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Curing metastatic testicular cancer
Lawrence H. Einhorn*

Indiana University Medical Center, 535 Barnhill Drive, RT 473, Indianapolis, IN 46202-5289 Contributed by Lawrence H. Einhorn, February 5, 2002 This contribution is part of the special series of Inaugural Articles by members of the National Academy of Sciences elected on May 1, 2001.
Our initial studies with cisplatin ؉ vinblastine ؉ bleomycin began
and death after an initial clinical response. The strategies of 27 years ago in 1974, changing the cure rate for disseminated
combination chemotherapy, then and now, remain the same: disease from 5 to 60%. Subsequently, through random prospective
(i) use drugs with known single-agent activity; clinical trials, we have modified the treatment regimen to reduce
(ii) use drugs with nonoverlapping toxicity. Because the major both the duration and dosages of the chemotherapy drugs. Cis-
dose-limiting toxicity for most drugs is myelosuppression, non- platin ؉ etoposide was first used at Indiana University as salvage
myelosuppressive antineoplastic agents are of particular value; chemotherapy in 1978, representing the first time that a solid
(iii) the cytolytic agents should have unique and separate tumor had been cured with second-line chemotherapy. We next
did a clinical trial comparing bleomycin ؉ etoposide ؉ cisplatin
(iv) develop combinations demonstrating a synergistic rather (BEP) to cisplatin ؉ vinblastine ؉ bleomycin. The BEP regimen was
proven to have less toxicity and a higher cure rate and therefore,
Although there was some success with single antineoplastic since 1984, has been standard chemotherapy. More recent studies
agents such as cyclophosphamide for Burkitt’s lymphoma, or have evaluated the use of lesser chemotherapy to maintain the
methotrexate for gestational choriocarcinoma, the more dra- same cure rate for patients with good-prognosis disease. Standard
matic improvements in survival and cure were the result of therapy for these patients is either three courses of BEP or four
combination chemotherapy. Hematologic malignancies such as courses of EP, and over 90% of these patients will be cured of their
childhood acute lymphoblastic leukemia and Hodgkin’s and disease. Patients who are not cured with their initial BEP chemo-
non-Hodgkin’s lymphoma were the initial beneficiaries of this therapy are usually treated with salvage chemotherapy. Approx-
approach. At about the same time (30 years ago), clinical trials imately 50% of these testicular cancer patients will subsequently
became a powerful tool for hypothesis generation and proof of be cured with salvage chemotherapy with tandem transplant of
principle through random prospective phase III studies. This led high-dose chemotherapy with peripheral stem cell rescue. Testic-
to dramatic improvements in survival of pediatric cancers such ular cancer has become a model for a curable neoplasm. In the early
as rhabdomyosarcoma, Ewing’s sarcoma, osteosarcoma, etc.
1970s, metastatic testicular cancer was associated with only 5%
Early Chemotherapy Studies
survival. Today, with modern chemotherapy and surgery tech-
niques, 80% of patients will survive their disease.

Before the usage of cisplatin combination chemotherapy, stan- dard chemotherapy for disseminated testicular cancer consisted Germ cell tumors are relatively uncommon, accounting for ofdactinomycin,aloneorincombinationwithmethotrexateand
only 1% of male malignancies in the United States. The chlorambucil. Thirty years ago, M. C. Li and colleagues at highest worldwide incidence is in Scandinavian countries; by Memorial Sloan Kettering Hospital (New York) recognized that contrast, testicular cancer is rare in African Americans. The testis cancer was chemosensitive, with a 50% objective response primary age group is 15–35 for nonseminomatous tumors and a rate including 10–20% complete remission and a 5–10% cure rate (1). M. L. Samuels and colleagues at M. D. Anderson In 2001, there were Ϸ8,000 newly diagnosed cases in the Hospital (Houston) later evaluated vinblastine ϩ bleomycin, a United States, contrasting sharply with the 190,000 cases of synergistic regimen in preclinical studies, and achieved a 25% prostate cancer, the most common male malignancy.
