partial soft tissue responses. Ten of 17 symptomatic patients (59%) had improvement in pain. The median survival for all patients was 13.5 months. The most prominent Grade 3 and 4 toxicities were reversible myelosuppression and fatigue. Nausea, emesis, diarrhea, and peripheral edema were minimal. No thromboembolic or hepatic complications were seen. CONCLUSIONS: Docetaxel plus 1 multidose day of oral EMP was active in patients with AIPC and was associated with an acceptable toxicity profile. Overall, the therapeutic index of this regimen compared favorably with regimens that employed a longer administration of EMP. Copyright 2002 American Cancer Society. Publication Types: Clinical Trial Clinical Trial, Phase II PMID: 11920502 [PubMed - indexed for MEDLINE] 17: Cancer 2002 Feb 1;94(3):847-53 Severe interstitial pneumonitis associated with docetaxel administration. Read WL, Mortimer JE, Picus J. Department of Medicine, Division of Medical Oncology at Washington University, St. Louis, Missouri, USA. readw@medicine.wustl.edu BACKGROUND: Interstitial pneumonitis has not been reported as a toxicity of docetaxel. The authors report the presentation and natural history of four patients who developed a severe interstitial pneumonitis after receiving docetaxel. METHODS: The hospital and outpatient records of patients treated with docetaxel were reviewed to identify whether any of these patients required an evaluation for respiratory problems. RESULTS: Four patients developed an interstitial pneumonitis that could be explained only as a toxicity of docetaxel. None had metastatic disease to the lung, and all had normal liver function before receiving chemotherapy. The patients presented with acute dyspnea and fever within 1-2 weeks of receiving docetaxel. All developed progressive interstitial infiltrates and respiratory failure that required mechanical ventilation. An exhaustive workup for other causes of pneumonitis was negative. Broad-spectrum antibiotics and corticosteroids were ineffective. Two patients died of complications related to the pulmonary process. The two survivors required ventilatory support for more than 21 days. The clinical and pathologic findings of these patients are presented. CONCLUSIONS: Interstitial pneumonitis is a rare and potentially fatal complication of docetaxel treatment. Prolonged ventilatory support is appropriate in patients with a favorable prognosis. Copyright 2002 American Cancer Society. DOI 10.1002/cncr.10263 PMID: 11857321 [PubMed - indexed for MEDLINE] 18: Front Radiat Ther Oncol 2002;36:72-80 Controversies in chemotherapy of prostate cancer. Heicappell R. Department of Urology, Universitatsklinikum Benjamin Franklin, Freie Universitat, Berlin, Germany. heicappell@medizin.fu-berlin.de Publication Types: Review Review, Tutorial PMID: 11842757 [PubMed - indexed for MEDLINE] 19: J Urol 2002 Jan;167(1):339-46 Enhanced transgene expression in androgen independent prostate cancer gene therapy by taxane chemotherapeutic agents. Li Y, Okegawa T, Lombardi DP, Frenkel EP, Hsieh JT. Department of Urology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9110, USA. PURPOSE: Chemotherapy is often used as a primary therapy for metastatic cancer because it kills cells en masse. However, high doses of chemotherapeutic drugs can cause toxicity in nontarget organs. Gene therapy may provide a better alternative to chemotherapy because its targeting of specific genes may reduce the undesirable toxicity associated with chemotherapy. We evaluated whether the chemotherapeutic agent docetaxel or paclitaxel may be combined with gene therapy to create a new therapeutic regimen for metastatic androgen independent prostate cancer. MATERIALS AND METHODS: The 2 androgen independent prostate cancer cell lines PC-3 and DU 145 were treated with docetaxel or paclitaxel. Three recombinant adenoviruses containing p21WAF-1/CIP1, p53 protein or beta-galactosidase complementary DNA under the control of cytomegalovirus promoter were used to determine transgene expression. They were evaluated by Western blot analysis, beta-galactosidase activity or in vitro growth assays. The [(3)H] labeled E1 deleted adenovirus dl312 was used to determine adenovirus uptake into cells. RESULTS: Docetaxel and paclitaxel enhanced adenovirus mediated transgene expression. Docetaxel appears to be a more potent growth inhibitor in vitro. Elevated transgene expression in virus infected cells induced by these 2 drugs was produced by increased cytomegalovirus promoter activity rather than increased virus uptake. CONCLUSIONS: The potential synergy of gene therapy with docetaxel and paclitaxel may be an important direction for future therapy for metastatic androgen independent prostate cancer. PMID: 11743353 [PubMed - indexed for MEDLINE] 20: Prostate 2002 Jan 1;50(1):27-37 Combined modality radioimmunotherapy for human prostate cancer xenografts with taxanes and 90yttrium-DOTA-peptide-ChL6. O'Donnell RT, DeNardo SJ, Miers LA, Lamborn KR, Kukis DL, DeNardo GL, Meyers FJ. Department of Internal Medicine, Division of Hematology and Oncology, Section of Radiodiagnosis & Therapy, University of California Davis Medical Center, Sacramento, California 95816, USA. rtodonnell@ucdavis.edu BACKGROUND: Therapy for prostate cancer in the PC3 tumor-nude mouse model with 90yttrium-(90Y)-DOTA-peptide-ChL6 (5.55 MBq;150 microCi) has resulted in durable responses. To make radioimmunotherapy (RIT) more effective, the radiation-enhancing drugs Taxol (paclitaxel) and Taxotere (docetaxel) were tested for synergy with 90Y-DOTA-peptide-ChL6. METHODS: Nude mice bearing human prostate cancer PC3 xenografts were treated with 90Y-DOTA-peptide-ChL6 (2.78 MBq; 75 microCi) and after 24 hr, paclitaxel (300 or 600 microg), or docetaxel (300 microg). Tumor size, survival, blood counts, and pharmacokinetics were monitored to assess efficacy and toxicity. RESULTS: Docetaxel plus RIT had a 67% cure rate, whereas no mice were cured among the RIT alone, chemotherapy alone, or untreated controls. Paclitaxel (600 microg) plus RIT produced a 100% response rate with 20% cures. Average tumor volume was reduced to a greater degree in the combined modality radioimmunotherapy (CMRIT) groups compared to controls and the anti-tumor response was durable. Myelotoxicity in the combined modality groups (RIT plus paclitaxel or RIT plus docetaxel) were similar to groups receiving the same dose of RIT alone. CONCLUSION: In the PC3-tumor nude mouse model, addition of paclitaxel or docetaxel to 90Y-DOTA-peptide-ChL6, in doses clinically achievable in humans, provided therapeutic synergy without increased or excessive toxicity. Copyright 2002 Wiley-Liss, Inc. PMID: 11757033 [PubMed - indexed for MEDLINE] 21: Urology 2002 Jan;59(1):137 Successful treatment of metastatic hormone-refractory prostate cancer with malignant pericardial tamponade using docetaxel. Hayes-Lattin BM, Kovach PA, Henner WD, Beer TM. Oregon Health and Science University, Portland, Oregon 97201, USA. Reports of malignant pericardial effusion due to adenocarcinoma of the prostate are few and describe only patients with hormone-naive disease. We report a case of malignant pleural and pericardial effusions due to metastatic hormone-refractory prostate cancer. Despite presenting with pericardial tamponade, this patient was successfully treated with pericardiocentesis and intrapericardial methylprednisolone and cisplatin, followed by a course of intravenous docetaxel. The patient was alive and free of disease-related symptoms nearly 2 years later. This case suggests that patients with pericardial tamponade due to hormone-refractory prostate cancer do not have a uniformly dismal prognosis and should be considered for aggressive treatment. PMID: 11796304 [PubMed - indexed for MEDLINE] 22: Tumori 2001 Nov-Dec;87(6):A12-4 [Chemotherapy of prostate cancer: potential role of docetaxel] [Article in Italian] Bracarda S. Publication Types: Review Review, Tutorial PMID: 11995697 [PubMed - indexed for MEDLINE] 23: Ann Oncol 2001 Sep;12(9):1273-9 Phase II study of weekly docetaxel in symptomatic androgen-independent prostate cancer. Beer TM, Pierce WC, Lowe BA, Henner WD. Department of Medicine, Oregon Health Sciences University, Portland 97201, USA. beert@ohsu.edu BACKGROUND: This study sought to define the activity and toxicity of weekly docetaxel in patients with androgen-independent prostate cancer and cancer-related pain. PATIENTS AND METHODS: Twenty-five patients were treated with docetaxel 36 mg/m2 i.v. administered weekly for six consecutive weeks followed by two weeks without treatment. This eight- week treatment cycle was repeated until progression or unacceptable toxicity. Endpoints included palliative response (a 2-point reduction on the 6-point Present Pain Intensity scale without an increase in analgesic consumption or a 50% decrease in analgesic use without an increase in pain), PSA response (a 50% decrease maintained at least four weeks), measurable disease response, survival, and toxicity. RESULTS: Twelve of 25 patients (48%, 95% confidence interval (95% CI): 28%-68%) had a palliative response. Eleven of the 24 patients who entered with an elevated PSA (46%, 95% CI: 25%-67%) had a PSA response. Two of five patients with measurable disease had a partial response. Toxicity of therapy was modest with no treatment-related mortality. Twenty-five percent of patients experienced a grade 3 or 4 hematologic toxicity and 36% of patients experienced a grade 3 non-hematologic toxicity. CONCLUSIONS: Weekly docetaxel is well tolerated in patients with androgen-independent prostate cancer and has significant activity as measured by relief of pain, reduction in PSA, and reduction in measurable disease. Publication Types: Clinical Trial Clinical Trial, Phase II PMID: 11697840 [PubMed - indexed for MEDLINE] 24: Curr Oncol Rep 2001 Sep;3(5):417 Combination therapy in hormone-refractory prostate cancer. Petrylak DP. Publication Types: Editorial PMID: 11489242 [PubMed - indexed for MEDLINE] 25: Semin Oncol 2001 Aug;28(4 Suppl 15):71-6 Docetaxel, estramustine, plus trastuzumab in patients with metastatic androgen-independent prostate cancer. Small EJ, Bok R, Reese DM, Sudilovsky D, Frohlich M. Urologic Oncology Program, University of California, San Francisco Comprehensive Cancer Center, San Francisco, CA 94143-1711, USA. The incidence of human epidermal growth factor receptor 2 (HER2) protein overexpression and its prognostic value are not well characterized in patients with prostate cancer. A phase I study was designed to evaluate docetaxel/estramustine plus trastuzumab, a humanized monoclonal antibody that binds to the HER2 receptor, in patients with metastatic androgen- independent prostate cancer (AIPC). HER2 positivity was not required because safety was the primary endpoint. Patients received oral estramustine 280 mg three times daily (days 1 to 5); docetaxel, 70 mg/m(2) intravenously (day 2); and trastuzumab, 2 mg/kg intravenously (days 2, 9, and 19), every 21 days until the disease progressed or toxicity became unacceptable. This regimen was well tolerated among the first 13 treated patients. Grade 4 neutropenia was seen in 10% of administered cycles. There were two episodes of febrile neutropenia and two thrombembolic events. Of the 13 patients evaluable for prostate- specific antigen (PSA) response, nine (69%) experienced a decrease in PSA level of >50%. Two (33%) of six patients with measurable disease had objective responses, and one complete response was seen on bone scan. Docetaxel/estramustine/trastuzumab appears to be a safe combination when used in the treatment of metastatic AIPC. The response data are too preliminary for speculation about the relative benefits of this 3-drug regimen compared with the combination of only docetaxel and estramustine in this clinical setting. Copyright 2001 by W.B. Saunders Company. Publication Types: Clinical Trial Clinical Trial, Phase I PMID: 11685733 [PubMed - indexed for MEDLINE] 26: Semin Oncol 2001 Aug;28(4 Suppl 15):67-70 Preliminary phase I results of G3139 (bcl-2 antisense oligonucleotide) therapy in combination with docetaxel in hormone-refractory prostate cancer. Tolcher AW. Institute for Drug Development, Cancer Therapy and Research Center, and the University of Texas Health Science Center, San Antonio, TX, USA. The transition from androgen-dependent to androgen-independent prostate cancer is accompanied by a number of molecular genetic changes, including overexpression of the bcl-2 gene. Overexpression of Bcl-2 protein decreases the pro-apoptotic response to such cellular insults as irradiation, chemotherapy, and androgen withdrawal. Reduction of Bcl-2 expression in hormone-refractory prostate cancer (HRPC) preclinical models markedly increases the antitumor efficacy of docetaxel both in vitro and in vivo. Thus, a phase I/II pharmacokinetic and biologic correlative study has been initiated in patients with HRPC to examine whether docetaxel therapy can be enhanced with a therapeutic antisense oligodeoxynucleotide (G3139) directed at bcl-2 gene expression. Semin Oncol 28 (suppl 15):67-70. Copyright 2001 by W.B. Saunders Company. Publication Types: Clinical Trial Clinical Trial, Phase I PMID: 11685732 [PubMed - indexed for MEDLINE] 27: Semin Oncol 2001 Aug;28(4 Suppl 15):62-6 A randomized phase II trial of docetaxel (taxotere) plus thalidomide in androgen-independent prostate cancer. Figg WD, Arlen P, Gulley J, Fernandez P, Noone M, Fedenko K, Hamilton M, Parker C, Kruger EA, Pluda J, Dahut WL. Medicine Branch, Division of Clinical Services, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. New therapeutic alternatives are needed to improve outcomes in patients with androgen-independent prostate cancer (AIPC). For several years, researchers at the National Cancer Institute have been interested in elucidating the importance of angiogenesis in the pathogenesis of prostate cancer and in identifying inhibitors of this process. Thalidomide has been shown to inhibit the ability of tumors to recruit new blood vessels. In a recent phase II trial of thalidomide in AIPC, 28% of patients achieved a prostate-specific antigen (PSA) decrease of >40%. The taxane docetaxel also produces PSA and measurable disease responses when used as monotherapy or as a component of combination chemotherapy for AIPC. Thus, based on the single-agent activity of thalidomide and docetaxel, we initiated a randomized phase II study of weekly docetaxel with or without thalidomide, 200 mg at bedtime, in patients with chemotherapy-naive metastatic AIPC. Docetaxel, 30 mg/m(2) intravenously, was administered every 7 days for 3 weeks, followed by a 1-week rest period. Both regimens have been well tolerated among the first 59 treated patients, with a near absence of grade (3/4) myelosuppression. Fatigue, hyperglycemia, and pulmonary toxicity were seen in both groups. Thrombotic events have been seen in the combination arm. Thirty-five percent (6 of 17) of the patients receiving docetaxel alone and 53% (19 of 36) of those receiving docetaxel and thalidomide have had a PSA decrease of at least 50%. Combining a cytotoxic agent with an angiogenesis inhibitor is a promising area of investigation for prostate cancer management. Copyright 2001 by W.B. Saunders Company. Publication Types: Clinical Trial Clinical Trial, Phase II Randomized Controlled Trial PMID: 11685731 [PubMed - indexed for MEDLINE] 28: Semin Oncol 2001 Aug;28(4 Suppl 15):56-61 Docetaxel and exisulind in hormone-refractory prostate cancer. Ryan CW, Stadler WM, Vogelzang NJ. Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL 60637, USA. Single-agent docetaxel has been shown to produce a significant decrease in prostate-specific antigen (PSA) levels among patients with hormone- refractory prostate cancer (HRPC). A recent study also showed that exisulind, a sulfone metabolite of the nonsteroidal anti-inflammatory drug sulindac, lengthens the median PSA doubling time in men who had increasing PSA levels after radical prostatectomy. Furthermore, exisulind has shown significant antineoplastic activity in prostate cancer cell lines in vitro and in nude mouse xenograft models. Because preclinical studies have suggested synergistic interactions between docetaxel and exisulind, a phase I/II clinical trial combining these agents has been initiated in patients with HRPC. The primary objective of this study is to determine PSA response and measurable disease response rate of the combination therapy; secondary objectives include toxicity assessment and determination of time to disease progression, duration of response, and overall survival. Accrual is ongoing. Copyright 2001 by W.B. Saunders Company. Publication Types: Clinical Trial Clinical Trial, Phase I Clinical Trial, Phase II PMID: 11685730 [PubMed - indexed for MEDLINE] 29: Semin Oncol 2001 Aug;28(4 Suppl 15):49-55 Weekly high-dose calcitriol and docetaxel in advanced prostate cancer. Beer TM, Hough KM, Garzotto M, Lowe BA, Henner WD. Department of Medicine, Oregon Health Sciences University and the Portland Veterans Affairs Medical Center, Portland, OR 97201, USA. Novel treatment regimens for androgen-independent prostate cancer (AIPC) are needed because currently available approaches have not been shown to improve survival. Docetaxel provides a good foundation for new therapeutic combinations because of its promising single-agent activity against prostate cancer and its favorable tolerability profile, particularly when administered weekly. In both tissue culture and animal models of prostate cancer, calcitriol (the biologically active form of vitamin D) enhanced the activity of docetaxel, paclitaxel, and platinum compounds. These effects were particularly notable at supraphysiologic calcitriol concentrations. Weekly calcitriol dosing is associated with minimal toxicity and permits substantial dose escalation over the daily schedule. A weekly calcitriol dose of 0.5 microg/kg produces plasma calcitriol levels 25-fold higher than the physiologic range. In a preclinical study at the Oregon Health Sciences University, calcitriol 5 micromol/L plus docetaxel 0.15 nmol/L was at least additive in inhibiting PC-3 colony formation. A phase II study is evaluating weekly administration of 0.5 microg/kg calcitriol orally on day 1 followed by 36 mg/m(2) docetaxel intravenously on day 2 in patients with AIPC (repeated for 6 consecutive weeks of each 8-week cycle). At the time of a preliminary analysis, 11 patients had been enrolled and were actively being treated. All 5 patients who had completed 8 weeks of calcitriol/docetaxel treatment achieved prostate-specific antigen (PSA) reductions of > or =50%. Two of these patients had confirmatory assessments, both meeting the formal PSA response criteria. Treatment has been well tolerated, with 1 patient experiencing a self-limited grade 3 toxicity and no patients experiencing grade 4 or 5 toxicities. Copyright 2001 by W.B. Saunders Company. Publication Types: Clinical Trial Clinical Trial, Phase II PMID: 11685729 [PubMed - indexed for MEDLINE] 30: Semin Oncol 2001 Aug;28(4 Suppl 15):45-8 Preliminary observations of single-agent docetaxel as neoadjuvant therapy for locally advanced prostate cancer. Dreicer R, Klein EA. Department of Hematology/Oncology, Taussig Cancer Center and the Urologic Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA. Patients with locally advanced prostate cancer present a significant therapeutic dilemma. Despite aggressive local therapies, including radical prostatectomy (RP), these patients are at high risk for biochemical failure. Several research groups have recently demonstrated the feasibility of hormonal and chemohormonal therapy before RP, but limited published data are available regarding the usefulness of chemotherapy without hormonal therapy in the neoadjuvant setting. At Cleveland Clinic Foundation, a phase II trial was initiated to evaluate a 6-week course of docetaxel, 40 mg/m(2) intravenously every 7 days, followed by RP in patients with locally advanced prostate cancer. RP was to be performed within 3 weeks of completion of neoadjuvant chemotherapy. The primary endpoint of this study is pathologic complete response. Preliminary toxicity