long-term disease-free survival (2). This was a higher success Despite the paucity of cases, this tumor has become an rate than would have been predicted from the modest 5% cure extremely important oncological disease. First, it is the most rates of these drugs as single agents and appeared to validate the common carcinoma in young men ages 15–35 and thus has the preclinical studies of this synergistic two-drug regimen. How- potential to greatly shorten productive years of life. Second, ever, the drug that revolutionized the cure rate for patients with available serum markers (alphafetoprotein and human chorionic metastatic testicular cancer was cisplatin. Cisdiamminedichlo- gonadotropin) allow the clinician to make important and accu- roplatinum (cisplatin) was the first heavy metal to be evaluated rate treatment-related decisions. Third, testicular cancer has as an anticancer therapy and resulted from the serendipitous been a model for multidisciplinary care, as surgical resection of finding and subsequent intellectual acumen of Barnett Rosen- postchemotherapy radiographically persistent disease can im- berg in the Department of Biophysics at Michigan State Uni- versity (3). In 1973, cisplatin was first evaluated in early phase prove the cure rate. Fourth, germ cell tumors have become an I–II clinical trials. Included among the patients in these studies excellent testing ground for active experimental drugs (e.g., were men with testicular cancer who had failed prior chemo- cisplatin, etoposide, and ifosfamide, all of which were approved therapy (usually dactinomycin) (4). There is enthusiasm when by the Food and Drug Administration primarily on the basis of novel agents are capable of achieving a modest partial remission data in testicular cancer). The goal of chemotherapy in germ cell rate in refractory carcinomas. However, cisplatin attained not tumors is never merely palliation or prolongation of survival, only three partial but also three complete remissions in 11 patients with refractory testicular cancer (4). Furthermore, despite initial severe nausea, vomiting, and nephrotoxicity, this Combination Chemotherapy and Clinical Trials
Combination chemotherapy began to be used in patients with
malignant diseases 30 years ago. The principle was that malig- Abbreviations: PVB, cisplatin ϩ vinblastine ϩ bleomycin; BEP, etoposide ϩ bleomycin; NED, nant clones of cells would rapidly develop drug resistance to a single cytolytic agent, thereby permitting disease progression 4592– 4595 ͉ PNAS ͉ April 2, 2002 ͉ vol. 99 ͉ no. 7͞cgi͞doi͞10.1073͞pnas.072067999 drug was relatively nonmyelosuppressive, leading to inclusion as PVB Versus Cisplatin ؉ Etoposide ؉ Bleomycin (BEP)
a component of combination chemotherapy. Subsequent im- Etoposide (VP-16) is an epipodophyllotoxin derivative with provements in supportive care have greatly mitigated the neph- demonstrated single-agent activity in refractory testicular cancer rotoxicity and emesis. This remains a dramatic example of the (7). In 1978, we began our initial salvage chemotherapy studies value, for patients and scientists, of clinical trials with novel with cisplatin ϩ etoposide in patients who were not cured with PVB or similar induction therapy. Schabel et al. demonstrated With this background, in August 1974, we began our initial remarkable synergism with cisplatin ϩ etoposide in numerous cisplatin ϩ vinblastine ϩ bleomycin (PVB) study at Indiana preclinical models (8). We confirmed the remarkable synergism University, using the established two-drug synergistic regimen of of these two active agents, as we achieved a 25% cure rate in vinblastine ϩ bleomycin and simply adding the then experimen- patients who were not cured with their initial cisplatin combi- tal promising drug cisplatin (5). The PVB regimen fulfilled the nation chemotherapy (9). This represented the first time an adult requirements for a successful combination chemotherapy regi- solid tumor was cured with second-line chemotherapy.
men: single-agent activity for each component of the PVB From 1981 through 1984, the Southeastern Cancer Study regimen, different and unique mechanism of action for the three Group conducted a randomized prospective study comparing agents, separate and nonoverlapping toxicity, allowing admin- PVB and BEP as initial induction chemotherapy (10), based on istration of each drug in full dosage, and evidence of preclinical the promising results of cisplatin ϩ etoposide as second-line synergism (vinblastine ϩ bleomycin).
therapy and the expectation for reduced neuromuscular toxicity with etoposide compared with vinblastine. No maintenance PVB Studies
therapy was given in either arm. Postchemotherapy residual From 1974 to 1976, we initiated and completed our first PVB disease was resected if anatomically feasible. Two additional study (5).† As was traditional in the mid-1970s, induction therapy courses of the original induction regimen were given, deleting was followed by maintenance chemotherapy (vinblastine 0.3 bleomycin, if carcinoma was found in the resected specimen.