data suggest that weekly docetaxel is well tolerated and does not increase the risk of perioperative or post operative complications. Reductions in prostate-specific antigen levels were noted in seven of 10 patients who completed the 6-week course of neoadjuvant docetaxel. The neoadjuvant use of investigational cancer therapies may allow for relatively rapid assessment of their antitumor activity. Copyright 2001 by W.B. Saunders Company. Publication Types: Clinical Trial Clinical Trial, Phase II PMID: 11685728 [PubMed - indexed for MEDLINE] 31: Semin Oncol 2001 Aug;28(4 Suppl 15):77-85 Prostate cancer: multimodality approaches with docetaxel. Senzer NN. Radiation Oncology Research, TOPA-Sammons Cancer Center, Dallas, TX 75246, USA. The trend toward earlier diagnosis of prostate cancer and technological advances in radiotherapeutics (eg, imaging enhancement, planning optimization, refinement of calculation algorithms, and computerized delivery systems) have led to increased use of radiation therapy (RT) as primary treatment for presumed localized disease. However, monomodal local therapy fails to achieve consistently successful long-term disease control, especially in patients with intermediate- and high-grade risk factors. Local-regional factors, such as absolute and relative resistance mechanisms, epigenetic influences, and clonogenic heterogeneity, and probable micrometastatic disease require consideration, evaluation, and potentially the implementation of combined modality approaches. Patients receiving combined RT and androgen suppression (AS) in various sequences (AS --> AS + RT, AS + RT, AS --> AS + RT --> AS, and RT --> AS) have shown enhanced disease-free survival, increased pathologic local control related to the duration of AS treatment, and improved overall survival with prolonged AS. Furthermore, limited but provocative trials suggest that multimodality chemoradiotherapy may also enhance tumor control in patients with locally advanced disease with acceptable toxicity. Several new trials that will test the efficacy and safety of docetaxel combined with radiotherapy as well as biologic modifiers are described. Copyright 2001 by W.B. Saunders Company. Publication Types: Review Review, Tutorial PMID: 11685734 [PubMed - indexed for MEDLINE] 32: Semin Oncol 2001 Aug;28(4 Suppl 15):40-4 Neoadjuvant docetaxel followed by radical prostatectomy in patients with high-risk localized prostate cancer: a preliminary report. Oh WK, George DJ, Kaufman DS, Moss K, Smith MR, Richie JP, Kantoff PW. Lank Center for Genitourinary Oncology, Department of Adult Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. Effective treatment options for high-risk localized prostate cancer are limited. Patients at high risk for recurrence include those with biopsy Gleason scores of 8 to 10, prostate specific antigen (PSA) levels > 20 ng/mL, and clinical stage T3 disease. Docetaxel chemotherapy is active in hormone-refractory prostate cancer, either combined with estramustine or used as a single agent. To determine if systemic therapy can improve the outcome of radical prostatectomy in men with high-risk localized prostate cancer, we are undertaking a pilot phase II clinical trial of weekly docetaxel at 36 mg/m(2) for up to 6 months, followed by surgery. Patients are monitored with weekly visits, monthly digital rectal examinations, PSA measurement, and testosterone tests, and endorectal magnetic resonance imaging done at baseline, after two cycles, and again after six cycles. To date, 15 patients have been enrolled, and 70 cycles of chemotherapy have been administered. Toxicity has been mostly grade 1 in intensity, and fatigue has been the most common grade 2 toxicity reported. The primary endpoint of the trial is measurement of pathologic complete response rate, for which data are not yet available. Recruitment to the trial is ongoing. Copyright 2001 by W.B. Saunders Company. Publication Types: Clinical Trial Clinical Trial, Phase II PMID: 11685727 [PubMed - indexed for MEDLINE] 33: Semin Oncol 2001 Aug;28(4 Suppl 15):32-9 Docetaxel, estramustine, and short-term androgen withdrawal for patients with biochemical failure after definitive local therapy for prostate cancer. Taplin ME, Bubley GJ, Rajeshkumar B, Shuster T, Ko YJ, Morganstern DE. Division of Hematology-Oncology, University of Massachusetts Memorial Health Center, Worcester, MA 01566, USA. Over the past 10 years, men with prostate cancer have received earlier diagnoses and are undergoing prostatectomy and/or radiation therapy with curative intent; however, many men have increasing prostate-specific antigen (PSA) levels without evidence of local progression or metastatic disease during the first 2 years after definitive local therapy. Optimal treatment of men with PSA-only recurrent prostate cancer has not been established. This ongoing phase II trial is evaluating docetaxel (70 mg/m(2) administered intravenously over 1 hour on day 2 every 21 days for four cycles) and estramustine (10 mg/kg/d orally on days 1 to 5 every 21 days for four cycles) followed by bicalutamide and goserelin acetate in men with increasing PSA levels after prostatectomy and/or radiation therapy. Patients received pretreatment with dexamethasone, and after the third patient enrolled, patients received warfarin for prophylaxis against thrombosis. Colony-stimulating factor support was allowed. In preliminary results, 11 of 15 patients completed protocol chemotherapy; 12 of 15 patients achieved complete response (ie, normalization of PSA) after four cycles of chemotherapy. In addition, testosterone levels were reduced to the castrate range in all patients after chemotherapy. The regimen was generally well tolerated, and toxicities were mostly hematologic, with grade (3/4) neutropenia reported in approximately half of patients. Preliminary results of this phase II trial are encouraging, and enrollment is ongoing. Copyright 2001 by W.B. Saunders Company. Publication Types: Clinical Trial Clinical Trial, Phase II PMID: 11685726 [PubMed - indexed for MEDLINE] 34: Semin Oncol 2001 Aug;28(4 Suppl 15):22-31 Docetaxel followed by hormone therapy after failure of definitive treatments for clinically localized/locally advanced prostate cancer: preliminary results. Hussain A, Dawson N, Amin P, Naslund M, Engstrom C, Chen T. Greenebaum Cancer Center, University of Maryland School of Medicine, and the Baltimore Veterans Affairs Medical Center, Department of Veterans Affairs, Baltimore, MD 21201, USA. An increasingly important issue in the management of prostate cancer is the occurrence of biochemical failure (ie, increasing serum prostate- specific antigen [PSA] levels) in patients with clinically localized prostate cancer who initially underwent definitive treatments with curative intent (prostatectomy and/or radiation therapy). This pilot trial evaluated chemotherapy followed by hormone therapy for a defined period in patients with biochemical (and possibly clinical) recurrence after initial local therapies for localized/locally advanced prostate cancer. Patients who developed increasing PSA > 4 ng/mL after initial prostatectomy and/or radiation therapy received docetaxel, 70 mg/m(2) every 3 weeks for up to 6 courses, followed by 4 months of total androgen suppression (using a luteinizing hormone-releasing hormone agonist plus bicalutamide, 50 mg/d) and 8 months of peripheral androgen blockade (using finasteride, 5 mg/d, plus bicalutamide, 50 mg/d). Twenty-seven patients have enrolled to date, 23 of whom received four or six cycles of docetaxel before hormonal therapies. Seventeen (74%) of 23 patients who completed four to six cycles of chemotherapy had a > or =40% decrease in PSA, and 16 (89%) of 18 patients who completed 4 months of total androgen suppression achieved PSA values of < or =0.1. The most common hematologic toxicity was grade (3/4) neutropenia; grade 3 nonhematologic toxicities were rare, and no grade 4 nonhematologic toxicities were reported. Thus, the preliminary results suggest that docetaxel before hormonal therapy includes a PSA response in many prostate cancer patients with biochemical failure after definitive local therapies. Copyright 2001 by W.B. Saunders Company. Publication Types: Clinical Trial PMID: 11685725 [PubMed - indexed for MEDLINE] 35: Semin Oncol 2001 Aug;28(4 Suppl 15):16-21 Weekly docetaxel and estramustine in patients with hormone-refractory prostate cancer. Sitka Copur M, Ledakis P, Lynch J, Hauke R, Tarantolo S, Bolton M, Norvell M, Muhvic J, Hake L, Wendt J. Saint Francis Cancer Center, Grand Island, NE 68802-9804, USA. The combination of docetaxel and estramustine has exhibited synergistic activity both in prostate cancer cell lines and in patients with hormone-refractory prostate cancer (HRPC). Based on these promising preclinical and phase I/II data, we conducted a study of weekly docetaxel and estramustine in patients with metastatic HRPC and a poor performance status. A total of 30 patients received (1) a 3-day course of oral estramustine during weeks 1 and 2 of each 3-week cycle plus (2) docetaxel, 35 mg/m(2) intravenously on day 2 of weeks 1 and 2. The median number of cycles per patient was 5, ranging from 1 to 22. The median patient age was 74 years (range, 61 to 90 years), and the median baseline Karnofsky performance status was 60% (range, 50% to 80%). Twenty-three patients (76%) had a > or =50% decrease in serum prostate- specific antigen (PSA); 17 (56%) of these patients had a > or =75% decrease in PSA. Pain scores and performance status likewise improved in 70% of patients. Three complete responses and four partial responses were observed among 12 patients with measurable disease. Toxicities were primarily nonhematologic in nature, with the most common being grade 1 through 3 nausea, asthenia, diarrhea, and edema. Given the activity and tolerability of weekly docetaxel and estramustine in this study, this regimen appears to be more suitable than previously studied docetaxel/estramustine administration schedules for treating metastatic HRPC in elderly patients with a poor performance status. Copyright 