A total of 244 patients from 24 institutions entered this trial.
mg͞kg monthly for a total of 2 years of chemotherapy), in an Of 121 patients treated with PVB, 74 (61%) had a complete attempt to achieve total cell kill, as popularized with mainte- remission (CR), and another 15 (13%) became disease-free after nance chemotherapy in childhood acute lymphoblastic leukemia.
resection of teratoma (10 patients) or carcinoma (five patients).
Four courses of PVB induction chemotherapy were used. This Among the 123 patients given BEP, 74 (60%) had a CR, and 28 number was chosen because of concern (in 1974) of cumulative (23%) became free of disease after resection of teratoma (22 cisplatin-induced nephrotoxicity. We had a good early estimate patients) or carcinoma (6 patients). Thus, 74% became disease- of optimal duration of induction chemotherapy, as 25 years after free after treatment with PVB and 83% after BEP. In the completion of this original PVB trial, there is still no evidence subgroup of advanced disseminated disease, there was a survival to support the administration of more than four consecutive advantage for BEP (P ϭ 0.02).
course of cisplatin combination chemotherapy.
Granulocytopenic toxicity, including granulocytopenic fever, Thirty-three of 47 (70%) patients attained a complete remis- was similar in the two arms. There was a major reduction in sion, and an additional five patients (11%) were rendered neuromuscular toxicity, as manifested by paresthesia, abdominal disease-free by postPVB surgical resection of radiographically cramps, ileus, and myalgias, favoring the BEP arm. This was persistent disease. Fifty-three percent of patients were cured significant not only statistically, but also clinically. On the basis with PVB, representing a 1-logarithmic increase in the cure rate of this study, which demonstrated a reduction in morbidity and compared with contemporaneous dactinomycin chemotherapy.
superior survival, we have used BEP since 1984 as first-line We next designed a series of phase III trials to answer clinically therapy for disseminated testicular cancer and have abandoned relevant questions. The first study addressed whether we could reduce the significant neuromuscular and myelosuppressive toxicity of vinblastine by reducing the dosage from 0.4 to 0.3 Subsequent Studies with BEP
mg͞kg and still maintain therapeutic efficacy. As expected, the Good Risk (Minimal–Moderate Disease). Several groups have de-
lower dose of vinblastine was associated with a reduction in signed staging systems that attempt to discriminate good-risk toxicity, but the complete remission and cure rates were similar from poor-risk disease (11, 12). This would allow the study of less toxic regimens in good-risk disease and more aggressive therapy Our subsequent phase III PVB study challenged one of the in those validated to have poor-risk testicular cancer. We began basic tenets of oncology, the utilization of maintenance therapy a phase III study in 1984, completed in 1987, evaluating the to prevent relapse. Patients achieving a disease-free status with standard four courses of BEP versus three courses (9 weeks) of BEP in good-risk disease. One hundred eighty-four patients PVB in this trial were randomized to a standard arm of 21 entered this study, and 97% achieved a NED status confirming months of maintenance vinblastine (total of 2 years of chemo- the accuracy of this definition of ‘‘good risk.’’ An identical 92% therapy) versus an experimental arm of just 12 weeks of PVB of patients on each arm are continuously NED (13). We have with no further therapy. One hundred thirteen patients entered updated this study for the 118 patients entered at Indiana this study at Indiana University or participating institutions in University (median followup 9 years). There remain no differ- SCIENCES
the Southeastern Cancer Study Group. The relapse rate was only ences between the two arms, with only four deaths in each arm.