2001 by W.B. Saunders Company. Publication Types: Clinical Trial PMID: 11685724 [PubMed - indexed for MEDLINE] 36: Semin Oncol 2001 Aug;28(4 Suppl 15):8-15 Phase II trial of single-agent weekly docetaxel in hormone-refractory, symptomatic, metastatic carcinoma of the prostate. Berry W, Dakhil S, Gregurich MA, Asmar L. US Oncology Inc, Houston, TX 77060, USA. The purpose of this study was to assess the efficacy of weekly administration of docetaxel as a single agent in patients with hormone- refractory, symptomatic, metastatic prostate cancer with respect to symptom palliation, tumor response, time to progression, and survival. Sixty men with progressive metastatic prostate cancer that had progressed on at least one hormonal regimen were enrolled in this multicenter phase II study. Twenty-one percent of patients had received prior palliative radiotherapy, and 25% had received prior chemotherapy for hormone-refractory disease. Patients were scheduled to receive three 8-week cycles of docetaxel (36 mg/m(2) on days 1, 8, 15, 22, 29, and 36) with 2-week intervals between cycles. The docetaxel dose could be decreased in the event of toxicity, but no dose escalation was permitted. A > or =50% decrease in serum prostate-specific antigen (PSA) levels from baseline with stabilization or improvement of performance status lasting 2 months or longer occurred in 24 (41%) patients, of whom 16 (27%) had a > or =80% decrease for 2 months or more. The median time to progression for all patients was 5.1 months (range, 0.9 to 18.2 months). The estimated median time to progression for patients who had and those who did not have a > or =50% reduction in serum PSA level with stable or improved performance status was 6.65 and 4.3 months, respectively. The median overall survival was 9.4 months (range, 1.6 to 18.2 months). Treatment toxicity was considered acceptable. Single-agent docetaxel at 36 mg/m(2) weekly was associated with a PSA response rate of 41%, increased time to progression and survival, and minimal myelosuppression in patients with hormone-refractory metastatic prostate cancer. Copyright 2001 by W.B. Saunders Company. Publication Types: Clinical Trial Clinical Trial, Phase II Multicenter Study PMID: 11685723 [PubMed - indexed for MEDLINE] 37: Semin Oncol 2001 Aug;28(4 Suppl 15):3-7 Preclinical mechanisms of action of docetaxel and docetaxel combinations in prostate cancer. Pienta KJ. Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan, Ann Arbor, MI 48109-0946, USA. Docetaxel, a semisynthetic taxane, has exhibited significant single- agent activity against prostatic tumors. In phase I/II studies, single- agent docetaxel and the combination of docetaxel plus estramustine were effective in inducing prostate-specific antigen reductions of > or =50% in men with androgen-independent prostate cancer (AIPC). The underlying reason for docetaxel's clinical activity against prostate cancer has been a focus of ongoing research. Docetaxel is believed to have a twofold mechanism of antineoplastic activity: (1) inhibition of microtubular depolymerization, and (2) attenuation of the effects of bcl-2 and bcl-xL gene expression. Taxane-induced microtubule stabilization arrests cells in the G(2)M phase of the cell cycle and induces bcl-2 phosphorylation, thereby promoting a cascade of events that ultimately leads to apoptotic cell death. In preclinical studies, docetaxel had a higher affinity for tubulin and was shown to be a more potent inducer of bcl-2 phosphorylation than paclitaxel. Laboratory evidence also supports the clinical evaluation of docetaxel-based combinations that include agents such as trastuzumab and/or estramustine. The pathways for docetaxel-induced apoptosis appear to differ in androgen-dependent and androgen-independent prostate cancer cells. Further elucidation of these differences will be instrumental in designing targeted regimens for the treatment of localized and advanced prostate cancer. Copyright 2001 by W.B. Saunders Company. Publication Types: Review Review, Tutorial PMID: 11685722 [PubMed - indexed for MEDLINE] 38: Semin Urol Oncol 2001 Aug;19(3):222-30 Complications of chemotherapy for prostate cancer. Beer TM, Bubalo JS. Department of Pharmacy, Oregon Health Sciences University, Portland 97201, USA. To date, all available therapies for prostate cancer are plagued by adverse effects. Chemotherapy is no exception. The mechanisms of activity of chemotherapy agents are not cancer-specific. Normal tissues, particularly those that require rapid cell proliferation, are vulnerable to the effects of growth inhibition by these cytotoxic agents. Furthermore, both predictable as well as idiosyncratic toxicities unrelated to the antineoplastic activity of these agents can occur. In some cases, the cause of adverse events may be linked to the vehicle required to suspend water-insoluble chemotherapy drugs. Patient-specific factors can also significantly contribute to the risk of chemotherapy side-effects. However, with optimal clinical care the toxicity of antineoplastic agents can be substantially reduced. Long before chemotherapy is contemplated, it is imperative to limit treatments that reduce patients' capacity to tolerate subsequent chemotherapy. Moreover, offering treatment before patients' performance status declines can significantly improve tolerance of treatment. Once chemotherapy is initiated, the incidence and severity of adverse effects can be reduced through individualized selection of chemotherapy regimens and appropriate use of adjunct medications. Finally, aggressive management of toxicities after they occur lessens their duration and severity. The common toxicities of current chemotherapy regimens for prostate cancer, as well as strategies to limit and manage these toxicities are reviewed. Publication Types: Review Review, Tutorial PMID: 11561990 [PubMed - indexed for MEDLINE] 39: Semin Urol Oncol 2001 Aug;19(3):212-21 Can chemotherapy alter the course of prostate cancer? Haas NB. Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA. Prostate cancer is perceived to be a disease of older men often diagnosed with widespread metastases that respond to hormonal ablation but for which there are few additional treatment options. Fortunately this perception is rapidly changing as newer combination chemotherapy trials demonstrate improved prostate-specific antigen and measurable response rates and enhanced quality of life. Still, treatment of prostate cancer lags behind treatment of other malignancies. Work remains in understanding the natural history of disease, refining our grouping of patients by stage into clinical trials, and adhering to new response criteria recently developed. Applying the newer active chemotherapy regimens to patients with earlier stage disease should lead to improvements in overall survival. Publication Types: Review Review, Tutorial PMID: 11561989 [PubMed - indexed for MEDLINE] 40: Br J Cancer 2001 Jun 1;84(11):1571-6 Modulation of docetaxel-induced apoptosis and cell cycle arrest by all- trans retinoic acid in prostate cancer cells. Nehme A, Varadarajan P, Sellakumar G, Gerhold M, Niedner H, Zhang Q, Lin X, Christen RD. Department of Medicine and the Cancer Center, University of California, 9500 Gilman Drive, San Diego, La Jolla, CA 92093-0058, USA. We report that all- trans retinoic acid (ATRA) enhanced the toxicity of docetaxel against DU145 and LNCaP prostate cancer cells, and that the nature of the interaction between ATRA and docetaxel was highly synergistic. Docetaxel-induced apoptotic cell death was associated with phosphorylation and hence inactivation of Bcl-2. ATRA enhanced docetaxel-induced apoptosis and combined treatment with ATRA and docetaxel resulted in down-regulation of Bcl-2. Docetaxel caused phosphorylation and hence inactivation of cdc2 kinase result ing in G2/M arrest. ATRA inhibited docetaxel-induced phosphorylation of cdc2 resulting in activation of cdc2 kinase and partial reversal of the G2/M arrest. ATRA also inhibited docetaxel-induced activation of MAPK indicating that the effects of docetaxel and ATRA on cdc2 phosphorylation are dependent on MAPK. We conclude that ATRA synergistically enhances docetaxel toxicity by down-regulating Bcl-2 expression and partially reverses the docetaxel-induced G2/M arrest by inhibiting docetaxel-induced cdc2 phosphorylation in a pathway that is dependent on MAPK. Copyright 2001 Cancer Research Campaign. PMID: 11384110 [PubMed - indexed for MEDLINE] 41: Hematol Oncol Clin North Am 2001 Jun;15(3):525-45 Paclitaxel and docetaxel in prostate cancer. Obasaju C, Hudes GR. Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA. Although their ultimate value in prostate cancer therapy remains to be defined in randomized trials, docetaxel and paclitaxel are active agents in HRPC. Combination therapies using either of these taxanes plus oral EMP show reproducible antitumor activity that appears to be greater and more durable than that of single-agent treatment. Although the optimal combination and schedule have not been determined, weekly paclitaxel and EMP and docetaxel given every 3 weeks or by weekly infusion with EMP are useful treatment options for patients with progressive HRPC. The gastrointestinal toxicity of EMP has been reduced by intermittent rather than continuous administration, and other toxicities may be reduced further by use of intravenous EMP. Although there has been progress, the median time to progression of 5 to 6 months for current taxane-based therapies suggests that they will not have major impact on overall survival for patients with HRPC. Greater benefit may be possible earlier in the course of prostate cancer, and the activity of the taxane-EMP combinations is sufficient to justify clinical trials of adjuvant or neoadjuvant chemotherapy for selected groups of patients with locally advanced and poor-prognosis tumors. Armed with many new molecularly targeted agents that may interact favorably with taxanes, it should be possible to build on current antimicrotubule regimens to improve activity in HRPC. Taxane-EMP combinations provide a platform on which to test additional agents that may enhance the apoptotic response or circumvent cellular stress adaptations that confer drug resistance. Further elucidation of signaling pathways that regulate microtubule dynamics and programmed cell death after exposure to microtubule inhibitors would provide a more rational guide for integrating specific inhibitors of signal transduction with current taxane-based therapies. Pharmacokinetic and pharmacodynamic studies will play a key role in the development of future taxane-based therapies for prostate cancer. Publication Types: Review Review, Academic PMID: 11525295 [PubMed - indexed for MEDLINE] 42: Ann Oncol 2001 May;12(5):633-41 The impact of docetaxel, estramustine, and low dose hydrocortisone on the quality of life of men with hormone refractory prostate cancer and their partners: a feasibility study. Kornblith AB, Herndon JE 2nd, Zuckerman E, Godley PA, Savarese D, Vogelzang NJ; Cancer and Leukemia Group B (CALGB). Department of Psychiatry and Behavioral Sciences, Memorial Sloan- Kettering Cancer Center, NYC, New York, USA. akornbli@bethisraelny.org OBJECTIVES: The quality of life (QoL) of 44 men with HRPC and 37 partners (primary caregivers, most residing with the patient) was assessed in a multicenter Phase II trial of docetaxel, estramustine and low dose hydrocortisone (CALGB 9780). A secondary objective was to test the feasibility of assessing partners' QoL in a cooperative group setting. PATIENTS AND METHODS: Patients and partners were separately interviewed by telephone at baseline, two, four and six months by a single trained research interviewer. Patients' QoL was measured by the FACT-P, Mental Health Inventory-17 (MHI-17), Brief Pain Inventory (BPI), a two-day log of pain medications, and the OARS for co-morbid conditions. Partners' QoL was measured by the MHI-17, Caregiver Burden Interview, and co-morbid conditions. RESULTS: The QoL study refusal rates were low for patients (4%) and partners (3%). Although patients tended to experience greater treatment side effects in the first two months (FACT Physical Well-Being item, P = 0.057), their cancer-specific emotions (e.g., worrying about worsening health) significantly improved at two and four months (FACT-Emotional Well-Being, P = 0.003, P = 0.03, respectively), as did their prostate cancer-specific physical problems (e.g., urination, pain), at two and four months (FACT-P, P = 0.001, P = 0.005, respectively). Partners' anxiety significantly decreased over time (MHI, P < 0.05). Patients' quality of life at two months was significantly related to their clinical response (FACT-P total and prostate cancer-specific problems, P < 0.05), and their clinical response was significantly related to a decrease in their partners' anxiety at two months (MHI, P < 0.05). CONCLUSIONS: Despite feeling worse from side effects, patients' prostate cancer-specific problems and emotional state significantly improved in the first four months of treatment. With treatment significantly affecting both patients' and partners' lives. and the successful assessment of partners' QoL, QoL of both patients and partners could be used as important endpoints in selected clinical trials. Publication Types: Clinical Trial Clinical Trial, Phase II Multicenter Study PMID: 11432621 [PubMed - indexed for MEDLINE] 43: J Clin Oncol 2001 May 1;19(9):2509-16 Phase II study of docetaxel, estramustine, and low-dose hydrocortisone in men with hormone-refractory prostate cancer: a final report of CALGB 9780. Cancer and Leukemia Group B. Savarese DM, Halabi S, Hars V, Akerley WL, Taplin ME, Godley PA, Hussain A, Small EJ, Vogelzang NJ. University of Massachusetts Memorial Health Care, Worcester, and Boston Medical Center, Boston, MA 01655, USA. dsavarese@uptodate.com PURPOSE: To investigate the combination of docetaxel, estramustine (EM), and low-dose hydrocortisone in men with hormone-refractory prostate cancer (HRPC). PATIENTS AND METHODS: Combinations of EM with other antimitotic agents such as docetaxel are synergistic in vitro and show significant clinical activity in patients with HRPC. We studied intravenous administration of docetaxel 70 mg/m(2), oral estramustine, and low-dose daily hydrocortisone in men with HRPC who demonstrated progression after initial hormone therapy. RESULTS: Of the 47 men enrolled onto this multicenter cooperative group study, 46 were assessable for response and/or toxicity. In the 24 patients with measurable disease, there were three complete and nine partial responses for a measurable disease response rate of 50% (12 of 24 patients; 95% confidence interval [CI], 27% to 73%). In the 44 patients in whom pretreatment prostate-specific antigen (PSA) was elevated, 30 (68%) had a 50% or greater decrease, and 25 (57%) had a 75% or greater decrease in PSA. The combined measurable disease and biochemical response rate in all 46 assessable patients was 54% (three complete responses, 22 partial responses, 95% CI, 37% to 71%). The predominant toxicity was neutropenia, with 26% of patients having grade 3 and 30% having grade 4 granulocytopenia; there were no episodes of febrile neutropenia. Other common but mild adverse effects included malaise/fatigue, peripheral edema, and hyperglycemia. The incidence of thromboembolic events during therapy was 9%. With a median follow-up of 17 months, the median survival was 20 months. The median time to disease progression was 8 months for all patients, and 10 months for those with measurable disease. CONCLUSION: This therapy is efficacious and moderately well tolerated in HRPC and should be compared in a phase III trial with mitoxantrone and prednisone. Publication Types: Clinical Trial Clinical Trial, Phase II PMID: 11331330 [PubMed - indexed for MEDLINE] 44: Curr Opin Investig Drugs 2001 Mar;2(3):424-7 CT-2584 (Cell Therapeutics). Bonfil RD. Fundacion de Investigacion del Cance, Buenos Aires, Argentina. fundic@velocom.com.ar CT-2584, an anticancer agent that inhibits phospholipid signaling, is under development by Cell Therapeutics Inc (CTI) as a potential treatment for various types of cancer. Phase II trials are underway for the treatment of prostate cancer and soft-tissue sarcoma [306617], [324290]. According to CIBC World Markets, completion of enrolment for these trials was expected in the fourth quarter of 2000. Furthermore, the initiation of phase II/III trials in combination with taxotere for the treatment of prostate cancer was anticipated in the second half of 2000, as were phase I/II trials in combination with cisplatin for the treatment of other cancers, including lung cancer [396582]. Results of a phase II study in patients with soft-tissue sarcomas evaluating pharmacokinetics, tolerance and therapeutic activity were presented at the 2000 American Society of Clinical Oncology (ASCO) meeting [367283]. Further data are expected to be presented at the ASCO meeting in May 2001 [396582]. Cell Therapeutics is seeking development and commercialization partners for CT-2584 [386398]. PMID: 11575717 [PubMed - indexed for MEDLINE] 45: Anticancer Drugs 2001 Feb;12 Suppl 1:S17-20 Docetaxel in prostate cancer. Small EJ. Urologic Oncology Program, UCSF Comprehensive Cancer Center, 1600 Divisadero St., 3rd Floor, San Francisco, CA 94115, USA. smalle@medicine.ucsf.edu In contrast to several other tumor types, there has been relatively little experience with docetaxel in hormone-refractory prostate cancer. However, two phase II trials investigated the combination of docetaxel with estramustine, and reported prostate-specific antigen response rates of 69 and 74% and objective responses in 23% and 57% of patients. This activity is comparable with that of other estramustine combinations. However, there is uncertainty about whether estramustine itself should be omitted from therapy because of its emetogenic and thromboembolic potential, and also over the optimal schedule of docetaxel to avoid neutropenia. Preliminary data suggest that weekly docetaxel, with or without limited exposure to estramustine, may provide the right balance between efficacy and tolerability. Phase III studies now in progress are comparing regimens containing docetaxel and estramustine with a recent standard therapy consisting of mitoxantrone plus prednisone. In the future, the efficacy of docetaxel plus estramustine may be enhanced by adding agents to this regimen. Publication Types: Review Review, Tutorial PMID: 11340899 [PubMed - indexed for MEDLINE] 46: Urology 2001 Feb;57(2):366-70 Erratum in: Urology 2001 Sep;58(3):500 Comment in: NIH Guide Grants Contracts. 2002 Oct 2;:NOT-OD-03-001. Different docetaxel-induced apoptotic pathways are present in prostate cancer cell lines LNCaP and PC-3. Muenchen HJ, Poncza PJ, Pienta KJ. Department of Internal Medicine (Division of Hematology/Oncology), University of Michigan, Ann Arbor, Michigan, USA. OBJECTIVES: To investigate the molecular machinery of docetaxel (Taxotere)-initiated death signaling on prostate cancer cell lines LNCaP and PC-3. Taxotere is a member of the taxane family of chemotherapeutic agents. It has been shown to disrupt microtubule dynamics causing mitotic arrest, which leads to cell death. Taxotere has demonstrated induction of cell death in LNCaP and PC-3 cells. However, the pathways by which apoptosis occurs differ in each cell line. METHODS: The prostate cancer cell lines, LNCaP and PC-3, were treated with 40 nM Taxotere for various lengths of time (0.5 to 24 hours). Western blot analysis was used for protein analysis. RESULTS: LNCaP cells demonstrated caspase-3 and caspase-7 cleavage, and PC-3 cells demonstrated only caspase-8 and BH3-interacting domain death agonist cleavage. Only LNCaP cells were observed to express clusterin expression; PC-3 cells expressed a novel apoptosis inhibitor, survivin. CONCLUSIONS: In this study, we demonstrated two distinctly different Taxotere-induced apoptotic pathways in LNCaP and PC-3 cells that may be of clinical importance when treating prostate cancer. PMID: 11182366 [PubMed - indexed for MEDLINE] 47: Cancer Res 2001 Jan 15;61(2):517-25 Antitumor synergy of CV787, a prostate cancer-specific adenovirus, and paclitaxel and docetaxel. Yu DC, Chen Y, Dilley J, Li Y, Embry M, Zhang H, Nguyen N, Amin P, Oh J, Henderson DR. Calydon, Incorporated, Sunnyvale, California 94089, USA. CV787, a PSA+ prostate cell-specific adenovirus variant, is currently in Phase I/II clinical trials for the treatment of prostate cancer. We have previously demonstrated that a single administration of CV787 at 1 x 10(11) particle/animal could eliminate established tumors within 6 weeks in nude mouse xenografts (Yu et al., Cancer Res., 59: 4200-4203, 1999). We now demonstrate that CV787-mediated replication-dependent cytotoxicity is synergistic with the chemotherapeutic agents paclitaxel (Taxol) or docetaxel (Taxotere) both in vitro and in vivo. In vitro, cells were pretreated with CV787 24 h before taxane, pretreated with taxane 24 h before CV787, or treated with both agents simultaneously. Cell viability was determined at various time points by 3-[4,5- dimethylthiazole-2-4]-2,5-diphenyl-2H-tetrazolium bromide assay, and virus yield was examined by plaque assay. Addition of taxane to CV787 resulted in a synergistic increase of cytotoxicity toward the human prostate cancer cell line LNCaP, regardless of the timing of administration. There was no reduction in virus replication or specificity of CV787-based cytopathogenicity for prostate cancer cells (approximately 10,000 to 1) with the taxanes. p53 expression was significantly elevated in the cells treated with CV787 and taxane. In vivo, using the PSA+ LNCaP xenograft model of prostate cancer, a single i.v. dose of 1 x 10(8) particles CV787 and docetaxel in combination eliminates large preexistent distant tumors. Toxicity studies do not show a synergistic increase of toxicity of CV787 and taxane. These experiments demonstrate a synergistic antitumor efficacy for CV787 when combined with taxane and demonstrate an in vivo single-dose curative therapeutic index for CV787 of over 1000:1. PMID: 11212244 [PubMed - indexed for MEDLINE] 48: Cancer Res 2001 Jan 15;61(2):759-63 Pretreatment with paclitaxel enhances apo-2 ligand/tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis of prostate cancer cells by inducing death receptors 4 and 5 protein levels. Nimmanapalli R, Perkins CL, Orlando M, O'Bryan E, Nguyen D, Bhalla KN. Moffitt Cancer Center and Research Institute, University of South Florida, Tampa 33612, USA. We have demonstrated that Apo-2 ligand (Apo-2L)/tumor necrosis factor- related apoptosis-inducing ligand (TRAIL) induces apoptosis of human prostate cancer PC-3, DU145, and LNCaP cells in a dose-dependent manner, with PC-3 cells displaying the greatest sensitivity to Apo-2L/TRAIL. Susceptibility of the prostate cancer cell types to Apo-2L/TRAIL-induced apoptosis did not appear to correlate with the levels of the Apo- 2L/TRAIL receptors death receptor (DR) 4 (TRAIL receptor 1) or DR5 (TRAIL receptor 2), decoy receptor (DcR) 1 and DcR2, Flame-1, or the inhibitors of apoptosis proteins family of proteins. Apo-2L/TRAIL- induced apoptosis of PC-3 cells was associated with the processing of caspase-8, caspase-10, and the proapoptotic Bid protein, resulting in the cytosolic accumulation of cytochrome c as well as the processing of procaspase-9 and procaspase-3. Cotreatment with the caspase-8 inhibitor z-IETD-fmk or DR4:Fc significantly inhibited Apo-2L/TRAIL-induced apoptosis. Treatment with paclitaxel or taxotere increased DR4 and/or DR5 protein levels (up to 8-fold) without affecting the protein levels of DcR1 and DcR2, Apo-2L/TRAIL, Fas, or Fas ligand. Up-regulation of DR4 and DR5 was not preceded by the induction of their mRNA levels but was inhibited by cotreatment with cycloheximide. Importantly, sequential treatment of PC-3, DU145, and LNCaP cells with paclitaxel followed by Apo-2L/TRAIL induced significantly more apoptosis than Apo-2L/TRAIL treatment alone (P < 0.01). This was also associated with greater processing of procaspase-8 and Bid, as well as greater cytosolic accumulation of cytochrome c and the processing of caspase-3. These findings indicate that up-regulation of DR4 and DR5 protein levels by treatment with paclitaxel enhances subsequent Apo-2L/TRAIL-induced apoptosis of human prostate cancer cells. PMID: 11212279 [PubMed - indexed for MEDLINE] 49: Ann Oncol 2000 Dec;11(12):1523-30 Chemotherapy in advanced androgen-independent prostate cancer 1990-1999: a decade of progress? Culine S, Droz JP. Department of Medicine, CRLC Val d'Aurelle, Montpellier, France. stculine@valdorel.fnclcc.fr BACKGROUND AND PURPOSE: A great number of clinical research studies have been reported in the field of chemotherapy for advanced androgen- independent prostate cancer during the last ten years. The aims of the present review were to assess their impact on management of the disease and on survival of patients. METHODS: The review of full published reports was facilited by the use of a MEDLINE computer search. RESULTS: Clinical research studies have focused on defining guidelines for eligibility criteria and accurate endpoints for patients to be enrolled onto clinical trials and developing new agents or combination of drugs including estramustine phosphate. Any combination of current chemotherapy has no impact on overall survival of patients. Among drugs in development, only the promising activity observed with docetaxel deserves randomized trials to assess its impact on survival. The major innovative advance of the 90s is the demonstration of the impact of chemotherapy (mitoxantrone + prednisone) on quality of life as compared to prednisone alone. A greater and longer-lasting improvement in quality of life along with a concomitant decrease in costs was observed. CONCLUSIONS: At the present time, chemotherapy should be considered as a palliative treatment in patients with symptomatic androgen-independent disease. The enrollment of patients into clinical trials dealing with quality of life as primary endpoint is strongly solicited. A standard methodology should be used in phase II trials with a primary goal of selection of agents which should progress to randomized trials using survival as an endpoint. Hopefully new specific strategies targeted to reverse the molecular changes that underlie prostate tumorigenesis should rapidly impact the multimodality management of AIPC in the third millenium. Publication Types: Review Review, Tutorial PMID: 11205458 [PubMed - indexed for MEDLINE] 50: Clin Cancer Res 2000 Dec;6(12):4885-92 Efficacy of cytotoxic agents against human tumor xenografts is markedly enhanced by coadministration of ZD1839 (Iressa), an inhibitor of EGFR tyrosine kinase. Sirotnak FM, Zakowski MF, Miller VA, Scher HI, Kris MG. Department of Medicine and Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA. sirotnaf@mskcc.org The blockade of epidermal growth factor receptor (EGFR) function with monoclonal antibodies has major antiproliferative effects against human tumors in vivo. Similar antiproliferative effects against some of these same tumors have also been observed with specific inhibitors of the EGFR-associated tyrosine kinase. One such inhibitor, the p.o. active ZD1839 (Iressa), has pronounced antiproliferative activity against human tumor xenografts. We now show that coadministration of ZD1839, as with anti-EGFR, will enhance the efficacy of cytotoxic agents against human vulvar (A431), lung (A549 and SK-LC-16 NSCL and LX-1), and prostate (PC- 3 and TSU-PR1) tumors. Oral ZD1839 (five times daily x 2) and cytotoxic agents (i.p. every 3-4 days x 4) were given for a period of 2 weeks to mice with well-established tumors. On this schedule, the maximum tolerated dose (150 mg/kg) of ZD1839 induced partial regression of A431, a tumor that expresses high levels of EGFR, 70-80% inhibition among tumors with low but highly variable levels of EGFR expression (A549, SKLC-16, TSU-PR1, and PC-3), and 50-55% inhibition against the LX-1 tumor, which expresses very low levels of EGFR. ZD1839 was very effective in potentiating most cytotoxic agents in combination treatment against all of these tumors, irrespective of EGFR status, but dose reduction of ZD1839 below its single-agent maximum tolerated dose was required for optimum tolerance. The pronounced growth inhibitory action of the platinums, cisplatin and carboplatinum, as single agents against A431 vulvar, A549 and LX-1 lung, and TSU-PR1 and PC-3 prostate tumors was increased several-fold when ZD1839 was added, with some regression of A431 and PC-3 tumors. Although the taxanes, paclitaxel or docetaxel, as single agents markedly inhibited the growth of A431, LX-1, SK-LC-16, TSU-PR1, and PC-3, when combined with ZD1839, partial or complete regression was usually seen. Against A549, the growth inhibition of doxorubicin was increased 10-fold (>99%) with ZD1839. The folate analogue, edatrexate, was highly growth inhibitory against A549, LX-1, and TSU-PR1, whereas edatrexate combined with ZD1839 resulted in partial or complete regression in these tumors. Against the A431 tumor, paclitaxel alone either was highly growth inhibitory or induced some regression, but when combined with ZD1839, pronounced regression was obtained. Combination with gemcitabine neither added nor detracted from baseline cytotoxic efficacy, whereas ZD1839 combined with vinorelbine was poorly tolerated. Overall, these results suggest that potentiation of cytotoxic treatment with ZD1839 does not require high levels of EGFR expression in the target tumors. They also suggest significant clinical benefit from ZD1839 in combination with a variety of widely used cytotoxic agents. PMID: 11156248 [PubMed - indexed for MEDLINE] 51: Ann Plast Surg 2000 Oct;45(4):438-41 Docetaxel (taxotere) extravasation: a report of five cases with treatment recommendations. Ascherman JA, Knowles SL, Attkiss K. Department of Surgery, Columbia-Presbyterian Medical Center, Columbia University College of Physicians & Surgeons, New York, NY 10032, USA. Docetaxel (Taxotere) is a relatively new antineoplastic agent that is proving to be clinically useful in the treatment of a number of major solid