5%, with or without maintenance vinblastine (6). This random- Furthermore, for patients with serum human chorionic gonad- ized clinical trial benefited patients by reducing duration of otropin less than 1,000 milliunits͞ml, there were only two deaths therapy and toxicity as well as lessening the financial expenditure out of 104 patients (14). Patients with good-risk metastatic disease (e.g., small pulmonary metastases) have a 98% cure rate with 9 weeks of chemotherapy, superior to surgical cure rates for most clinically localized cancers. Therefore, we have greatly ameliorated the toxicity and reduced the duration of therapy †PVB: cisplatin, 20 mg͞m2 days 1 to 5; vinblastine, 0.2 mg͞kg, days 1–2; bleomycin, 30 units, from the original PVB study in 1974 to the completion of this days 2, 9, and 16. (i) Courses were repeated every 3 weeks for four courses; (ii) after PVBinduction, single-agent maintenance vinblastine (0.3 mg͞kg) every 4 weeks was utilized clinical trial in 1987. We have demonstrated that we could reduce for a total of 24 mo of chemotherapy.
vinblastine dosage, eliminate 20 months of maintenance vinblas- PNAS ͉ April 2, 2002 ͉ vol. 99 ͉ no. 7 ͉ 4593
Table 1. Poor–risk disease (all nonseminomatous patients)
variable was the cisplatin dosage (20 mg͞m2 ϫ 5 versus 40 mg͞m2 ϫ 5) with BEP in both arms. One hundred fifty-three patients Lactic dehydrogenase Ͼ 10 times upper limit of normal; human were evaluable. As expected, patients receiving double-dose chorionic gonadotropin Ͼ 50,000 units͞ml, or cisplatin experienced considerably more toxicity than standard BEP. Unfortunately, there was no evidence of therapeutic Any primary mediastinal nonseminomatous germ cell tumor superiority for the high-dose cisplatin arm, with 62.2% contin- Nonpulmonary visceral metastases (bone, liver, brain, etc.) uously NED with high-dose and 63.6% with standard BEP (18).
tine, substitute etoposide for vinblastine with improved efficacy Salvage Therapy. Our concept for salvage therapy has always been
to use cisplatin plus other active agents not previously used, as and decreased toxicity, and finally, delete the fourth and final long as there was no progression during cisplatin combination course of BEP in good-risk patients. This resulted in the elimination of the most toxic of the four courses because of potential for cumulative toxicities (bleomycin pulmonary fibro- salvage therapy after PVB (9). Our initial salvage therapy after sis, cisplatin neurotoxicity, and ototoxicity). Also, during the BEP had been vinblastine 0.11 mg͞kg day 1 and 2 ϩ ifosfamide years of this phase III study (1984–1987), we did not have 1.2 grams͞m2 ϫ 5 ϩ cisplatin 20 mg͞m2 ϫ 5 every 3 weeks for availability of effective antiemetics, and the cumulative toxicities four courses. Between 1984 and 1989, 135 patients received this of anorexia, nausea, and vomiting were also a formidable regimen as second-line therapy. Sixty-seven patients (49.6%) challenge for patients with their fourth courses of BEP.
achieved NED status, including 15 (11%) who were NED after A larger European Organization for Research and Treatment postchemotherapy resection of teratoma and 10 (7.4%) NED of Cancer phase III study randomized 812 good-risk patients to after postchemotherapy resection of carcinoma. Thirty- BEP ϫ 3 versus BEP ϫ 3 with a fourth course of EP. This study two (23.7%) are continuously NED with minimal followup of 5 was performed to attempt to detect a 5% difference favoring four courses. The results were again identical, with 90.4% (three High-dose therapy, with carboplatin and etoposide and au- courses) versus 89.4% progression-free survival (15).