tumors, including breast, ovarian, lung, and prostate carcinoma. Common systemic toxicities include neutropenia, alopecia, nausea, and vomiting. The authors report 5 patients (age range, 54-89 years) who experienced extravasation injuries with dramatic clinical presentations during peripheral intravenous administration of docetaxel. The authors did not find any other reported series of docetaxel extravasation in an extensive literature review. They present these 5 patients and provide treatment recommendations. PMID: 11037169 [PubMed - indexed for MEDLINE] 52: Prostate 2000 Sep 1;44(4):275-8 Treatment of androgen-independent prostate cancer using antimicrotubule agents docetaxel and estramustine in combination: an experimental study. Williams JF, Muenchen HJ, Kamradt JM, Korenchuk S, Pienta KJ. Division of Hematology/Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor 48109-9480, USA. BACKGROUND: Estramustine in combination with other chemotherapeutic agents has demonstrated synergy in hormone-refractory prostate cancer. Docetaxel has demonstrated antineoplastic activity in a variety of chemotherapeutic-unresponsive tumors. We evaluated the effects of estramustine and docetaxel in preclinical models of prostate cancer. METHODS: Cell viability of PC-3 and MAT-LyLu (MLL) cells were assessed 48 hr after drug treatment. For in vivo studies, each flank of five animals in six groups was injected with 1 x 10(6) MLL cells: control, estramustine, docetaxel (low- and high-dose), and low-and high-dose docetaxel with estramustine. Animals were treated on days 4 and 11, and sacrificed on day 14. RESULTS: The IC(50) value for docetaxel was 2 nM in the PC-3 cells and 40 nM in the MLL cells. The addition of 100 nM of estramustine did not alter the IC(50) value for PC-3 cells. In the MLL cells, however, the IC(50) value was lowered to 15 nM. In vivo, low-dose docetaxel with estramustine demonstrated antineoplastic activity similar to that of high-dose docetaxel alone, suggesting additive activity between the drugs. CONCLUSIONS: These results demonstrate that when used in combination, docetaxel and estramustine can be more effective at lower dosages than when the individual drugs are used alone. Copyright 2000 Wiley-Liss, Inc. PMID: 10951491 [PubMed - indexed for MEDLINE] 53: Lancet 2000 Jun 17;355(9221):2164 Comment on: Lancet. 2000 Jan 22;355(9200):281-3. Lancet. 2000 Mar 25;355(9209):1098-9. Colitis and docetaxel-based chemotherapy. Kreis W, Petrylak D, Savarese D, Budman D. Publication Types: Comment Letter PMID: 10902651 [PubMed - indexed for MEDLINE] 54: Clin Cancer Res 2000 Jun;6(6):2146-56 Rapid in vivo monitoring of chemotherapeutic response using weighted sodium magnetic resonance imaging. Kline RP, Wu EX, Petrylak DP, Szabolcs M, Alderson PO, Weisfeldt ML, Cannon P, Katz J. Department of Medicine, Columbia University, New York, New York 10032, USA. rpk1@Columbia.edu A novel pulse sequence strategy uses sodium magnetic resonance imaging to monitor the response to chemotherapy of mouse xenograft tumors propagated from human prostate cancer cell lines. An inversion pulse suppresses sodium with long longitudinal relaxation times, weighting the image toward intracellular sodium nuclei. Comparing these weighted sodium images before and 24 h after administration of antineoplastics, we measured a 36 +/- 4% (P < 0.001; n = 16) increase in signal intensity. Experiments with these same drugs and cells, treated in culture, detected a significant intracellular sodium elevation (10-20 mM) using a ratiometric fluorescent dye. Flow cytometry studies showed that this elevation preceded cell death by apoptosis, as determined by fluorescent end-labeling of apoptotic nuclei or Annexin V binding. Histopathology on formalin-fixed sections of explanted tumors confirmed that drug administration reduces proliferation (2.2 versus 8.6 mitotic figures per high power field; P < 0.0001), an effect that inversely correlates with the sodium magnetic resonance image response on a tumor- to-tumor basis (P < 0.02; n = 10). Morphological features, such as central zones of nonviable cells, rims of active apoptosis, and areas of viable tumor, could be distinguished by comparing weighted and unweighted images. Advantages of this sodium imaging technique include rapid determination of drug efficacy, improved diagnosis of lesions, ease of coregistration with high resolution proton magnetic resonance imaging, and absence of costly or toxic reagents. PMID: 10873063 [PubMed - indexed for MEDLINE] 55: Semin Oncol 2000 Apr;27(2 Suppl 3):24-9 Docetaxel (Taxotere) in hormone-refractory prostate cancer. Petrylak DP. Division of Medical Oncology, College of Physicians and Surgeons of Columbia University, Columbia Presbyterian Medical Center, New York, NY 10032-3789, USA. Considerations of both molecular biology and data from in vitro studies suggest a potential for the combination of docetaxel (Taxotere; Rhone- Poulenc Rorer, Antony, France) with estramustine in the treatment of patients with hormone-refractory prostate cancer. Based on data from two phase I studies, the docetaxel dose recommended for phase II study in combination with estramustine in minimally and extensively pretreated patients is 70 mg/m2 and 60 mg/m2, respectively. The dose-limiting toxicity was neutropenia. In one phase I study, 63% of the 34 patients treated showed at least a 50% decline in prostate-specific antigen. An objective response was seen in 28% of patients with measurable disease, and overall median survival (22.8 months) is highly encouraging. In the second study, 82% of 17 patients showed a greater than 50% decline in prostate-specific antigen and, at the 70 mg/m2 dose level, two of six patients showed prostate-specific antigen normalization. Phase II studies have demonstrated more than 50% declines in 59% to 88% of patients treated at 70 mg/m2. Although reduction of the dose of estramustine appears to result in a somewhat lower response rate, the contribution made by estramustine to the efficacy of the estramustine/docetaxel combination must be established by randomized trials. Dexamethasone, however, does not appear to significantly contribute to the response rate of estramustine and docetaxel. Phase III studies comparing docetaxel plus estramustine with mitoxantrone plus corticosteroids are currently being planned. If the promise of docetaxel hormone-refractory prostate cancer is realized, it may be appropriate to design clinical trials that evaluate docetaxel-based regimens as adjuvant therapy in patients who are at a high risk for relapse after definitive local therapy. Publication Types: Review Review, Tutorial PMID: 10810935 [PubMed - indexed for MEDLINE] 56: Semin Oncol 2000 Apr;27(2 Suppl 3):1-2 Docetaxel (Taxotere) in the treatment of cancer. Burris HA 3rd. Department of Drug Development, The Sarah Cannon Cancer Center, Nashville, TN 37203, USA. Publication Types: Review Review, Tutorial PMID: 10810931 [PubMed - indexed for MEDLINE] 57: Gan To Kagaku Ryoho 2000 Mar;27(3):382-7 [New combination chemotherapy in urological cancers] [Article in Japanese] Hattori K, Akaza H. Department of Urology, University of Tsukuba, Tennodai, Japan. Although several effective therapeutic modalities are currently available for each urological cancer, there are still many patients for whom cure is not possible. Interleukin-2 (IL-2) and interferon-alpha (IFN-alpha) are both standard agents for patients with metastatic renal cell carcinoma (RCC). However, only up to 20% of patients can attain a complete response with these agents. It has been reported that for bladder transitional cell carcinoma (TCC), a cisplatin-based chemotherapy such as M-VAC chemotherapy can give patients a prognostic benefit in an adjuvant setting. There has been no therapy to improve upon M-VAC for more than a decade. In this review, several trials with new combination chemotherapies that were developed to overcome the limitations of the current therapy are discussed. These include the combination of IL-2, IFN-alpha and 5-fluorouracil for RCC, paclitaxel/gemcitabine and cisplatin/carboplatin for TCC, and paclitaxel/docetaxel and estramustine for hormone-refractory prostate cancer. The results of initial trials with these new combination therapies are promising. Large scale clinical trials, however, have yet to be done. Publication Types: Review Review, Tutorial PMID: 10740631 [PubMed - indexed for MEDLINE] 58: J Urol 2000 Mar;163(3):834-7 Dexamethasone does not significantly contribute to the response rate of docetaxel and estramustine in androgen independent prostate cancer. Weitzman AL, Shelton G, Zuech N, Owen CE, Judge T, Benson M, Sawczuk I, Katz A, Olsson CA, Bagiella E, Pfaff C, Newhouse JH, Petrylak DP. Department of Medicine, Columbia Presbyterian Medical Center, New York, New York 10032, USA. PURPOSE: We evaluated the independent response rate of dexamethasone before docetaxel and estramustine administration as measured by changes in serum prostate specific antigen (PSA) in patients with androgen independent prostate cancer. MATERIALS AND METHODS: A total of 12 patients received 20 mg. dexamethasone orally every 6 hours for 3 doses repeated every 3 weeks before starting cytotoxic therapy with estramustine and docetaxel. After progression on dexamethasone 280 mg. estramustine orally 3 times daily on days 1 to 5 and 70 mg./m.2 docetaxel intravenously for 1 hour on day 2 were given. RESULTS: None of the patients initially treated with dexamethasone monotherapy (median 1 cycle, range 1 to 5) had a PSA decline of 50% or greater. Median PSA increase on monotherapy was 47% (range 0% to 22%). On estramustine and docetaxel therapy PSA decreased 50% or greater in 11 patients (92%, 95% confidence intervals [CI] 60 to 99) and 80% or greater in 7 (58%, 95% CI 29 to 84), and normalized in 5 (42%, 95% CI 16 to 71), with a median duration of response of 153 (range 42 to 371), 132 (range 84 to 287) and 84 (range 21 to 174) days, respectively. Median times to reach 50% and 80% decreases in baseline PSA were 21 (range 21 to 209) and 63 (range 21 to 138) days, respectively. In 9 patients (75%, 95% CI 43 to 93) PSA decreased at least 50% by week 9. Of 4 patients with bidimensionally measurable disease 3 had a partial response. Median time to progression was 263 days (range 91 to 378). CONCLUSIONS: Administration of 20. mg. dexamethasone orally every 6 hours for 3 doses every 3 weeks does not significantly contribute to the PSA response rate of estramustine and docetaxel. Publication Types: Clinical Trial PMID: 10687988 [PubMed - indexed for MEDLINE] 59: Cancer Invest 2000;18(3):191-6 Reversion of primary hyperfibrinogenolysis in patients with hormone- refractory prostate cancer using docetaxel. Sallah S, Gagnon GA. Department of Medicine, University of Tennessee, Memphis, USA. Ssallah@utmem1.utmem.edu Tumor-associated proteases play a major role in determining the biologic behavior and aggressiveness of prostate cancer. Several authors have described the association between the increased levels of urokinase plasminogen activator in the plasma and in the malignant prostatic tissue with the metastatic potential of prostate cancer. However, the direct effect of this activity in producing fibronogenolysis in patients with prostate cancer has not been addressed. To evaluate the role of chemotherapy in reversing fibrinogenolysis in patients with prostate cancer, eight patients with hormone-refractory prostate cancer, bleeding, and laboratory evidence of primary hyperfibrinogenolysis were treated with docetaxel. The drug was given 48 hr after initiation of all supportive measures. Laboratory data, including plasminogen, alpha 2- antiplasmin, and fibrinogen, were recorded before and after treatment. Prostate-specific antigen (PSA) was measured at the time of referral and before subsequent cycles (3 weeks). Five patients had resolution of the fibrinolytic process after one cycle of treatment with docetaxel. This was demonstrated by improvement in both the laboratory parameters and the bleeding episodes. Further follow-up showed stabilization of the hematologic parameters and reduction in PSA values in these patients. Two patients died from uncontrolled bleeding despite all supportive measures. One patient did not demonstrate response to this treatment in terms of normalization of the fibrinolytic indicators or reduction in PSA. Primary fibrinogenolysis associated with metastatic prostate cancer is a serious complication. Docetaxel appears to be effective in reversing this process in some hormone-refractory patients. Although this response appears to be due to antitumor activity, a direct effect on the fibrinolytic pathway induced by the tumor cannot be excluded. Further work in this area is warranted. Publication Types: Clinical Trial PMID: 10754987 [PubMed - indexed for MEDLINE] 60: Urology 1999 Dec;54(6A Suppl):22-9 Taxanes: an overview of the pharmacokinetics and pharmacodynamics. Vaishampayan U, Parchment RE, Jasti BR, Hussain M. Department of Internal Medicine, Wayne State University, and Barbara Ann Karmanos Cancer Institute, Detroit, Michigan, USA. Paclitaxel and docetaxel have emerged in the last two decades as effective antitumor agents in a variety of malignancies. Paclitaxel is a semisynthetic taxane isolated from bark of the Pacific yew tree. Docetaxel is a semisynthetic taxane derived from the needles of the European yew (Taxus baccata). These compounds bind to tubulin, leading to microtubule stabilization, mitotic arrest and, subsequently, cell death. Plasma clearance of paclitaxel exhibits nonlinear kinetics, which results in a disproportionate change in plasma concentration and area under the curve (AUC) with dose alterations. In contrast, docetaxel has a linear disposition over the dose ranges used clinically, so its concentration changes linearly with changes in the dosage. Premedicating with corticosteroids and histamine H1 and H2 receptor antagonists is advocated prior to paclitaxel administration; prior to docetaxel administration, premedication with corticosteroids is suggested. The taxanes are metabolized in the liver by the cytochrome P-450 enzymes and are eliminated in the bile. The known metabolites are either inactive or less potent than the parent compounds. The toxic effects associated with paclitaxel therapy are mainly neutropenia, peripheral neuropathy, and, rarely, cardiotoxicity. Docetaxel toxicity produces mainly myelosuppression and a cumulative dose fluid retention syndrome. Paclitaxel demonstrates sequence-dependent interactions with cisplatin, cyclophosphamide, and doxorubicin. Docetaxel has shown increased myelosuppression with preceding ifosfamide in a preliminary study. The future holds increasing indications for taxanes in newer combination regimens; consideration of their pharmacologic characteristics is an important aspect of designing and applying new taxane-based treatment regimens. Publication Types: Review Review, Tutorial PMID: 10606281 [PubMed - indexed for MEDLINE] 61: Urology 1999 Dec;54(6A Suppl):36-46 Targeting bcl-2 gene to delay androgen-independent progression and enhance chemosensitivity in prostate cancer using antisense bcl-2 oligodeoxynucleotides. Gleave ME, Miayake H, Goldie J, Nelson C, Tolcher A. The Prostate Centre, Vancouver General Hospital, British Columbia, Canada. Bcl-2 expression is upregulated in prostate cancer cells after androgen withdrawal and is associated with the development of androgen independence and chemoresistance. Induction of apoptotic cell death after androgen ablation, or chemotherapy, may be enhanced through functional inhibition of bcl-2. In this report, we tested the effects of antisense bcl-2 oligodeoxynucleotides (ODN) with androgen ablation and taxane therapy on time to androgen-independent (Al) progression in the androgen-dependent Shionogi tumor model. Treatment of Shionogi tumor cells in vitro with 500 nmol/L antisense bcl-2 ODN decreased bcl-2 mRNA by 85%, compared with treatment with 500 nmol/L mismatch control ODN. Although bcl-2 expression levels in Shionogi cells were not changed by docetaxel treatment, docetaxel treatment induced bcl-2 phosphorylation. Consequently, the formation of bcl-2/Bax heterodimer formation was inhibited in a dose-dependent manner. Treatment of Shionogi tumors in vitro with either 500 nmol/L antisense bcl-2 ODN or 10 nmol/L docetaxel alone did not induce apoptosis or reduce growth rates. However, combined treatment reduced the concentration that reduces cell viability by 50% (IC50) of docetaxel from 100 nmol/L to 10 nmol/L and induced characteristic apoptotic DNA laddering and cleavage of the poly(ADP- ribose)polymerase (PARP) protein. Adjuvant in vivo administration of antisense bcl-2 ODN and polymeric micellar paclitaxel after castration resulted in a significant delay in time to Al recurrence when compared with administration of either agent alone. Furthermore, combined treatment of mice bearing Al recurrent Shionogi tumors with antisense bcl-2 ODN and micellar paclitaxel synergistically induced tumor regression and growth inhibition when compared with treatment with either agent alone. These findings suggest that down-regulation of bcl-2 by antisense ODN chemosensitizes Al Shionogi tumors to taxanes, over and above the effects of taxane-induced phosphorylation of bcl-2. Antisense bcl-2 ODN combined with taxanes may be a novel approach to the treatment of both established and emerging Al disease. PMID: 10606283 [PubMed - indexed for MEDLINE] 62: Semin Oncol 1999 Oct;26(5 Suppl 17):19-23 A phase II trial of docetaxel (Taxotere) in hormone-refractory prostate cancer: correlation of antitumor effect to phosphorylation of Bcl-2. Friedland D, Cohen J, Miller R Jr, Voloshin M, Gluckman R, Lembersky B, Zidar B, Keating M, Reilly N, Dimitt B. Oncology-Hematology Association, Allegheny Cancer Center, and the Triangle Urological Group, Pittsburgh, PA 15212, USA. Twenty-one patients with hormone refractory prostate cancer were enrolled to receive single-agent docetaxel (Taxotere; Rhone-Poulenc Rorer, Collegeville, PA) 75 mg/m2 intravenously every 21 days. Six patients consented to biopsies of the prostate tumor before and following the first cycle of chemotherapy and 11 patients underwent periodic blood collection for isolation of the mononuclear cell fraction. The toxicities of treatment were moderate but included eight episodes of grade III and two episodes of grade IV nonhematologic toxicity as well as seven episodes of grade III and 11 episodes of grade IV hematologic toxicity (primarily neutropenia, including four episodes of febrile neutropenia). An objective response of more than 50% reduction in prostate-specific antigen was observed in seven patients (38%) and more than half of the patients with symptomatic disease at the initiation of therapy had improvements on treatment. Radiographic or scintigraphic evidence of tumor regression was observed in six patients. Nine patients experienced a prolonged period of stable disease on treatment (median, six cycles). Tumor specimens are currently being analyzed for bcl-2 expression and phosphorylation. The current series confirms the substantial single-agent activity of docetaxel in hormone refractory prostate cancer and may help to further elucidate its mechanism of action at the molecular level. Publication Types: Clinical Trial Clinical Trial, Phase II PMID: 10604264 [PubMed - indexed for MEDLINE] 63: Semin Oncol 1999 Oct;26(5 Suppl 17):1-2 Docetaxel (Taxotere) in hormone-refractory prostate cancer: a new addition to the physicians' toolbag. Vogelzang NJ. Department of Medicine and Surgery, University of Chicago School of Medicine, IL, USA. PMID: 10604260 [PubMed - indexed for MEDLINE] 64: Semin Oncol 1999 Oct;26(5 Suppl 17):3-7 Mechanisms of action of taxanes in prostate cancer. Stein CA. Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA. Taxanes appear to have significant clinical activity in hormone- refractory prostate cancer and are entering increasing numbers of clinical trials. In general, they appear to initiate the apoptotic process by binding to beta-tubulin and promoting its polymerization. However, it is possible, at least in prosta