tologous bone marrow transplant, was first started at Indiana University in 1986. Initially, this was used as a last attempt at curative therapy (third-line or later or after progression during Definition of Poor-Risk (Advanced) Disease. Poor-risk disease con-
sists of a more heterogeneous patient population and has been cisplatin therapy). Six of these first 40 patients are 5ϩ years defined based on tumor markers, volume of metastatic disease, continuously NED (20). We now use peripheral stem cells and and multiplicity of anatomic sites (11, 12). These patients will granulocyte colony-stimulating factor, and we are able to safely have a 40–60% cure rate with standard therapy. In this group, administer carboplatin 700 mg͞m2 ϫ 3 ϩ etoposide 750 mg͞m2 the impetus has been to evaluate more aggressive chemotherapy ϫ 3. We currently use this therapy as initial salvage chemother- in phase II and III studies to try to improve the therapeutic apy. Thirty-five of 65 (54%) are continuously disease-free for a minimum of 2 years with this approach (21), demonstrating the An international group was convened to develop a consensus remarkable chemosensitivity and curability of testicular cancer.
classification for poor-risk (and good-risk) germ cell tumors.
Over 70% of patients with metastatic testicular cancer will be Data were available on 5,862 patients, with a median followup cured with BEP. Approximately half of patients who are not time of 5 years. Only 14% of these patients comprised the cured with their initial chemotherapy will still be cured with poor-risk category, with a 41% 5-year disease-free survival and overall 48% 5-year survival (16). The cure rate with standard BEP is probably 10% higher, because the intergroup consensus Future Studies. Testicular cancer has been a model for a curable
included older regimens that did not include etoposide. This new neoplasm. We are currently exploring whether there are molec- definition (Table 1) is now incorporated in the current American ular as well as clinical differences that separate curable from intergroup trial for poor-risk disease.
incurable disease. We will evaluate specific poor-risk subsets, including salvage chemotherapy patients, primary mediastinal Advanced Disease. The National Cancer Institute in the United
nonesminomatous germ cell tumors (22), transformation of States randomized poor-risk patients to PVB versus an experi- teratoma to primitive neuroectodermal tumors (23), and late- mental regimen that used double-dose (40 mg͞m2 ϫ 5) cisplatin.
relapse patients (24). This latter group is particularly intriguing.
This phase III study revealed a statistically significant disease- Metastatic testicular cancer grows very rapidly and is uniquely free and overall survival favoring the double-dose cisplatin arm curable with cisplatin combination chemotherapy. However, (17). This study seemed to validate the concept of dose intensity.
2–3% of patients initially diagnosed with testicular cancer will However, there were several flaws in the study methodology.
experience a late relapse beyond 2 years of last therapy. Most late First, there was a very small sample size (n ϭ 57 with a 2:1 relapses occur beyond 5 years, with our latest relapse 32 years randomization). Second, and most important, the experimental after chemotherapy. Patients with late relapse may respond to arm also included a fourth drug, etoposide, with PVB. BEP had cisplatin combination chemotherapy but are rarely curable with superior survival compared with PVB in advanced poor-risk chemotherapy alone. We hope to identify an important molec- disease, with standard-dose cisplatin on both arms (10). There- ular mechanism and then be able to exploit it as a therapeutic fore, we designed a study in advanced disease in which the only 1. Li, M. C., Whitmore, W. F., Golbey, R. & Grabstald, H. (1960) J. Am. Med. 7. Fitzharris, B. M., Kaye, S. B., Saverymuttu, S., Newlands, E. S., Barrett, A., Assoc. 174, 145–153.
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D. P., Jr. (1979) Cancer Treat. Rep. 63, 1459–1473.
3. Rosenberg, B., VanCamp, L. & Krigas, T. (1965) Nature (London) 205, 678–699.
9. Williams, S. D., Einhorn, L. H., Greco, F. A., Oldham, R. & Fletcher, R. (1980) 4. Higby, D. J., Wallace, H. J., Albert, D. J. & Holland, J. F. (1974) Cancer 33,
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10. Williams, S. D., Birch, R., Irwin, L., Greco, A., Loehrer, P. J. & Einhorn, L. H.
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PNAS ͉ April 2, 2002 ͉ vol. 99 ͉ no. 7 ͉ 4595



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